Review pubs.acs.org/CR

Chromogenic/Fluorogenic Ensemble Chemosensing Systems Jiasheng Wu,† Bomi Kwon,‡ Weimin Liu,† Eric V. Anslyn,§ Pengfei Wang,*,† and Jong Seung Kim*,‡ †

Key Laboratory of Photochemical Conversion and Optoelectronic Materials and CityU-CAS Joint Laboratory of Functional Materials and Devices, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China ‡ Department of Chemistry, Korea University, Seoul 136-701, Korea § Department of Chemistry, The University of Texas at Austin, 105 E. 24th, Street-Stop A5300, Austin, Texas 78712-1224, United States 4.2. Multiple-Analyte Sensing for Complex Samples 4.3. Biological Screening 5. Concluding Remarks Author Information Corresponding Authors Notes Biographies Acknowledgments Abbrevations References

CONTENTS 1. Introduction 2. Background, Design Principles, Advantages, and Classification of Ensembles 2.1. Background 2.2. Ensemble Design Principles 2.2.1. Thermodynamic Equilibrium 2.2.2. Molecular Design and Environmental Factor 2.2.3. Signal Transduction Mechanism 2.3. Advantages of Ensembles 2.4. Ensemble Classification 2.4.1. Two-Component Ensembles 2.4.2. Three-Component Ensembles 2.4.3. Multicomponent Ensembles 2.4.4. Inorganic−Organic Hybrid Ensembles 3. Various Ensemble Systems 3.1. Two-Component Ensembles 3.1.1. Anion Sensing 3.1.2. Biomolecular Sensing 3.2. Three-Component Ensembles 3.2.1. Anion Sensing 3.2.2. Sensing of Neutral Molecules 3.2.3. Biomolecule Sensing 3.3. Multicomponent Ensembles 3.3.1. Cation Sensing 3.3.2. Anion Sensing 3.3.3. Sensing of Neutral Molecules 3.3.4. Biomolecule Sensing 3.4. Organic−Inorganic Hybrid Ensembles 3.4.1. Au, Ag, and Si NP-Based Ensembles 3.4.2. Carbon Dot (CD)-Based Ensembles 3.4.3. Other Hybrid Ensembles 4. Applications 4.1. Single-Analyte Sensing

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1. INTRODUCTION Nature has endowed human beings with many useful functions, by virtue of supramolecular chemistry. As is well-known, nature can self-assemble relatively small molecular precursors into very complicated biomolecules. These supramolecular ensembles are very important for various biological processes and entities such as protein folding, phospholipid membranes, nucleic acid assembly and tertiary structures, ribosomes, and microtubules.1 Supramolecular chemistry has been growing as a research area in recent decades since the discovery of crown ethers, cryptands, and spherands by three outstanding scientists, namely Pedersen,2 Lehn,3 and Cram,4 in the early 1960s; these achievements were subsequently recognized by the awarding of the Nobel prize in 1987. Host−guest interactions, in which two or more complementary molecules are able to recognize each other to form a “programmed” supramolecular ensemble via natural noncovalent interactions are known. Compared with the precursor molecules, such preorganized supramolecular ensembles have unusual optical, magnetic, sensing, and catalytic and biological properties.5 Supramolecular chemistry has been developed as a mature research field in modern science, and it has interfaces with many other disciplines, including chemistry, physics, materials, catalysis, and biology. It is a highly interdisciplinary field that exceeds the conventional boundaries of natural science. Supramolecular chemistry provides a good opportunity for scientists to design new molecular materials with various unusual structures and functions. A particularly attractive development in the last two decades is the use of supramolecular ensembles as sensors; these rely on the usage of a dye bound to a receptor via noncovalent interactions

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Special Issue: 2015 Supramolecular Chemistry Received: September 29, 2014 Published: May 12, 2015 7893

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Figure 1. Chemosensing ensemble for citrate detection.

such as hydrogen bonding, electrostatic, donor−acceptor, π−π stacking, van der Waals force, and hydrophilic and hydrophobic interactions. Chemosensing ensembles, which were proposed by Anslyn and co-workers in 1998 and then used for the determination of a variety of substrates, by the same authors and other groups, are based on a competitive assay, in which the indicator and guest species are used to compete for the receptor.6,7 These ensembled chemosensors are based on the combination of an indicator, a receptor, and a substrate in which the receptor is able to bind both the dye and substrate, but with different affinity; they have been named as “chemosensing ensembles”.8 In the classical approach, the binding site and signal unit are covalently bonded in which the interaction between a foreign species and the binding site produces color or emission changes. However, for the ensemble approach, the binding site and signal subunit are not covalently linked but form a supramolecular ensemble. As such, the interaction between the receptor and foreign species causes replacement of the receptor, which gives major variations in the optical features. Furthermore, construction of the supramolecular ensemble is kinetically reversible and represents the thermodynamic minimum of the system by means of different association and dissociation processes. By controlling different conditions, the reaction equilibrium could be moved to the desired target. Supramolecular ensembles therefore have obvious advantages over conventional, stepwise, and synthetic procedures when using large molecules to obtain specific properties and functions.1 The chemosensing ensemble strategy has been developed since the early examples reported by Inouye9 and Shinkai10 and their co-workers in 1994 and 1996. In earlier exploration of this field, Anslyn and co-workers took inspiration from antibodybased biosensors in immunoassays and, in 1998, introduced a displacement approach for the design of new chemosensors to detect citrate in aqueous media.11,12 In their ensemble approach, a three-guanylation-appended receptor and a fluorescein indicator form a supramolecular ensemble by multiple electrostatic and intermolecular hydrogen bonding interactions (Figure 1). The fluorescein is displaced from the host cavity by citrate species and released into the solution, which results in recovery of fluorescence. However, only a few examples were reported before 2000.11−13 This area has continuously evolved during the past decade, and many new ensemble systems have emerged. Anslyn and other research groups used this approach and have reported the formation of chemosensing ensembles for the determination of a number of guest species such as gallic acid, tartrate, heparin, carbonate, phosphate, amino acid, and short peptide. The design of ensemble systems has continuously evolved during the past ten years, and the concept of an ensemble is no

longer limited to displacement assays. An ensemble chemosensing system can be broadly defined as the formation by two or more precursor molecules of a supramolecular ensemble [even the participation of inorganic materials, i.e., quantum dots and nanoparticles (NPs)] by means of noncovalent interactions, which interacts with foreign species, causing significant changes in optical signals, depending on whether or not the indicator is released from the ensemble. Depending on the formation process, various supramolecular ensembles have been well summarized in this review, following a systematic classification of two-component, three-component, multicomponent, and organic−inorganic hybrid ensembles. This review will focus on the development of supramolecular chromogenic/fluorogenic ensembles over the past decade. We first begin with the design principles and a systematic classification of supramolecular ensembles. The subsequent sections contain detailed discussions of the design strategies for various colorimetric/fluorometric chemosensing ensembles and their potential applications.

2. BACKGROUND, DESIGN PRINCIPLES, ADVANTAGES, AND CLASSIFICATION OF ENSEMBLES 2.1. Background

Supramolecular ensembles have been widely used in sensing, imaging, catalysis, medicine, and biology, because of their unusual properties. Chemical sensing is one of the main achievements in advances in supramolecular ensembles. This has been especially true during the past 20 years, and there have been a number of reviews describing recent advances in chromogenic/fluorogenic chemosensors based on different design strategies or guest species.14 Chromogenic/fluorogenic chemosensors are molecular devices that transform chemical information into optical signals to indicate the presence of matter or energy.15,16 Optical chemosensors are widely used in food safety, process control, medical diagnosis, environmental detection, molecular catalysis, and fluorescence imaging, because fluorescence signals offer high selectivity, sensitivity, real-time detection, nondestructive determination, and low-cost instrumentation.14h Because of the merits of spatial and temporal resolutions, fluorescence signals has been conveniently utilized as analytical tools to monitor many biological related processes in vitro and in vivo to understand their functions.17,18 Moreover, the molecular dimensions along with the available techniques such as confocal imaging, provide high temporal and spatial resolutions in the determination of analytes, that enables intracellular monitoring for chemical and biological research available.19 Fluorescent chemosensors focus on weak supramolecular interactions; therefore, they are especially suitable for 7894

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sandwich-like 2:2 complex first proposed by Anderson,23 cyclic systems,24 and the cooperative aggregate of monomers into oligomers.25 (ii) The Gibbs free energy changes (ΔG). In addition to binding constants, the ΔG is also used to predict and design ensemble-based displacement assays, according to following equations:21

the study of biological processes, signal transduction, and complicated environmental systems. A chromogenic/fluorogenic chemosensor is a molecular device that induces the changes of photophysical properties upon binding with a guest species to give a detectable signal. The classical design approach for fluorescent chemosensors involves the covalent connection of a fluorophore and a receptor to produce a fluorophore−spacer−receptor framework. Upon interaction with a receptor, a photophysical characteristic (i.e., emission intensity, wavelength, and lifetime) will change based on different mechanisms (electron transfer, proton transfer, and energy transfer), and such a change provides a variation in absorbance and fluorescence, which indicates guest binding. A number of chromogenic/fluorogenic chemosensors have been synthesized based on this well-established strategy. Alternatively, in the ensemble approach, noncovalent bonding interactions, instead of covalent linking, form a supramolecular ensemble between the receptor and indicator subunit. In this case, a competitive substrate is added to the ensemble system, resulting in replacement of the indicator on the receptor, which tunes changes in the optical signals. The chemosensing ensemble strategy uses a supramolecular assembly with a competitive assay, in which it works in the same way as that of antibody-based immunoassay. Similarly, the supramolecular ensemble in such assays uses a receptor, designed for competitive complexation with a guest species, together with an indicator to sense presence of the analyte.20

ΔG = RT ln K a

(1)

ΔG = ΔH − T ΔS

(2)

This method relies on measurement of the enthalpy increase (ΔH) when the guest is added to the host, in a specially designed apparatus (usually an isothermal calorimeter) for measuring the heat (Q) formed or absorbed. Calorimetric titrations yield not only the free energy changes (ΔG) from the association constant (eq 1) but can also be used to calculate the enthalpy change, and thus the entropy change (ΔS), from eq 2. It should be noted that isothermal titration calorimetry (ITC) is also a powerful tool to determine the binding constant and stoichiometery. 2.2.2. Molecular Design and Environmental Factor. For designing a displacement assay, the indicator and receptor should be carefully designed and selected, based on the target species and the following criteria: (i) appropriate and compatible binding affinity with the targets, (ii) appropriate absorption and emission wavelengths to eliminate interference, (iii) required determination concentration and limit of detection, (iv) water solubility, and (v) an optimized screening strategy to save time, etc. In addition, different experimental conditions (i.e., solvents, concentration, polarity, viscosity, pH, and temperature) enable tuning to obtain the desired Ka values for the indicator and analyte with the receptor. 2.2.3. Signal Transduction Mechanism. The interactions of supramolecular ensembles are mainly noncovalent interactions such as hydrogen bonding, electrostatic, π−π stacking, donor−acceptor, van der Waals, and hydrophilic and hydrophobic interactions. These interactions depend on the geometry, charge, and hydrophobicity of the guest and the solvent system used. Environmental changes (such as changes in local ionic strength, pH, polarity, and viscosity) usually result in distinct changes in the spectral responses.25,26 A number of photophysical signaling mechanisms in ensemble systems for signal modulation have been developed, e.g., photoinduced electron transfer (PET),14j,k,m,24,22,27 intramolecular charge transfer (ICT),14j,k,m,24,27b,28 fluorescence resonance energy transfer (FRET),29−31 electron energy transfer (EET),14j,k metal−ligand charge transfer,14n,32 excited-state intramolecular proton transfer (ESIPT),14d and excimer/exciplex formation.14j,k,p,m In recent years, conformational changes such as CN isomerization,14d aggregation-induced enhancement fluorescence (AIE),33,34 and twisted internal charge transfer (TICT)14j have also been used for the signal transduction in the ensemble systems. In addition, the combined use of more than one sensing mechanism has also been reported; for example, both PET and ICT were used in one system to give a pronounced signal;35 ESIPT and PET were also used in one sensing molecule for efficient determination of thiols.36 Readers should refer to the relevant references to gain an understanding of sensing mechanisms, which have been well documented.

2.2. Ensemble Design Principles

For the design of efficient ensemble systems, the design principles can be considered mainly based on the criteria including the thermodynamic equilibrium (known as binding constant and Gibbs free energy change), molecular design, environmental factor, signal transduction mechanism, etc. 2.2.1. Thermodynamic Equilibrium. (i) Binding constant (Ka). In the design of an efficient ensemble system, the optical properties of the coordinated indicator unit should be significantly different from those in its noncoordinated state. Ensemble sensing is based on a competitive binding process between the guest species and indicator toward the receptor; therefore, the major requirement for an ensemble system is that the affinity (the binding constant) between the indicator and the receptor is higher than that between the analyte and the receptor. When an ensemble-based displacement assay is designed, one of the fundamental issues is quantitative analysis of the intermolecular interactions to predict the possibility of replacement. Without precise quantitative analysis, the use of cooperative interactions in supramolecular ensembles becomes an empirical rather than a predictable science. The binding constant (Ka) between the indicator (or the guest) and receptor can be determined using methods such as supramolecular titration, based on changes in absorption or fluorescence, or NMR signals. The stoichiometry should be determined prior to calculation of the binding constant, based on the method of a continuous variation (Job’s plot), various mass analyses, consistency with host−guest complex structure, and specific experimental clue such as the isosbestic and isoemissive points.21 The simplest 1:1 host−guest equilibrium and related binding constant calculation have been widely studied.22 Complicated complexes, i.e., 1:2 or 2:1 host−guest equilibrium, can be regarded as two consecutive 1:1 equilibria for data analyses. Detailed data analysis methods have been discussed in various textbooks and reviews.21 More complicated structures include a

2.3. Advantages of Ensembles

The ensemble approach has a number of advantages over conventional sensing methods.8 (i) The ensemble system does not require the covalent connection between the indicator 7895

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receptor, which decreases the difficulty of organic synthesis. (ii) For practical requirements, different detection wavelengths can be used by selecting an appropriate indicator. (iii) The resulting ensemble can be obtained in situ and used in aqueous solutions, which is the basic requirement for biologically important substrates. (iv) Since no covalent connections are used between the receptor and indicator, a couple of different indicators with one receptor can be utilized as a sensing array for efficient analysis in practical application. (v) The ensemble assay is easily applied with different receptors and indicators for real-time analysis of complicated samples.

Figure 3. Schematic diagram of three-component ensemble.

case, the supramolecular interaction between the receptor moiety and guest species change the molecular conformation and charge density, and this significantly changes the optical features of the indicator, not only the absorption/emission intensity, but also the wavelength shifts. This provides a simple method for understanding two-component or three-component ensembles. Such ensemble systems can be used in ratiometric methods. The use of such an ensemble system is valuable, because in many cases it produces a ratiometric fluorescence signal that can avoid most ambiguities via self-calibration of two fluorescent bands. This enables a ratiometric measurement to be made that is independent of the probe concentration.14d 2.4.3. Multicomponent Ensembles. The self-organization of organic fluorescent or potentially fluorescent molecules to form an organized assembly can provide an efficient strategy for producing and optimizing fluorescent chemosensors.8 Some molecules aggregate via supramolecular self-assembly under appropriate conditions to form a multicomponent ensemble system. In the first case, multiple fluorescent or potentially fluorescent molecules can form an aggregate induced by the guest molecule, in which the optical properties will change significantly via aggregate-induced fluorescence enhancement, as shown in Figure 4. In the second case, multiple fluorescent or

2.4. Ensemble Classification

With the speedy development of supramolecular community, a large number of ensemble-based sensors have emerged in recent years. However, there is no systematic classification for ensemble-related sensors. Herein, ensemble systems can be systematically classified, based on their components, into categories such as two-component, three-component, multicomponent, and organic−inorganic hybrid ensembles. 2.4.1. Two-Component Ensembles. A two-component ensemble means a displacement assay. As shown in Figure 2, the

Figure 2. Schematic diagram of two-component ensemble (indicator displacement assay).

indicator (A) and the receptor (B) can form a two-component ensemble (A−B) via various weak, noncovalent (supramolecular) interactions such as hydrogen bonding, electrostatic, metal− ligand, π−π stacking, van der Waals forces, and hydrophilic− hydrophobic interactions. The guest molecule or substrate (C) interacts with the ensemble to undergo a competitive displacement assay, with the formation of B−C. The indicator (A) is displaced from the host cavity and released into the solution, which results in significant recovery of absorption/emission, but in most cases no obvious shifts in the absorption/emission wavelength. There are two main basic requirements for the design of displacement-based ensembles: the interaction between the receptor and indicator must not be too strong or too weak and the indicator must show significantly different optical properties with and without the receptor and when dispersed from the ensemble into solution. The indicator can be selected based on the following considerations: (i) a suitable binding capability with the receptor; (ii) good solubility in aqueous solutions; and (iii) longer absorption and/or emission wavelength and suitable fluorescence quantum yield. 2.4.2. Three-Component Ensembles. In the first step, the indicator and the receptor form a two-component ensemble (A− B) via various weak, noncovalent interactions. The guest molecule or substrate then interacts with the two-component ensemble to form a three-component ensemble (A−B−C), in which the indicator is not released from the ensemble system, as shown in Figure 3. In this process, the indicator is bound both to the receptor and to the guest species. This is clearly different from the competitive displacement assay described above. In this

Figure 4. Schematic diagram of multicomponent ensemble.

potentially fluorescent molecules can form an aggregate by supramolecular self-assembly. The interaction between the aggregate and the guest species will deaggregate the sensing system, and the aggregate-induced fluorescence decreases accordingly. The aggregates involved in this system induce variations in the absorption and/or emission spectra by interaction with the guest species. Because of the remarkable conformational changes between the single molecule and aggregates, their absorption/emission spectra generally give rise to enormous changes. As a result, fluorescent sensors based on the design of multicomponent ensemble are very suitable for the supersensitive detection of the guest species. 7896

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2.4.4. Inorganic−Organic Hybrid Ensembles. Functionalized preorganized nanomaterials have been widely used in chemosensing strategies. In most cases, the combinational use of such nanomaterials with a supramolecular idea produces new sensing strategies which are very difficult to realize by simple organic-molecule-based systems. Organic−inorganic hybrid materials have been widely used in the design of fluorescent chemosensors, because they combine the advantages of nanomaterials and organic ensembles. Surface-modified inorganic materials (such as quantum dots and nanoparticles) can interact with receptors via supramolecular interactions to form inorganic−organic hybrid ensembles (Figure 5). The

The indicator should be screened, so that it does not bind too strongly or too weakly with the receptor. The indicator is generally charged or contains a hydrogen donor/acceptor to facilitate its supramolecular interactions with the receptor. The indicator can be colorimetric and/or fluorometric. As shown in Figure 6, common indicators used in this method include fluorescein (Fl), pyrocatechol violet (PV), boron-dipyrromethene (BODIPY), alizarin (ARS), pyronine Y (PYY), coumarin, methylene blue (MB), acridine orange (AO), Evans blue (EB), thionine (TH), oxonine (OX), proflavine (PF), eosine (EY), and methylcalcein blue (MCB). A number of research groups have used the two-component ensemble (indicator−displacement assay) design strategy to develop various chemosensing ensembles to check a variety of organic or inorganic anions (i.e., F−, I−, AcO−, CN−, HS−, S2−, ClO−, SCN−, citrate, oxalate, H2PO4−, pyrophosphate (PPi), and phosphonoformate anions) and biomolecules [e.g., adenosine monophosphate (AMP), adenosine triphosphate (ATP), adenosine diphosphate (ADP), guanosine monophosphate (GMP), cysteine (Cys), homocysteine (Hcy), glutathione (GSH), folate, amino acid, and short peptide]. 3.1.1. Anion Sensing. 3.1.1.1. F−. Biologically important fluoride anions play a pivotal role in human physiology, such as prevention of dental caries and treatment of osteoporosis.37,38 Excess fluoride anions can result in dental or skeletal fluorosis39 and are related to nephrolithiasis, kidney failure, and nephrolithiasis as well.40 Fluoride anions can interact with groups such as hydroxyl, amino, amide, urea, and guanidinium via hydrogen-bonding interactions, because of its high electronegativity and small volume.41 Many fluoride-selective sensors based on hydrogen bonding have been reported, but most of these examples are restricted to organic solvents because of strong solvation interactions.42,43 The chemical ensemble strategy provides multiple supramolecular interactions not only via hydrogen bonding but also via electrostatic, metal−ligand, π−π stacking, and hydrophobic interactions, enabling the design of sensors in both organic solvents and aqueous media. Here, several ensemble-based examples for fluoride analysis are described. Calix[4]pyrrole (1) and coumarin derivative 2 form a 1:1 ensemble adduct by means of multiple intermolecular hydrogenbonding interactions (Figure 7).44 Receptor 2 has an intense fluorescence band peaked at 500 nm in CH3CN, and the introduction of 1 leads to gradual fluorescence quenching by PET from 1 to the bonded 2. The formed ensemble complex 1− 2 was used for the selective fluorescence detection of F− anions. Once F− was added to the ensemble 1−2, a remarkable fluorescence increase at 500 nm was observed because of a preferential interaction of F− with 1 and subsequent release of indicator 2 from the ensemble adduct. This ensemble system shows a high selectivity to F−, with a limit of detection down to 2.3 ppb, whereas other anions (i.e., Cl−, Br−, I−, HSO4−, PF6−, H2PO4−, HP2O73−, AcO−, BzO−, SCN−, CN−, and NO3−) did not produce distinctly spectral changes, indicating its selective recognition of F−. High selectivity of the present system for fluoride relies on the preferential coordination of calix[4]pyrrole scaffold for F−. In addition, the ensemble adduct between 1 and F− is interfered upon addition of Li+, allowing regeneration of the sensing ensemble that can be repeatedly used in another sensing cycle. Organoboron derivatives generally showed a good affinity to F− because of their inherent fluorophilicity.45 In this case, the BODIPY 3 reacted with dimethylaminopyridine (DMAP) in the

Figure 5. Schematic diagram of inorganic−organic hybrid ensemble.

addition of the guest species to a solution of the hybrid ensemble results in aggregation, which clearly changes the optical features. New sensing properties and functions result from molecular organization or assembly into a supramolecular ensemble and lead to potential important applications.

3. VARIOUS ENSEMBLE SYSTEMS 3.1. Two-Component Ensembles

Two-component ensembles are mainly used in indicator displacement assays, which are very popular strategies combining many target-selective receptors with suitable indicators to give effective optical sensing. In this strategy, the indicator binds with the receptor via various noncovalent interactions, producing significant spectral changes. When the substrate replaces the indicator, the emission intensity of the solution recovers. However, in this case, no obvious wavelength shift takes place. The basis of the displacement assay is the different affinity between the indicator−receptor and substrate−receptor affinities. In this section, a number of indicator displacement assays are reviewed, along with their chemical and biological sensing of various anions and biomolecules, based on colorimetric and/or fluorescence analyses. It should be noted that in the case of some metal complex-based sensors a pendant indicator is not required since these metal complexes act both as receptor and fluorophore. In the presence of species, it also undergoes a replacement of metal ion with the release of the ligand, but not indicator, as a result of occurrence of a displacement assay. Accordingly, these metal complexes for sensing of analytes were also included in this section. Because of the general applicability of this method for a diverse range of analytes, it will clearly be an important method to design synthetic receptors. 7897

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Figure 6. Various colorimetric and/or fluorogenic indicators used for ensemble systems.

presence of I− to form a cationic ensemble [3−DMAP]+ (Figure 8).46 Only weak fluorescence at 525 nm was observed probably

arisen from an external heavy atom effect which was enhanced via the formation of [3−DMAP]+/I− pairs. The formed ensemble 37898

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Figure 7. Molecular structures of receptor 1 and indicator 2.

Figure 8. BOFIPY-based ensemble complex 3−DMAP for F− sensing.

DMAP interacted with 1 equiv of F− to give rise to the corresponding neutral fluoroborate species, BODIPY 3, with a 5fold increase in the fluorescence intensity at 525 nm. Obviously, this fluorescence enhancement is related to formation of a neutral species 3, which is not quenched from the external spin orbit coupling effect by I−. Meanwhile, a much weaker fluorescence enhancement was found with the addition of Cl− (0.48 fold) or Br− (0.06 fold), indicating its selective sensing of F−. The present ensemble system provides a possibility for the development of a quantitative and fast fluoride assay. The ensemble complex 4−Fe3+ was designed for fluoride sensing, because Fe3+ can coordinate with the carboxylic group in 4 and quench the solution fluorescence (Figure 9).47 The affinity

Figure 10. Molecular structures of 3-hydroxyflavone derivatives (6 and 7) and their ensemble systems with Zr-EDTA for selective detection of F−.

emission spectrum produces a red shift from 554 to 567 nm, because of the formation of the ensemble complex Zr−EDTA− 6. Subsequent introduction of F− to Zr−EDTA−6 results in fluorescence recovery at 554 nm, because of the preferential coordination of F− anions with Zr−EDTA and the release of 6 from the ensemble. Competitive anions (i.e., AcO−, Cl−, Br−, I−, HSO4−, NO3−, and H2PO4−) were used to evaluate its selectivity, and negligible interferences with F− sensing were found because other anions cannot show the specific affinity ability to Zr− EDTA as F− does. The same group used a similar design strategy to develop a 3-hydroxyflavone derivative 7 with a longer emission wavelength, i.e., 570 nm.49 The addition of Zr−EDTA caused an emission red shift from 570 to 610 nm, along with a new emission band at 470 nm. The ensemble system Zr−EDTA−7 can be used for the selective test for F− in 99% aqueous solution. The two ensembles above provide good cases for the selective sensing of fluoride anions in almost pure aqueous solution. A commercially available receptor 8 bearing tetracarboxylic groups was found to show a specific affinity to Ca2+ (Figure 11).50 Complexation with Ca2+ causes distinct fluorescence

Figure 9. Molecular structures of complexes 4−Fe3+ and 5−Cu2+.

of Fe3+ for fluoride anions is much higher than those of Fe3+ for other halide anions, therefore it is suitable for selective sensing of fluoride. As a result, 4−Fe3+ shows a selective real-time determination for fluoride in water media, based on a displacement assay. A similar complex, 5−Cu2+, can selectively determine histidine in aqueous solutions over other typical amino acids, i.e., L-glutamic acid, L-glycine, methionine, L-serine, L-arginine, L-ornithine, 3-methylhistidine, L-tyrosine, L-cystine, and L-histidine. An ESPIT-based fluoride-selective probe has been reported (Figure 10).48 3-Hydroxyflavone derivative 6 shows an extensive emission band peaked at 554 nm as a result of proton transfer. When Zr−EDTA is introduced into an aqueous solution of 6, its

Figure 11. Molecular structure of receptor 8.

quenching of receptor 8 at 370 nm, and its resulting ensemble complex 8-Ca2+ has a fluorescence “turn-on” response for fluoride anions, with partial precipitation of CaF2, indicating that it undergoes a F−-promoted replacement assay. Furthermore, this system works in aqueous media, because it does not rely on hydrogen-bonding interactions. The fluorescence intensity of the ensemble complex 8-Ca2+ was dependent on the concentration 7899

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of F− within 0.5−5.0 mM. Moreover, this fluoride assay can be further applied for the analysis of dental health products. 3.1.1.2. Cl−. In supramolecular systems, chloride anions play pivotal roles in various biological and cellular processes, and disease states; for example, control of the cell volume, pH, and membrane transport, which involve chloride transport across the cell membrane.51 Cl− channels are present in both intracellular organelles and plasma membrane, and can help ion homeostasis in transepithelial transport, regulation of cell volume, and electrical excitability.52,53 The misregulation of chloride across the cell membrane is responsible for cystic fibrosis. Compared with fluoride-selective sensors, very few chloride-selective sensors have been reported, because of the inherent properties of Cl−, such as a large volume and low charge density.54 Cl− is a challenging analyte; it is extremely well hydrated, therefore only a couple of examples of artificial sensors that are capable of analyzing chloride in aqueous solution have been reported. To date, chloride-selective sensors have mainly been designed based on hydrogen-bonding interactions and size matching, that are greatly diminished in competitive polar and/or protic solvents.55 As a result, such sensors lack sensitivity in the presence of substantial amounts of water. Alternative chemosensing ensemble-based strategies have been developed as chlorideselective sensors in recent years; these are summarized below. An ensemble system can be assembled in situ by mixing a Rh complex, a bidentate N,N-chelated ligand, and an indicator, namely, hydroxypyrene-1,3,6-tertsulfonate (11), in buffered aqueous solution for chloride detection at near physiological pH (Figure 12).56 The associations of two closely related receptors, 9 and 10, with fluorophore 11 to give a nonfluorescent ensemble adduct that in turn responds to chloride with a fluorescence turn-on signal have been studied. Dye 11 shows an intense emission band peaked at 510 nm and significant fluorescence quenching is observed on addition of complex 9 or 10, as a result of the formation of sensing ensembles 9−11 and

10−11. Dye 11 interacts with complex 10 through coordination of a hydroxyl group with the Rh2+ center via electrostatic forces and π−π dispersive interactions. Ensembles 9−11 and 10−11 have been used for the sensing of anions, i.e., Cl−, F−, NO3−, AcO−, H2PO4−, H3P2O7−, HCO3−, SO42−, and salicylate. Two ensembles can selectively respond to Cl− with a turn-on fluorescence signal and can be used for selective testing of chloride down to midmicromolar levels. In addition, the introduction of a small amount of a commercially available surfactant, cetyltrimethylammonium (CTA) hydrogen sulfate, to the ensembles can be used to tune generation of a turn-off signal for low-to-midmicromolar level of Cl−. The same research group also reported a micelle-based chemosensing ensemble system, consisting of a half-sandwich Rh complex 10, indicator 11, and cationic surfactant CTA, enabling selective and sensitive sensing of chloride in buffered aqueous solution.57 As shown in Figure 13, the Rh complex 10, which was

Figure 13. Micelle-based chemosensing ensemble for Cl−.

designed as a receptor, has a good affinity for Cl− coordination in water. The receptor−chloride adduct 10−Cl− in the micelles is bound to the micelles, and this quenches the fluorescence of indicator 11. The micellar dispersion of CTA not only generates a secondary pseudophase for the selective stabilization of the receptor−chloride complex 10−Cl− but also provides a platform for signal transduction between the receptor and reporter subunits. As a result, the addition of chloride to the ensemble system produces a clear fluorimetric turn-off response at 528 nm. It is also found that preferential solvation of 10 within the micelles also leads to an apparent binding increase in the affinity of receptor 10 for chloride; this leads to high sensitivity for quantitative determination of chloride in water media down to low-micromolar ranges. This ensemble system can selectively determine Cl− in the presence of other anions, i.e., AcO−, HP2O73−, HPO42−, NO3−, SO42−, and HCO3−. As such, introduction of micelle to the ensemble system helps to improve the solubility, selectivity, and sensitivity, which provides an alternative way to design supramolecular ensembles for guest sensing. Two N-acylhydrazone-substituted BODIPY-based fluorescent sensors, i.e., 12 and 13, have been reported to show exclusive sensing of Hg2+ (Figure 14).58 Both 12 and 13 show absorption bands at 615−650 nm and emission bands at 625−660 nm. The BODIPY-based receptors 12 and 13 show exclusive distinct fluorescence quenching in the presence of Hg2+. The resulting ensemble complexes 12−Hg2+ and 13−Hg2+ showed good selectivity and specificity for Cl− under physiological conditions, whereas other anions, i.e., F−, Br−, I−, ClO4−, H2PO4−, HPO4−, HSO4−, N3−, SCN−, NO3−, and RSH in CH3CN−PBS (7:3; v/v, pH 7.4), did not change the solution fluorescence. On addition of Cl− to 12−Hg2+ or 13−Hg2+, Hg2+ ions were extracted from the complex, with release of the BODIPY dye 12 or 13, which produced significant fluorescence enhancement (22-fold), with a

Figure 12. Rh complexes 9 and 10, and dye 11 for ensemble sensing of Cl−. 7900

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Figure 14. BODIPY−Hg2+-based ensemble complex for Cl− sensing.

A ratiometric fluorescent sensor for Ag+ ions was developed, and the resultant ensemble complex 15−Ag+ was used for iodide anion detection in aqueous solution, based on a displacement assay (Figure 16).64 The ligand selectively interacts with Ag+,

limit of detection of 108 nM. This ensemble system for the determination of Hg2+ and Cl− is reversible and was reusable for six cycles. Moreover, the probe is cell membrane permeable and readily applied to monitor intracellular Cl−. The present system based on such a cascade molecular structure provides a good platform to design the ensemble complex for the sensing of anions. 3.1.1.3. I−. Iodide anions have biologically important roles in several neurological processes.59 NaI symporter is an important plasma membrane glycoprotein and mediates I− transportation in the thyroid gland, that will cause thyroid hormone biogenesis.60 Thyroid hormones mediate the metabolic processes of growth of organ systems.61 In clinics, the iodide concentration is frequently determined to check thyroid disorders. Although iodide anions are very important in various physiological processes, only a few I−-selective sensors based on conventional methods have been reported.62 Recently, several ensemble-based sensors for probing iodide anions have been developed; these are described below. The example shown in Figure 15 involves a displacement assay and uses Hg2+ complexes for the selective recognition of I−

Figure 16. Ensemble complex 15−Ag+ for I− sensing.

based on resonance inhibition, with a large hypsochromic shift from 565 to 481 nm and ratiometric emission changes of up to 26-fold. An aqueous solution of complex 15−Ag+ also displays a ratiometric response to iodide anions over other anions; this is due to the replacement of Ag+ from the ensemble complex 15− Ag+ to form a precipitate of AgI. Complex 15−Ag+ has a limit of detection for I− down to 0.9 ppm due to its high affinity of Ag+ to I−. 15−Ag+ also gives rise to a high selectivity over other competing anions, i.e., F−, Cl−, Br−, HSO4−, CO32−, H2PO4−, AcO−, SCN−, CN−, and S2−. Such a N or S-containing crown ether can be used as a good scaffold candidate to form ensemble complexes with Hg2+, Cu2+, and Zn2+, which can be further applied for the sensing of anion species. Thiosemicarbazone-based receptors are good candidates for coordination with Hg2+, because of their suitable binding abilities. In the following two cases, carbazole- or dimethylbenzylthiosemicarbazone-based receptors were used to bind Hg2+ to form an ensemble-based fluorescent sensor for iodide in aqueous solution, based on the displacement approach (Figure 17). The ensemble complex 16−Hg2+ displayed significant fluorescence enhancement at 425 nm on addition of I−, because of the release of the receptor 16 from the ensemble and formation of HgI2.65 16−Hg2+ can selectively sense iodide over other anions (e.g., F−, Cl−, Br−, NO3−, NO2−, N3−, SO42−, SO32−, CO32−, PO43−, AcO−, and CN−) at pH 7.4 in aqueous media. The ensemble system 16−Hg2+ was used to determine iodide in Candida albicans cells. Similarly, the ensemble complex 17−Hg2+ was found to show a selective and sensitive fluorescence increase toward iodide over

Figure 15. Ensemble complex 14−Hg2+ for I− sensing.

anions.63 The thymine−Hg2+−thymine complex 14−Hg2+ shows a weak fluorescence band at 418 nm, resulting from PET from the anthracene fluorophore to the bonded Hg2+. The introduction of I− into a buffer solution of 14−Hg2+ induced a 6fold emission enhancement, because of the release of the thymine−anthracene fluorophore and formation of HgI2. By virtue of such fluorescence decreasing and recovery processes, the complex 14−Hg2+ can detect iodide with a limit of detection down to 126 nM. Furthermore, this ensemble system is capable of selectively testing iodide toward other competing anions (i.e., Cl−, F−, Br−, SO42−, HCO3−, CO32−, H2PO4−, HPO42−, PO43−, AcO−, and NO3−) and can be applied for sensing of iodide levels in the samples of drinking water and urine. 7901

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sensitive sensing for both F− and AcO− toward other anions (i.e., Cl−, Br−, HSO4−, H2PO4−, I−, NO3−, N3−, SO42−, SO32−, and Cr2O72−), because of deprotonation of dansyl moiety. The ensemble system 18−Hg2+ was also used for anionic sensing. AcO− resulted in a 60-fold enhancement in its emission intensity at 500 nm, with a limit of detection of 100 nM, and F− induced a smaller enhancement; other species (i.e., Cl−, Br−, I−, HSO4−, H2PO4−, NO3−, N3−, SO42−, SO32−, and Cr2O72−) caused negligible emission changes. The ensemble 18−Hg2+ was also used for sensing of AcO− in a blood plasma. A rhodamine 6G−phenylurea conjugate derivative was found to detect Fe3+ ions selectively in aqueous media (Figure 19).70 The addition of Fe3+ produced a color change from colorless to pink, indicating the presence of rhodamine in the ring-opened conformation. The resultant 1:1 complex, 19−Fe3+, is strongly fluorescent at 556 nm, and its emission quantum yield reaches 86%. The ensemble complex (19−Fe3+) was confirmed to selectively and sensitively respond to AcO− anions in H2O:CH3CN solution. Addition of AcO− to an aqueous solution of 19−Fe3+ caused a color change and fluorescence switch-off, indicating that the conformation of 19 is reversible on alternating additions of Fe3+ and AcO− ions. 19−Fe3+ can sense AcO− with a limit of detection of about 0.18 μM, while other competitive anions such as F−, Cl−, Br−, HSO4−, I−, H2PO4−, NO3−, and CO32− do not induce any spectral changes. It should be noted that Fe(III) exhibits yellow color in aqueous solution due to the formed species such as [Fe(III)(H2O)5OH]2+, that can give strong absorbance band in the blue-near UV region through charge transfer transitions.71 It was found that some fluorophores (i.e., naphthyl, anthracene, or pyrene), even without the receptors of Fe(III), produced fluorescence quenching because [Fe(III)(H2O)5OH]2+ could absorb the light for the excitation of these fluorophores. The ensemble systems based on Fe(III) complex maybe suffer from its own disturbance and give a false signal. As a result, for the design of Fe(III)-based ensemble complex, it is better to select the fluorophore with an excitation wavelength over 410 nm. 3.1.1.5. CN−. Cyanide anions occur widely and are extremely toxic. Cyanide in human blood can bind cytochrome oxidase to form a stable complex, resulting in inhibition of enzymatic functions, cytotoxic hypoxia, and cellular asphyxiation.72 Thiocyanates are the ultimate products of the detoxification of cyanide derivatives; they show a strong affinity tendency to interact with proteins as noncompetitive inhibitors for iodine. Thiocyanate in saliva, urine, and serum has been recognized as a biomarker to evaluate cyanide contamination and distinguish smokers from nonsmokers.73 Abnormal concentration of thiocyanate in body fluids are toxic and involved in vertigo, local goiter, and unconsciousness.74 Fluorescent sensors for cyanide is therefore of considerable interest, and many

Figure 17. Molecular structures of ensemble complexes 16−Hg2+ and 17−Hg2+.

F−, Cl−, Br−, H2PO4−, CH3CO2−, S2−, EDTA, SCN−, and SO42−; this was also ascribed to an I−-induced displacement assay.66 3.1.1.4. AcO−. Acetate is an important anion and is of particular interest because of its biological functions, especially in the treatment of uremia.67 The acetate anion is also a critical component of, or related to, some enzymes and antibodies.68 An elevated acetate level as a result of oxidation of ethanol is a major cause of hangovers. Most acetate-selective sensors can only work in organic solvents, due to its strong solvation. Several ensemblebased sensing systems have therefore been developed for the determination of acetate anions in aqueous media. A terphenyldansyl-based crown ether was synthesized and its Hg complex, 18−Hg2+, was developed as an ensemble system for the detection of AcO− anions (Figure 18).69 Receptor 18 shows

Figure 18. AcO− sensing by complex 18−Hg2+.

absorption bands centered at 255 and 298 nm, together with a fluorescence band centered at 500 nm in THF. When Hg2+ is added, the absorption profiles increase and complete fluorescence quenching at 500 nm is observed. Ligand 18 gives

Figure 19. AcO− sensing by ensemble complex 19−Fe3+. 7902

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Figure 20. CN− sensing by ensemble complex 21.

Figure 21. CN− sensing by ensemble complex 22−Cu2+.

Figure 22. CN− sensing by ensemble complex 23−Cu2+.

ratiometric fluorescence signal for the sensing of CN−, different from the common turn-on or turn-off fluorescence mechanism. Near-IR fluorescent chemosensors can be applied to determine CN− in water media based on metal ion displacement, in which a Cu2+ complex of polyamine-substituted heptamethine cyanine dye was used as an example for illustration. A complex of Cu2+ coordinated to the near-IR fluorescent dye 22 can selectively detect CN− in water media (Figure 21).78 With the progressive addition of Cu2+, the absorption peak of 22 at 718 nm decreased along with the concurrent growth of a new peak at 743 nm. The fluorescence of 22 was significantly quenched, because of PET between the fluorophore and the metal center. In the presence of CN− anions, the ensemble 22−Cu2+ produces an increased emission band at 748 nm, as a result of removal of Cu2+ ions and the formation of [Cu(CN)x]n−. It was also found that it is possible to detect CN− in some microorganisms on infection with Pseudomonas aeruginosa and contamination with exogenous CN−. A fluorescein-based Cu2+ complex was used in an ensemble based on a displacement assay for the determination of cyanide anions in 100% water media at pH 7.4 (Figure 22).79 The ligand

irreversible-reaction-based sensors have been reported and well reviewed in recent years.75,76 Among the various systems for CN− detection, ensemble systems using the affinity of CN− for Cu2+ have been widely used, because they form very stable and water-soluble species, namely [Cu(CN)x]n−. In this section, only the design strategy that uses ensemble chemosensing to produce fluorometric and colorimetric responses is discussed. Receptor 20 was designed based on a bipyridyl conjugated thiophene unit, and its Zn2+ complex 21 were applied for the determination of endogenous CN− anions in natural products (Figure 20).77 When Zn2+ ions were introduced to the HEPES buffer solution of 20, a distinct color change from colorless to yellow was found together with an emission red shift from 480 to 530 nm, caused by the formation of the complex 21. Subsequent introduction of CN− to 21 produced revival of the original absorption and emission bands due to the decomplexation of Zn2+ from 21, thus regenerating the receptor 20. Other anions including I−, Cl−, Br−, F−, N3−, HSO4−, HClO4−, and AcO−, together with possible biological interferents (various phosphates, amino acids, and thiols), did not lead to detectable emission changes. The present ensemble complex can provide a 7903

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Figure 23. Molecular structures of receptors 24−26.

affinity of CN− toward Cu2+ and the resulting displacement was utilized for the spectral responses above. It should be noted that for similar reversible sensors based on Cu2+-complexation and decomplexation, the Cu2+ amount added should be in a proper concentration range because the excess Cu2+ can distinctly quench fluorescence and cause a less absorption/emission recovery. Ir(III)-polypyridyl-complexes have been widely applied for chemical and biological sensing because of their favorable photophysical properties, i.e., good photostability, high emission quantum yield, and long emission lifetime.82 They can be designed for the phosphorescence-based sensors and imaging reagents for intracellular studies.83 In this case, an Ir(III) complex bearing a dipicolylamine (DPA) unit was coordinated with Cu2+ in an ensemble complex for the phosphorescent detection of CN− in HEPES−CH3CN buffer (Figure 25).84 The introduction

23, designed for this purpose, produced significant fluorescence quenching with addition of Cu2+. Subsequent introduction of cyanide to a solution of 23−Cu2+ gave “off−on” fluorescence via formation of Cu(CN)2. Present ensemble was incorporated in a microfluidic platform that 23−Cu2+ displayed a fluorescence enhancement on addition of CN−. Further study for biological applications of Caenorhabditis elegans indicated that this ensemble example can be used for cyanide imaging in vivo. Three similar 2,2′-dipyridylaminoanthracene−Cu2+ complexes, i.e., 24−Cu2+, 25−Cu2+, and 26−Cu2+, with 1:1 stoichiometries, were reported for displacement assays for the detection of CN− in methanol−H2O solution (Figure 23).80 It was found that different connection manner in the receptors 24− 26 distinctly affected their sensing behaviors. The complexes 24−Cu2+ and 25−Cu2+ showed higher sensitivity and selectivity toward cyanide than did complex 26−Cu2+. The limits of detection for 24−Cu2+ and 25−Cu2+ were 3 × 10−7 and 2 × 10−7 M, respectively. These results indicate that a carbon linkage between DPA and fluorophore is important for the design of CN−-selective ensembles. This ensemble complex also showed a good emission recovery to CN− over other competitive anions, i.e. F−, Cl−, Br−, AcO−, H2PO4−, I−, SO42−, CO32−, SCN−, and S2−. The proposed sensing mechanism involves a CN−-induced replacement reaction, which leads to strong fluorescence enhancement. In addition, the fluorescence of 24 and 25 can be repeatedly switched off and on via alternating addition of Cu2+ and CN−, indicating the highly reversible property of both complex ensembles. 2-Carboxy-2′-hydroxy-5′-sulfoformazylbenzene (27) as an efficient ligand can be used cooperatively with Cu2+ to form an ensemble complex 27−Cu2+ for selective and sensitive determination of cyanide in water media, with a limit of detection down to 0.13 ppm (Figure 24).81 With the progressive addition of Cu2+, a new absorption band of 27 at about 600 nm appears and grows with the expense of the peak at 463 nm, because of the formation of 27−Cu2+. Subsequent addition of CN− to the resulting complex 27−Cu2+ induces an absorption increase at 463 nm, with clear changes resulting from release of the ligand and formation of Cu(CN)2. Obviously, the high

Figure 25. Molecular structure of complex 28−Cu2+.

of CN− to 28−Cu2+ produced a phosphorescence turn-on response at 583 nm, as a consequence of the removal of Cu2+ anions via formation of Cu(CN)n(n−2)− (n = 2 or 4). This ensemble complex has been applied for emission imaging to sense CN− in living HeLa cells, with a limit of detection down to 0.38 ppm. In addition, 28−Cu2+ has been used to detect the biological activity of hydroxynitrile lyase that can catalyze the decomposition of mandelonitrile with the formation of HCN. Compared to the fluorescence-based ensembles, phosphorescent ensembles can provide a longer emission lifetime which facilitates the time-resolved imaging techniques. However, one disadvantage is that the longer excited state in this sensing ensemble is subject to the disturbance of oxygen. 4,5-Disubstituted-1,8-naphthalimide-basd analogues 29 and 30 can probe CN− anions, based on a displacement assay (Figure 26).85 Receptor 29 in HEPES buffer solution shows an extensive naphthalimide emission peak at 534 nm. Introduction of Cu2+ gives gradual fluorescence quenching at 534 nm, together with a progressive enhancement of a new emission band at 478 nm, resulting from formation of the ensemble 29−Cu2+. Receptor 30 gives a wide fluorscence band at 550 nm, whereas it is completely

Figure 24. CN− sensing by ensemble complex 27−Cu2+. 7904

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The fluorescent derivative 33, which consists of two triazole groups and a carbazole subunit, was utilized for the determination of CN− anions via ligand exchange (Figure 28).87 The ligand 33 in acetonitrile gives two absorption bands

Figure 26. Molecular structures of receptors 29 and 30.

quenched on addition of Cu2+, because of formation of complex 30−Cu2+. Both Cu2+ complexes have been utilized as ensembles for probing of CN−, because the addition of CN− induces recovery of the fluorescence of 29 and 30, with the formation of Cu(CN)2. However, other anions tested (i.e., F−, Cl−, NO3−, Br−, I−, SO42−, and H2PO4−) produced negligible emission changes of ensembles 29−Cu2+ and 30−Cu2+. An ensemble complex 31−Cu2+, which contains a coumarin dye, was used to distinguish CN− from other anionic species in aqueous environments, and gave significant fluorescence enhancement (Figure 27).86 Complex 31−Cu2+ is nonfluorescent and addition of CN− induces demetalation process to afford a stable complex [Cu(CN)x]n−. The formed ligand 31 is hydrolyzed to give the strongly emissive coumarinaldehyde 32, giving strong fluorescence “turn-on” sensing. The addition of CN− to 31−Cu2+ induced an absorption change from 521 to 464 nm, with a color change from orange-red to green, and concomitant emission enhancement at 514 nm, with a limit of detection down to 10 nM in aqueous solution. Other competitive anions (i.e., F−, Cl−, Br−, AcO−, I−, H2PO4−, HSO42−, NO3−, ClO4−, HCO3−, SCN−, OH−, CO32−, HPO42−, AMP, PO43−, ADP, and ATP) in biological media were found to give negligible spectral changes. Competitive assays confirmed selective detection of CN−. In addition, CN− detection with 31−Cu2+ was successfully performed in HepG2 cells. Such a design strategy in this case includes a rapid decomplexation process and a slow hydrolysis reaction of the released receptor, which is different from other ensemble systems.

Figure 28. Molecular structures of receptor 33 and its complex 33− Cu2+.

peaked at 300 and 370 nm and an emission band peaked at 385 nm, respectively. The introduction of Cu2+ produces an absorption band shift from 326 to 405 nm, and complete fluorescence quenching as a result of formation of a 1:1 ensemble complex, 33−Cu2+. When CN− was introduced into a solution of 33−Cu2+, the absorption and emission profile of 33 was restored, because of demetalation of 33−Cu2+ to form the complexes Cu(CN)2 or Cu(CN)4. Negligible spectral changes were found when using other anions (i.e., F−, Cl−, Br−, AcO−, I−, H2PO4−, HSO4−, NO3−, and ClO4−). In short, the traditional method for the design of CN−selective sensors is based on the nucleophilic substitution reaction that needs a longer response time in aqueous solution, in which the sensitivity is not very high in some cases. In contrast, the ensemble-based sensing system for CN− only involves in Cu2+ or Zn2+ decomplexation process, which can be completed within several seconds. As a result, ensemble-based sensors are generally sensitive to CN−. In addition, most of these examples are designed on the basis of positively charged, hydrogen bonding interactions, and unsaturated metal centers coordinated to receptors to give a “fly trap” conformation. 3.1.1.6. HS−, S2−, and SCN−. H2S is not only a toxic gas, but is also a biologically important mediator. Various biological

Figure 27. CN− sensing by ensemble complex 31−Cu2+. 7905

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(i.e., F−, Cl−, Br−, NO3−, NO2−, N3−, SO42−, CO32−, PO43−, AcO−, and CN−) did not result in distinct fluorescence enhancements, because of precipitation of CuS, that led to the release of the fluorescent cyanine dye. In the following two examples, similar Cu2+ ensemble complexes were used to develop fluorescent sensors to detect H2S species (Figure 31). Based on the displacement strategy, a

signaling functions of H2S have been widely explored,88 including cardioprotective,89 neuroprotective,90 and gastroprotective effects,91 the regulation of insulin release, and antiinflammatory effects.92 H2S has been also considered as a third gasotransmitter along with NO and CO, which have a number of effects on biological targets, producing either cytotoxic or cytoprotective responses.93 H2S species can also exist as HS− and S2− under different pH conditions. As a result, biocompatible and selective sensing methods to determine H2S species are highly desirable, especially ensemble-based sensors. It is known that quinoline and 2,2′-DPA have good binding affinities with Cu2+ ions. A boron−dipyrromethene ensemble complex, 34−Cu2+, was utilized for the colorimetric sensing of H2S in HEPES buffer (5% DMSO; Figure 29).93 The aqueous

Figure 31. Molecular structures of complexes 36−Cu2+ and 37−Cu2+.

1,4-dihydroxyanthraquinone 36−Cu2+ ensemble was developed as a fluorescent ensemble for selective sensing of sulfide in aqueous solution.96 The addition of sulfide resulted in distinct fluorescence enhancement of 36−Cu2+, with a limit of detection of 59.8 nM. Receptor 36 shows an “on−off−on” fluorescence mode on alternating addition of Cu2+ and S2−, which can be repeated for at least four cycles. The ensemble 37−Cu2+ was designed as a colorimetric sensor for detection of H2S at neutral pH.97 The sensing mechanism was attributed to the release of receptor 37 and formation of CuS on addition of Na2S. It gave good selectivity for H2S over other competitive anions. Cyclometalated Pd complexes have been used as functional materials for chemical sensing, because of their excellent electronic and steric properties. Two dinuclear cyclopalladated azobenzene complexes, 38 and 39, based on H-shaped chlorobridged dimers, were obtained via exchange reactions of chloride bridges with different anions (Figure 32). The ligand-exchange reactivity of cyclopalladated compound is remarkably affected by the “metalloaromaticity”.98,99 Anion-induced demetalation and replacement of a simple ligand (not a dye) were applied as a sensing protocol. Complexes 38 and 39 showed selective and sensitive spectral responses to SCN− in water media at physiological pH.100 The addition of SCN− to 38 at pH 7.4 led to a distinct visual change from red to yellow, with the formation of a 1:2 ensemble complex, as confirmed from Job’s plot and IR analyses. However, negligible changes took place on introduction of other competitive anions (i.e., F−, Cl−, Br−, I−, NO3−, NO2−, SO42−, HCO3−, BzO−, AcO−, and CN−). The addition of S2−, SO32−, and SCN− anions to solutions of 39 resulted in respective

Figure 29. HS− sensing by ensemble complex 34−Cu2+.

solution of 34−Cu2+ gave an intensive absorption band centered at 520 nm. Subsequent introduction of HS− produced a progressive absorption diminish at 520 nm and a concomitant appearance of a new absorption band at 569 nm, with a visual change from orange to pink. The BODIPY dye released from the ensemble on formation of a HS−−Cu2+ complex was responsible for the new absorption peak at 569 nm. The ratiometric signal at 569 and 520 nm showed a 34-fold absorbance enhancement, enabling a sensitive agent for detecting HS− species via absorption colorimetry and ratiometry. Introduction of F−, Cl−, Br−, I−, HCO3−, H2PO4−, SO42−, SO32−, N3−, SCN−, CN−, NO2−, and NO3− induced negligible changes. Cyanine dyes as near-infrared (NIR) fluorescent materials have been widely applied in the sensing and detection.94 In this example, a complex of a cyanine dye 35 with Cu2+ was reported to be an efficient and selective probe for S2− anions, based on a replacement assay (Figure 30).95 8-Aminoquinoline moiety bearing piperazine linker was used as the binding sites for metal ions. Complex 35−Cu2+ is nonfluorescent, but addition of S2− to a solution of 35−Cu2+ produces significant fluorescence enhancement (27-fold) at 794 nm. Other examined anions

Figure 30. S2− sensing by ensemble complex 35−Cu2+. 7906

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3.1.1.8. Citrate and Oxalate. Pyridinium-based symmetrical diamides 41 and 42 were designed as an ensemble to detect citrate in CH3CN:H2O Tris buffer solution (4:1, v/v, pH 6.3), using Fl as an indicator (Figure 34).104 41 and Fl formed an

Figure 32. SCN− sensing by complexes 38 and 39.

color changes from purple to yellow, orange, and colorless. In this displacement assay, the displacement process takes place between two ligands (SCN− and Cl−), not with the indicator, which is obviously different from other displacement assays. 3.1.1.7. ClO−. Hypochlorite ClO− (its protonated form, HClO) is widely involved in the water treatment, household bleaching, and disinfection of drinking water with a concentration level from millimolar to micromolar range.101 The critical involvement of ClO− will cause tissue damages and diseases, such as arthritis, atherosclerosis, cancers, etc.102 It is necessary to develop efficient sensing system for the sensing of OCl−. A rhodamine−Cu+ complex, shown in Figure 33, was reported as a potential hypochlorite-selective probe, based on the

Figure 34. Molecular structures of receptors 41 and 42.

ensemble system, and the sequent introduction of citrate produced a displacement of indicator Fl. Both absorbance and emission spectra were restored to their original status of Fl, with distinct naked-eye detection. Other competitive species (F−, Cl−, Br−, I−, H2PO4−, AcO−, tartrate, pimelate, malate, glutarate, adipate, malonate, succinate, N-Ts, and glutamate) did not produce the positive response to the 41−Fl ensemble. Virtually the same results were obtained to selectively sense citrate using ensemble 42−Fl. In addition, 42 can form a gel in the presence of citrate in the concentration range ∼10−3 M in CH3CN, because of their strong supramolecular interaction. However, under identical conditions, 41 and citrate cannot produce a gel, indicating that the pyrene unit plays an important role in maintaining a hydrophobic/hydrophilic balance in 42. Dinuclear Cu(II) complexes 43 and 44 were reported as ensembles for the selective testing of citrate at physiological pH condition via a displacement assay, in which PV was used as a colorimetric dye (Figure 35).105 It was found that citrate

Figure 33. ClO−-induced Cu+ oxidation and ring opening of rhodamine derivative 40.

oxidizing properties of hypochlorites and different coordination abilities with Cu+ and Cu2+.103 The rhodamine-based dye 40, which exists predominantly in the spirolactam form, remains unchanged with the addition of Cu+ ions. It gives rise to emission light-on signals once Cu+ ions are oxidized to Cu2+ on addition of ClO−, because of the formation of a Cu2+ complex with a ringopened conformation. With the presence of Cu+ and sodium ascorbate, on addition of ClO− to solutions of 40, a new absorption band peaked at 555 nm emerges with a 198-fold growth within 30 min. These results indicate that 40 exists in the form of spirolactam ring-opening induced by Cu2+. This present ensemble was found to selectively respond to ClO−, with a limit of detection down to 0.81 μM in water media. Other anions, such as CO3−, SO42−, ClO4−, ClO3−, NO2−, AcO−, and P2O74−, could not lead to virtual changes, whereas H2O2 can also respond to a positive response with a relatively smaller extent. This ensemble complex was also utilized to sense the ClO− concentration even in real tap water samples. In this example, the combination of ClO−-induced oxidation reaction and Cu2+-induced ring open of rhodamine moiety was used for the design of ensemble system, which is very efficient for the detection of ClO−.

Figure 35. Molecular structures of receptors 43 and 44.

produced a gradual absorption increase peaked at 434 nm, and a decrease in the fluorescence of 44−PV at 597 nm, indicating release of PV from the ensemble complex 44−PV. However, other tested anions such as oxalate, malonate, glutarate, succinate, and adipate caused negligible spectral changes. In addition, complex 43 showed similar spectral changes with citrate but gave lower sensitivity. The receptor 45 is designed as a heteroditopic cage in which one unit is suitable for coordination with Cu2+, while the other unit interacts with guest species via hydrogen-bonding and electrostatic supramolecular interactions (Figure 36).106 In7907

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Figure 38. PPi sensing by receptor 47, with MCB as indicator.

is fully restored. This present ensemble displays a selective sensing of P2O74− over other anions, i.e., F−, Cl−, Br−, SO42−, AcO−, HCO3−, NO3−, and salicylate. Only H2PO4− and ClO4− caused minor fluorescence increases. Tripodal amine p-tert-butylcalix[4]arene-based mono- and dinuclear Cu2+ complexes 48 and 49 were used for an ensemble system to recognize P2O74− in semiaqueous solution (Figure 39).109 PV was chosen as the competitive indicator bound to the receptor. The maximum absorption band of PV in HEPES buffer solution changed from 430 to 670 nm on addition of 49, because of formation of a 1:1 ensemble complex (49−PV). Of the anions F−, Cl−, Br−, AcO−, I−, H2PO4−, P2O74−, and BzO− tested, only P2O74− gave a visual change from green to yellow. In addition, both ATP and ADP displaced PV from the ensemble complex, whereas AMP did not. However, the reference complex 48−PV could not give distinct color changes in the presence of anions, indicating that the cooperative action requirement of both two Cu2+ ions is necessary for selective detection of P2O74−. The selectivity is arisen from the control of the proper distance between the two donor arms of the anion guests. Steric hindrance of the two bulky tripodal amine units and the preorganization of calix[4]arene into the cone conformation are also important factors to control the distance of two metal centers. The binuclear Zn2+ complex 50 and boronic acid 51 were utilized in a replacement method for the selective sensing of P2O74− and nucleoside triphosphates (NTPs) (Figure 40).110 Complex 50 in CAPS buffer solution at pH 10.5 gives an intense fluorescence band peaked at 440 nm. However, it is partly quenched on gradual addition of dye 51, as a result of formation of a supramolecular ensemble 50−51, with weak emission, in which the boronic acid interacts with two Zn2+ centers in 50. The introduction of P2O74− to an aqueous solution of the ensemble system of 50−51 results in an 8-fold increase of the emission profile. The sensing mechanism is ascribed to the supramolecular interaction of complex 50 with P2O74−, which induces the release of 51 from the ensemble system 50−51. Additionally, introduction of NTPs (i.e., ATP, CTP, GTP, and UTP) causes significant fluorescence quenching of 50−51, because of formation of a ternary complex 50−51−NTP, in which two Zn2+ centers are coordinated with the phosphate moieties, and the boronic acid unit of 51 reacts with the hydroxyl units of the sugar. The supramolecular ensemble 50−51 therefore selectively recognizes P2O74− in the presence of various NTPs. A family of cyclic peptide derivatives bearing DPA side chains (52−57), to bind with Zn2+, were used for anion sensing (Figure 41).111 Coumarin indicator 58 is strongly fluorescent, whereas its complexation with the receptors 52−57 can form a 1:1 supramolecular ensemble with weak fluorescence. On titration by P2O74−, ATP, or ADP in HEPES buffer (pH 7.4) of ensembles (52−57)-58, significant enhancements of the fluorescence profiles were observed, because P2O74−, ATP, or ADP can preferentially coordinate with receptors 52−57 to induce the

Figure 36. Oxalate sensing by heteroditopic Cu2+ receptor 45 with PV as an indicator.

troduction of the dye PV into the Cu2+ polyaza macrobicyclic receptor 45 to form a supramolecular ensemble provides selective recognition of oxalate using indicator displacement assays in aqueous media. Among all dicarboxylates tested (succinate, malonate, fumarate, and maleate), only oxalate anion could replace the indicator from the receptor 45−PV, giving a visual change from blue to green. This recognition mechanism arises from cooperation interactions including the metal−anion coordination and electrostatic and hydrogen bonding interactions, together with the appropriate size match between the receptor and dicarboxylate. 3.1.1.9. H2PO4− and PPi. Macrocycle receptors provide boatshaped cavities for cationic complexation and anion sensing. The dinuclear ligand 46 and eosine Y (EY), which is a fluorescent dye, were used in a displacement assay for anions (Figure 37).107 On

Figure 37. Molecular structure of receptor 46.

gradual addition of 46 to EY in HEPES solution at pH 7.0, the EY fluorescence was gradually quenched, because of formation of a 1:1 ensemble complex 46−EY. The addition of H2PO4− to a solution of 46−EY resulted in a distinct fluorescence increase as a result of release of EY from the ensemble complex. The dinuclear complex used in this case provides a stronger binding affinity between the pentacoordinated metal centers with the cavity well suitable for the proper anions, which can tune its sensitivity and selectivity. The present ensemble does not give any affinity toward inorganic anions, i.e., F−, Cl−, Br−, I−, SO42−, NO3−, and ClO4−, but is capable of selectively responding to H2PO4− in water media. 2,2-Bipyridine (bipy) has a good affinity to Pd(II) with the formation of [Pd(NO3)2(bipy)] (47). The formed 47 and the indicator MCB form a chemosensing ensemble for PPi testing (Figure 38).108 The Pd complex and P2O74− form both 1:1 and 2:1 Pd:P2O74− complexes in HEPES buffer solution at pH 7. In the 1:1 complex, P2O74− acts as a bidentate ligand via the replacement of two weak nitrate groups bound opposite the bipy ligand. A mixture of MCB and 47 shows weak fluorescence, and in the presence of P2O74−, the strong emission of MCB at 440 nm 7908

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Figure 39. Molecular structures of mono- and dinuclear Cu2+−calixarene-based receptors 48 and 49.

antiviral drug, phosphonoformate anion (PFA) through a colorimetric and fluorescent displacement assay (Figure 43).113 Yb3+ and the indicator PV form a 1:1 blue complex that can probe the presence of PFA by release of yellow PV. The resulting ensemble Yb3+−PV shows a characteristic absorption band peaked at 605 nm in HEPES buffer solution (pH 7). With the addition of PFA, the absorption band at 605 nm decreases significantly, with progressive increase of a new band peaked at 444 nm with a visual change from blue to yellow. The ensemble Yb3+−PV responds linearly to the PFA concentration, with a limit of detection of 2 μM. This is attributed to the release of free PV into the solution and formation of the complex Yb3+−PFA. A similar method was applied for the fluorescent sensing of PFA, in which ME and Cu2+ ions were used to form an ensemble, i.e., ME−Cu2+, instead of PV−Yb3+. Differently in this strategy, the introduction of an aromatic amine [i.e., phenanthroline (61) and 2-(aminomethyl)pyridine (62)] gives rise to a ternary adduct with Cu2+ and ME, which can finely control the sensitivity of such a displacement assay. 3.1.2. Biomolecular Sensing. 3.1.2.1. ADP, ATP, and AMP. ATP is an importantly biological substrate and called “molecular unit of currency”. It is ubiquitous for metabolism and involved in the intracellular energy transportation.114 ATP also plays a pivotal role in the pathways of signal transduction and transmission115 and can be biosynthesized into nucleic acids with the aid of polymerases in the process of DNA replication and transcription.116 In the presence of ATP synthase, ATP is biosynthesized by phosphate, ADP, or AMP in the metabolic processes. As a result, the determination of ATP, ADP, and AMP is very important for many biological processes. For the design of chemosensing ensembles, transition-metal ions, i.e., Zn2+ or Cu2+, are used to cooperate with DPA, because they can provide beneficial electrostatic interactions in polar aqueous solutions. Zn2+−DPA complexes have been widely used for sensing of phosphate species, in which the complex provides a coordination cage to match an appropriate indicator.117 In this case, the dinuclear Zn2+−DPA complex (63−2Zn2+) detected ATP in DMSO−H2O solution based on a replacement assay, using Fl as an indicator (Figure 44).118 The absorption spectrum showed two absorption bands at 450 and 480 nm, and these shifted to higher wavelengths, along with absorbance enhancement, on addition of dinuclear complex 63−2Zn2+. The

Figure 40. Molecular structures of receptor complex 50 and boronic acid 51.

subsequent release of 58 from the ensemble system. However, negligible fluorescence changes were observed on addition of H2PO4−, indicating selective recognition toward di- and triphosphate anions over monophosphates. Different sensing behaviors were also observed for different receptors. For instance, 52−57 displayed selective determination for P2O74− over ATP and ADP, whereas ensembles (53−57)−58 displayed distinct discrimination between P2O74− and ATP or ADP, which were in accordance with the binding distance. Bis(2-pyridinmethyl)amine-based chiral ligand was designed to prepare two dinuclear complexes 59 and 60 (Figure 42). The resulting dinuclear complexes can form two 1:1 supramolecular ensembles with the indicator PV, respectively.112 On addition of P2O74− to 60−PV, a visual change from blue to yellow was found, as a result of displacement of PV with the formation of a 1:1 adduct 60−P2O74−. Other anions gave weaker responses and the binding constants were in the order of P2O74− ≫ ATP > PO43− > ADP > AMP. Both ternary complexes (59−PV and 60−PV) showed much better recognition selectivity to P2O74− over other anions such as acetate, phosphate, ATP, ADP, AMP, and halogen anions. The selective recognition ability for P2O74− can be ascribed to the suitable size of P2O74− and to the corresponding structure between the receptor and P2O74−, whereas each phosphoryl oxygen atom can bind with a metal center. 3.1.1.10. Phosphonoformate Anion. Two commercial indicators, PV and 6,7-dihydroxy-4-methylcoumarin (ME), were utilized as indicators for the selective detection of a simple 7909

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Figure 41. Molecular structures of receptors 52−57 and indicator 58.

Figure 43. Molecular structures of phosphonoformate anion and indicators PV and ME.

Figure 42. Molecular structures of receptors 59 and 60.

ensemble system 63−2Zn2+−Fl was also used for sensing of biomolecules, i.e., adenine, thymine, guanine, cytosine, AMP, ADP, and ATP. It was found that only ATP caused a distinct displacement of Fl from the ensemble, with a limit of detection of 0.1 μM. ADP, thymine, guanine and cytosine produced negligible disturbance for the detection of ATP, but ADP gave a little disturbance for ATP analysis. 3.1.2.2. GMP. Cryptate 64 and Cu2+ form a dinuclear complex 64−2Cu2+, which further interacts with 6-carboxyfluorescein (CF) to produce an ensemble system for the selective sensing of guanosine monophosphate (GMP) over other nucleoside monophospates (NMPs), based on a displacement assay (Figure 45).119 The dye CF gives a characteristic emission band peaked at 516 nm, and addition of complex 64−2Cu2+ produces complete fluorescence quenching of CF, because of the consecutive formation of 1:1 and 2:1 ensemble of 64−2Cu2+−CF. The

Figure 44. Molecular structure of binuclear complex 63−2Zn2+.

introduction of GMP to the ensemble increases the CF fluorescence, because of replacement of CF into the solution as a result of the formation of 64−2Cu2+−GMP. The present ensemble system produces selective fluorescence enhancement for GMP, whereas other nucleotides [i.e., adenosine mono7910

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Figure 45. Molecular structure of receptor 64.

phosphate (AMP), cyclic adenosine monophosphate (CMP), and uridine monophosphate (UMP)] does not induce obvious enhancements. This selective sensing mechanism is arisen from the fact that GMP can well match the distance of the two Cu2+ ions inside the cryptate. 3.1.2.3. Cys, HCy, and GSH. Thiol-containing biomolecules such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) are very important for conserving various biological systems. For instance, the deficiency of Cys is related to many disorders, including liver damage, neurotoxicity, edema, and hair depigmentation.120 An abnormal elevated concentration of Hcy in plasma is very dangerous to suffer from osteoporosis, Alzheimer’s and cardiovascular diseases, and neural tube defects.121 GSH is the most abundant nonprotein thiol in cells and plays an essential role to maintain the reductive environment in cells and works as a redox regulator.122,123 Till now, many efforts have paid attention to the determination of thiolcontaining biomolecules, because of their pivotal roles in biological systems. A quinazoline-based receptor 65 provided a good binding cavity for metal ions, and its Cu2+ complex was applied for Cys sensing (Figure 46).124 Ligand 65 shows two intense emission

Figure 47. Molecular structure of receptor 66.

progressively diminished, which could be ascribed to Hg2+− induced H-aggregation. The resultant ensemble produced a selective and sensitive fluorescence turn-on response for Cys, with a limit of detection as low as 9.6 nM. The strength of the Hg−S bond is much stronger than that of the Hg−N bond; therefore, the nonfluorescent aggregates 66−Hg2+ dissociated into monomers with the addition of Cys. The ensemble complex 66−Hg2+ was used to determine various amino acids including Hcy, GSH, DTT, mercaptoacetic acid, and 2-mercaptoethylamine. It was found that only thiol-containing amino acids caused distinct changes in their fluorescence profiles. The next example is also related to a displacement assay using a Hg2+ complex for the fluorescent sensing of thiols. A coumarinbased aminothiourea derivative 67 with a very strong green emission was developed, as shown in Figure 48. The crystal structure shows that it can form a 2 + 2 complex 68 with Hg2+, which can be used as an ensemble complex for the selective fluorescent determination of mercapto derivatives.126 A 99% aqueous solution of complex 68 gives a weak emission band peaked at 520 nm (quantum yield: 0.031), because of the heavyatom effect of Hg2+. The addition of Cys to 68 induced progressive fluorescence enhancement (quantum yield: 0.5), ascribed to replacement assay of Hg2+ from the ensemble adduct, with a release of the strongly emissive 67. Similar spectral responses were found with the presence of other mercapto derivatives such as GSH and Hcy. Other thiol-free amino acids (i.e., Gly, Ala, Ilc, Val, Pro, Tyr, Lys, Ser, Leu, His, Met, and Trp) did not produce obvious emission enhancements. 8-Hydroxyquinoline derivatives have been widely employed to construct functional chromophores for chemical sensing because of their excellent photophysical property and complexation

Figure 46. Molecular structures of receptor 65 and its Cu2+ complex.

bands peaked at 430 and 490 nm, and it gives sensitive and selective emission quenching toward Cu2+ over other metal ions. Subsequent addition of Cys to the in situ prepared ensemble complex 65−Cu2+ produces an efficient emission off−on response, with a limit of detection of 5.41 × 10−7 M. The emission of ensemble 65−Cu2+ was completely restored by addition of Cys, because of displacement of Cu2+ from the ensemble. The perylene bisimide derivative 66 was used for specific Hg2+mediated aggregation for sensing of thiol-containing amino acids, based on the noncovalent ensemble in a ‘‘thymine−Hg2+− thymine’’ binding scaffold (Figure 47).125 When 66 was titrated by gradual addition of Hg2+, the fluorescence peaked at 532 nm 7911

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Figure 50. Molecular structure of squaraine derivative 70.

of Hg2+ to a solution of 70 in CH3CN−H2O, the characteristic absorption band peaked at 636 nm and the emission band peaked at 678 nm decreased and completely disappeared; these results were due to the formation of a 1:1 ensemble complex. Hg2+ chelation disrupts the conjugation structure of 70 and leads to fluorescence turn-off. The ensemble complex 70−Hg2+ was tested for sensing of various amino acids and short peptides. It was found that only Cys, Hcy, GSH, and His produced emission revival peaked at 678 nm, because of preferred interaction of these species with Hg2+, which resulted in the release of free squaraine 70. 3.1.2.4. Folic Acid. In this case, the tripodal squaramido-based receptor 71 and 5-carboxyfluorescein (5-CF) as indicator constitute an ensemble system for the recognition of folate anions (Figure 51).131 A buffer solution of 5-CF at pH 9.0 displayed a characteristic emission peak at 525 nm. The emission was progressively quenched on addition of 71, with the formation of a 1:1 ensemble adduct. Subsequent introduction of folate substrate to the ensemble complex produced a fluorescence increase at 525 nm, as a result of formation of an adduct between 71 and folate, resulting in the release of 5-CF from the ensemble complex. This present strategy was further developed to probe folic acid in pills. In short, we have summarized a large number of twocomponent chemosensing ensemble examples based on the indicator-displacement assay for a variety of target analytes, including anions (i.e., F−, I−, AcO−, CN−, HS−, S2−, ClO−, SCN−, citrate, oxalate, H2PO4−, pyrophosphate, and phosphonoformate) and biomolecules (ATP, ADP, AMP, GMP, Cys, Hcy, GSH, folate, amino acids, short peptides, etc.). Some metal complex-based sensing examples based on metal-displacement assays (not indicator) were also summarized in this section. The breadth of examples above involved in various ions and biomolecules enables us to believe that the indicator-displacement assay is a facile and useful strategy to constitute optical sensing systems. Receptors were designed based on the supramolecular cooperative interactions (i.e., hydrogen bonding, metal−ligand coordination, π−π stacking, electronstatic, and hydrophilic and hydrophobic interactions, etc.) to capture the indicator and analyte through a competitive displacement.

Figure 48. Reversible interconversion of ligand 67 and complex 68 on modulation by Hg2+/Cys.

ability.127 In this case, a 8-hydroxyquinoline complex, 69−Cu2+, was reported as a colorimetric sensor for determining Cys and Hcy in aqueous solution (Figure 49).128 Complex 69−Cu2+ displayed an extensive absorption band peaked at 421 nm. When Cys or Hcy was introduced to an aqueous solution of 69−Cu2+ at pH 7.0, the absorption band at 421 nm decreased and a concomitant band at 497 nm increased, providing a ratiometric signal for quantitative determinatiion by absorption titration. These changes were attributed to the demetalation process involved in the release of dye from complex 69−Cu2+ and the formation of Cu2+−amino acid adducts. With the addition of other amino acids including His, Phe, Thr, Ala, Arg, Asn, Leu, Pro, Val, Tyr, Gly, Lys, Gln, Met, Ser, Ile, Trp, Glu, and Asp, negligible changes in the absorption profiles of 69−Cu2+ were observed. Squaraine dyes have been extensively applied in nonlinear optics, solar cell, optical data storage, and chemical sensing, because of their specific photophysical properties, and intense emission band in the visible to NIR region.129 The electron deficient feature of cyclobutene ring in squaraine has been used to interact with nucleophilic substrates. The squaraine derivative 70 interacted with Hg2+ to form an ensemble, which was utilized as a colorimetric and fluorescent off-on sensor for mercapto amino acids (Figure 50).130 The combined use of squaraine dye and different concentrations of Hg2+ to control the measuring range was used to detect mercapto amino acids. On introduction

Figure 49. Molecular structures of quinine ligand 69 and its Cu2+ complex. 7912

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In this section, three-component ensemble systems have been realized for the detection of a variety of anions (i.e., F−, Cl−, I−, CN−, ClO4−, H2PO4−, pyrophosphate, InsP3, and oxalate), neutral molecules (H2S), and biomolecules (ATP, ADP, AMP, GMP, Cys, Hcy, and GSH). 3.2.1. Anion Sensing. 3.2.1.1. F−. A water-soluble uranyl− salophen complex 72, bearing two glucose subunits, was developed. It showed strong binding affinities for F− and HPO42− in water media because of the strong Lewis acid−base interaction between uranyl and the anion (Figure 52).132 On

Figure 52. Molecular structure of uranyl−salophen complex 72.

introduction of F−, 72 produced distinct responses in absorbance profiles within 280−450 nm as a result of a 1:1 adduct since the strong electrostatic interactions can overcome the high hydration enthalpy of F− in water media. The affinity between 72 and HPO42− in water was attributed to the formation of a H-bonding intracomplex. In addition, the possibility of binding of 72 toward the biologically related anions AMP2−, ADP3−, ATP4−, and P2O74− under physiological pH conditions was explored, concluding that 72 has a stronger affinity to polyphosphate than that to monophosphate derivatives. The specific structure in 72 provides a strong hydrogen bonding interaction that can probe F− in aqueous solution. 3.2.1.2. Cl−. Two ring-like rigid quinoline−amide receptors were reported and their Eu3+ metallic complexes (73−Eu3+ and 74−Eu3+) were utilized as selective ensemble probes for Cl− and NO3− (Figure 53).133 73−Eu3+ and 74−Eu3+ in CH3CN have

Figure 51. Molecular structures of tripodal squaramido-based receptor 71 and folic acid.

However, some disadvantages still exist and need to be modified in the future. For example, the binding affinity strongly relies on the polarity of solvent, pH, and temperature. Any minor changes of these parameters will affect the selectivity and sensitivity of the ensemble system. In addition, the indicator needs highly charged species along with hydrogen-bonding donor and/or acceptor, and many fluorophores should be modified prior to use as indicators. 3.2. Three-Component Ensembles

In the design of three-component ensembles, the guest species (C) interacts with the indicator−receptor adduct (A−B) to give rise to a three-molecule ensemble (A−B−C). In this case, the receptor is bound together with the indicator and guest species to form the adduct (A−B-C) via a variety of weak, noncovalent interactions; this is different from the competitive displacement assay. The advantage is that the receptor need not have the exact binding affinity and selectivity to a target analyte and it is not necessary for the release of indicator from the adduct. The threecomponent ensemble system results in obvious changes in the molecular conformations, charge densities, and hydrophilic and hydrophobic environments, resulting in characteristics that are significantly different from those of the free indicator, in terms of both the emission intensity and wavelength shifts. This property can be developed for ratiometric sensing of guest that can eliminate interferences from sources such as instruments, noise, and impurities. It should be noted that many metal complexes containing a chromophore and a receptor have been reported for fluorescent sensing, in which the metal ion is not released from the complex on interaction with the guest, and a ternary “metal−ligand− guest” adduct is generally formed. The spectrum of such a ternary adduct is, in most cases, very different from that of complex itself, in terms of both emission intensity and wavelength. Zn(II), Cu(II), and Hg(II) complexes have been most effectively used for sensing of anions and biomolecules.

Figure 53. Molecular structures of receptors 73 and 74.

characteristic absorption bands peaked at 317 and 320 nm, respectively. Their corresponding emission bands are peaked at 592 and 617 nm. The luminescence of 73−Eu3+ and 74−Eu3+ with the introduction of competitive anions (i.e., F−, Cl−, Br−, I−, ClO4−, NO3−, AcO−, HSO4−, and H2PO4−) was tested. It was found that only Cl− and NO3− can induce significant emission enhancements. The proposed sensing mechanism was that Cl− or NO3− coordinated with the metal center with the formation of ternary complex ensembles that inhibits quenching by the solvent molecules. 3.2.1.3. I−. The water-soluble Zn−porphyrin complex 75 has intense absorption bands at 425 nm and two weaker absorption 7913

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Another cyanide-selective sensor was developed based on a cyano-bound metal complex. In this case, Cu2+−hydrazide complex 77, bearing rhodamine fluorophore units, was designed for the determination of CN− in Tris−HCl buffer solution (Figure 56).138 Complex 77 is weakly fluorescent because of Cu2+-induced PET quenching of the rhodamine. However, when CN− was introduced to a solution of 77, a cyano-ligated Cu2+ complex is formed, with significant fluorescence enhancement, resulting from prevention of quenching of the excited rhodamine. Negligible changes were found in the emission profile of 77 on addition of other competitive anions, i.e. F−, Cl−, Br−, I−, HPO42−, SO42−, PO43−, H2PO4−, AcO−, SCN− and N3−, even S2− and C2O42− that show strong affinity to Cu2+.139 Furthermore, CN− anions still caused in the similar fluorescence enhancements even in the presence of a miscellaneous mixture of competitive anions, indicating the present ensemble system is capable of selectively sensing CN−. Complex 77 can detect CN− within 5 min with a limit of detection down to 1.4 × 10−7 M. The next two examples are involved in the ditopic manner for the ensemble sensing of cyanide species. In this case, two Zn− porphyrin-bearing crown ether conjugates were used as ensemble complexes for NaCN sensing (Figure 57).140 The ditopic neutral receptors (78 and 79) contain a Zn−porphyrin subunit (Lewis-acidic binding site) and a crown ether subunit (Lewis-basic binding site). Both 78 and 79 showed selective color changes from red to green on addition of NaCN. The proposed mechanism is based on the ditopic binding mode, in which the Zn−porphyrin interacts with CN− and the crown ether binds with Na+. In contrast, other sodium salts are bound to receptors 78 and 79 only in a monotopic manner. Similarly, an ensemble strategy was reported using ditopic receptors based on azacrownether-capped porphyrins 80 and 81 (Figure 57).141 The ensemble complexes 80 and 81 cooperate with NaCN and KCN via ditopic binding interactions in methanol. The binding constant of receptor 80 with NaCN is 56 times higher than that of 80 with KCN, whereas 81 shows a 12fold higher affinity for KCN than for NaCN. However, receptors 80 and 81 both showed substantially weaker binding affinities for NaSCN and KSCN, presumably because of the monotopic binding mode. 3.2.1.5. ClO4−. The terpyridine (tpy) Pt(II) complex 82 was used as a colorimetric sensor for the selective sensing of ClO4− in water media, using a solid-state anion-exchange resin (Figure 58).142 Powdered samples of complex 82 were subject to a color change from yellow to red when they were exposed to ClO4−, whereas other anions, i.e., F−, Cl−, SO42−, Br−, I−, PO43−, HCO3−, and NO3−, did not induce such changes. Similar changes were found when 82 was introduced into polymer films of HYPAN80. Such polymer films displayed intense tpy-centered π−π* transition peaks at 340 nm; immersion in aqueous solutions of ClO4− produced a new absorption peak at 525 nm, as a result of metal−metal-to-ligand charge transfer (MMLCT). On immersion of the ClO4− solution in 0.5 M NH4PF6, it was restored to the original yellow. 3.2.1.6. H2PO4−. A conformation-restricted chiral receptor with two quinoline fluorophores has been developed. Its Cu2+ ensemble complex 83 shows a weak emission band centered at 398 nm, because of effective PET from the quinoline unit to Cu2+ (Figure 59).143 Of the tested anions (i.e., F−, Cl−, Br−, I−, BzO−, AcO−, HSO4−, H2PO4−, isophthalate, oxalate, and L-(+)-mandelate), only H2PO4− induced a distinct fluorescence increase. High selectivity is a consequence of the encapsulation effect of H2PO4− inside the cavity via the metal center preorganized

bands at 560 and 595 nm, respectively. These absorption bands progressively increased on introduction of I− anions (Figure 54).134 Correspondingly, Zn−porphyrin complex 75 has a weak

Figure 54. Molecular structure of he Zn−porphyrin complex 75.

emission band at 607 nm and a strong emission band at 659 nm, which give rise to moderate quenching of both bands induced by addition of I−, because of the heavy atom effect. 3.2.1.4. CN−. Metal−ligand interactions are one of the main sensing driving forces for ensembling molecular chemosensors for CN−, affording high selectivity and simplicity in water media. Many metal complexes of transition metals (e.g., Cu2+, Zn2+, Hg2+, and Co2+) have been used as colorimetric and/or fluorescent chemosensors for environmentally important species for convenient detection or imaging.135,136 Several strategies that rely on metal complex ensembles were proposed for cyanide anions; for example, Hong et al. reported the Co(II)−salen complex 76, bearing two coumarin moieties, for the selective determination of CN− (Figure 55).137 Complex 76 has a weak

Figure 55. Molecular structure of Co2+−salen complex 76 and its ensemble sensing of CN−.

fluorescence band peaked at 460 nm, as a result of PET from the coumarin to Co2+. Introduction of CN− results in distinct fluorescence enhancement, because the interaction between CN− and the metal center will inhibit the PET process. Other anions (i.e., HSO4−, N3−, F−, Br−, and H2PO4−) induce negligible fluorescence changes. A 1:2 adduct between 76 and CN− is proposed by HRMS analysis; the cyano complexes binding constants are K1 ≥ 107 M−1 and K2 = 4.0 × 105 M−1. 7914

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Figure 56. Molecular structure of rhodamine−Cu2+ complex 77 and its ensemble sensing of CN−.

Figure 59. Ensemble complex 83 for H2PO4− sensing.

as a ratiometric sensor for H2PO4−.144 Receptor 84 shows monomer emission at 396 nm and excimer emission at 485 nm, respectively (Figure 60). Addition of Zn2+ to a solution of 84

Figure 57. Ditopic receptors 78−81 for ensemble sensing of CN−.

macrocyclic receptor. Ensemble 83 interacts with H2PO4− via hydrogen bonding and electrostatic interactions. The fluorescence enhancement on coordination with H2PO4− is mainly ascribed to an increased rigidity of the formed ensemble complex. However, although PET was observed in 83, its restriction in the ensemble cannot be ruled out. The pyrenetriazole-based homooxacalix[3]arene receptor 84 and Zn2+ form a supramolecular ensemble, which can be utilized

Figure 60. Calixarene-based Zn2+ receptor 84 as ensemble complex for H2PO4− sensing.

Figure 58. Ensemble complex 82 for ClO4− sensing. 7915

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results in an increase in the monomer emission with the expense of the excimer emission. The subsequent introduction of H2PO4− into ensemble 84−Zn2+ induces a 67% excimer enhancement and monomer decrease. NMR studies showed that the metal center in 84−Zn2+ was located in the negative cavity of the N-rich triazole unit and the carbonyl group; therefore, only the N atoms in three triazole groups were involved in Zn2+ complexation in supramolecular interactions with H2PO4−, probably because of coordination of H2PO4− to the metal center. 3.2.1.7. PPi. The (Zn2+)2−(cyclen)2 complexes 85−87 were designed for sensing of P2O74− anions (Figure 61).145 On

Figure 62. P2O74− detection by ensemble complex 88−Sn(CH3)2. Figure 61. Molecular structures of ensemble complexes 85−87.

introduction of P2O74−, the emission of receptor 85 at 385 nm was completely quenched, with the formation of a 1:2 complex between 85 and P2O74−. Emission quenching is a consequence of the π−π stacking interaction between two planar benzene− triazine moieties. Receptor 86 shows a 3.4-fold emission increase at 455 nm on addition of P2O74−. Similar emission enhancement (5.5-fold) at 456 nm was also found for 87. Receptors 86 and 87 are weakly emissive, because Zn2+ is softly coordinated with the N atoms which are directly bound to the triazine moiety that enables PET from the lone electron pair to the photoexcited anthracene. Coordination with P2O74− results in an increase in interactions of the N atoms in the cyclen macrocycle with Cu2+, and this inhibits the PET process and increases the emission. In addition, phenyl phosphate produced no remarkable emission responses of the three receptors. Alizarin red 88 was utilized to synthesize the metal ensemble complex, 88−Sn(CH3)2, for selective sensing of P2O74− (Figure 62).146 88 in phosphate buffer (pH 6.7) is weakly emissive, but addition of (CH3)2SnCl2 to 88 yields the highly fluorescent 88− Sn(CH3)2 complex, with emission at 610 nm. Emission spectrum of 88−Sn(CH3)2 was investigated with the addition of anions (i.e., F−, Cl−, (CH3)OPO42−, AcO−, P2O74−, AMP, ADP, ATP, and glucose 6-phosphate). Of the tested anions, the most remarkable response was found with P2O74− to show emission quenching (90%). AcO−, F−, and Cl− induced negligible changes in the emission profiles; AMP, glucose 6-phosphate, and (CH3)OPO42− caused quenching (ca. 10%), whereas ADP and ATP produced moderate emission quenching (20% and 30%, respectively). The moderate changes observed with ADP, AMP, and ATP are relevant to the formation of a ternary complex by replacement of the water molecule coordinated with the metal center, while addition of P2O74− induces formation of a nonemissive hexacoordinated complex. 2-Hydroxy-6-cyanonaphthalene-DPA-derived mononuclear 89−Zn2+ and 89−Cu2+ complexes were designed for the sensing behavior for P2O74− (Figure 63).147 A solution of the complex 89−Zn2+ in HEPES buffer produced a 17-fold emission enhancement at 435 nm on addition of P2O74−. Other anions

Figure 63. Molecular structures of ligand 89 and its complexes with Zn2+ or Cu2+.

(i.e., ATP, ADP, PO43−, AcO−, HPO42−, HSO4−, F−, and Cl−) caused negligible emission responses. Similarly, a solution of 89− Cu2+ also gave a 24-fold emission enhancement upon interaction with P2O74−. It is selective for P2O74− over other anions tested. The proposed mechanism for emission enhancement on addition of P2O74− was probably due to the direct coordination of the OH group (or in alkoxy form) in 89 with the metal center, which plays a crucial role for the sensing process. Complex 90−Cd2+ was used for recognition of polyphosphate anions with the formation of a 1:1:1 ternary ensemble complex (Figure 64).148 The addition of ATP to a solution of 90−Cd2+ in HEPES buffer at pH 7.4 produced an increased emission band at 397 nm with the expense of emission at 497 nm, providing a ratiometric emission signal for the sensing of ATP. Of the other anions tested, only P2O74− produced a similar ratiometric emission change of the complex 90−Cd2+. Excesses citrate and oxalate could only lead to a substantial emission change of 90− Cd2+, whereas ADP, AMP, F−, Cl−, Br−, I−, H2PO4−, HPO42−, HSO4−, NO3−, and AcO− induce negligible fluorescence changes. An ensemble complex 91−2Zn2+, composed of tetraphenylethylene and dinuclear Zn2+, was reported for the sensing of P2O74− (Figure 65).149 The 91−2Zn2+ ensemble is weakly emissive at 472 nm, whereas distinct emission enhancement was found on addition of P2O74−; this was ascribed to the formation of a three-component adduct of 91−2Zn2+ with P2O74−. Emission enhancement is the consequence of the restricted 7916

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coordination weakens Zn2+ interactions with the tertiary amine, restoring PET to some extent. A binuclear system, 93−Zn2+, was used as an ensemble for the ratiometric sensing of P2O74− in aqueous solution (Figure 67).151

Figure 64. Ensemble complex 90−Cd2+ for ATP sensing.

Figure 67. Molecular structures of complexes 93−2Zn2+ and 94−Zn2+.

Introduction of P2O74− into 93−2Zn2+ in HEPES (pH 7.4) results in a red shift from 420 to 518 nm in its emission band, with formation of a three-component adduct. Negligible changes were observed in the presence of other anions (i.e., HCO3−, H2PO4−, Cl−, F−, AcO−, ATP, citrate, and HPO42−). An optimized molecular model showed that the two DPA−Zn2+ groups in 93− 2Zn2+ were located at suitable distances to produce a strong binding cavity for the selective recognition of P2O74− over similar anions. Ensemble 93−2Zn2+ was also utilized as a rapid and effective method for detecting P2O74− released from deoxynucleotide triphosphates in polymerase chain reactions. A terpyridine-based complex, 94−Zn2+, bearing a coumarin moiety, was designed for the sensing of various biologically important phosphates, i.e., AMP, ADP, and PPi in mixed aqueous media (Figure 67).152 The complex 94−Zn2+ displayed three absorption bands at 286, 325, and 347 nm, and two emission bands peaked at 381 and 467 nm, respectively. Addition of P2O74− to an aqueous solution of 94−Zn2+ produced significant absorption changes and fluorescence enhancement, with a blue shift. AMP and ADP also produced similar spectral changes to 94−Zn2+. However, ATP, CTP, F−, Cl−, Br−, I−, NO3−, AcO−, BzO−, SO42−, HSO4−, and H2PO4− induced negligible spectral changes. In all cases, the complex 94−Zn2+ and the tested species (P2O74−, AMP, and ADP) form 1:1 complexes. Receptor DPA-appended phenoxide was coordinated to Zn2+ ions to form a dinuclear zinc complex, which is a good ensemble candidate for the selective sensing of PPi. The complex 95− 2Zn2+ was designed as a selectively colorimetric sensor for PPi in aqueous media, on the basis of the synergistic effect of hydrogen bonding and metal coordination interactions (Figure 68).153 The binding affinity was remarkably improved using four amide hydrogen bonding donors, which are well preorganized to interact with PPi bound to two Zn2+ ions. The association constant between 95−2Zn2+ and PPi was calculated to be 5.39 × 1010 M−1, indicating a very strong binding affinity to PPi in water media. A Zn2+ complex composed of acridine and two DPA ligands (96−2Zn2+) shows different spectral responses to PPi and phosphate in aqueous solution (Figure 69).154 Various anions were tested, and 96−2Zn2+ showed selective chelation-enhanced fluorescence (CHEF) with phosphate and selective chelationenhanced fluorescence quenching effect (CHEQ) with PPi in

Figure 65. Molecular structure of complex 91−2Zn2+.

intramolecular rotation of the phenyl rings in 91. AMP and ATP also induced less emission enhancements than that observed for P2O74−, but other anions such as F−, Cl−, Br−, AcO−, I−, H2PO4−, HCO3−, N3−, NO3−, and SO42− did not induce distinct emission changes. Coumarin-based DPA receptor was reported, and its complex 92−2Zn2+ was acted as a fluorescent ensemble for sensing of P2O74− (Figure 66).150 Receptor 92 is weakly emissive, whereas a

Figure 66. Molecular structure of complex 92−2Zn2+.

HEPES buffer solution of 92−2Zn2+ at pH 7.4 has an intense emission band peaked at 511 nm, because the PET process from the tertiary amine to coumarin is effectively inhibited upon interaction with Zn2+. Of all the examined anions (i.e., ADP, AMP, cAMP, P2O74−, Br−, Cl−, ClO4−, H2PO4−, HCO3−, N3−, AcO−, PO43−, and SO42−), only P2O74− quenched the emission intensity of 92−2Zn2+ to some extent. Emission quenching is due to preferential coordination of P2O74− with two Zn2+ ions in 92− 2Zn2+ by formation of a three-component ensemble. This 7917

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produces an intense excimer band peaked at 490 nm only in the presence of PPi, which was ascribed to the formation of a unique 2 + 2 type excimer via π−π interactions. It can selectively detect PPi, ATP, or phosphate, and the association constant for PPi was estimated to be 4.1 × 105 M−1. Zn2+−cyclen complexes 98 and 99 can be utilized as ensembles to interact with phosphate via a reversible coordination, resulting in ternary complexes with thymine- and uracil-based nucleotides (Figure 71).156 A buffered solution of 98 Figure 68. Molecular structure of complex 95−2Zn2+.

Figure 69. Molecular structure of complex 96−2Zn2+. Figure 71. Molecular structures of complexes 98 and 99.

100% aqueous solutions. However, other competitive anions, i.e., HSO4−, CH3CO2−, I−, Br−, Cl−, and F−, did not cause distinct changes in the fluorescence. The association constants of the three-component ensemble for PPi and phosphate were 4.85 × 107 and 9.36 × 104 M−1, respectively. The authors ascribed the large CHEF effect with phosphate to additional hydrogen bonding interactions between the acridine N atom and phosphate hydroxy group. Among different ensemble sensing systems for ppi, only a few fluorescent chemosensors display a good selectivity for PPi over ATP or phosphate in aqueous solution. A naphthalimide−DPA and Zn2+ complex, i.e., 97, was used as a complex ensemble for selective sensing of PPi in 100% water media (Figure 70).155 97

displayed an intense monomer emission band at 400 nm. The addition of P2O74−, TTP, UDP, and UTP produced a new excimer peak at 500 nm with the expense of monomer emission. The formation of a three-component ensemble adduct produced the two pyrenes being closer to the two receptor molecules. Fructose 1,6-diphosphate only produced a 5-fold increase in the excimer profile, while other phosphate species including HPO4−, AMP, ATP, CDP, GDP, CMP, GMP, GTP, ITP, IMP, IDP, and UMP did not produced marked emission changes for 98. For 99, under the same test conditions, UDP, UTP, IDP, and ITP led to obvious emission enhancement of the pyrene excimer. The recognition of ATP from various NTPs, i.e., GTP, CTP, UTP, and TTP, is difficult, but important. Two pyrene-based DPA−Zn2+ complexes, 100 and 101, were used as nucleoside polyphosphate receptors for selective detection of ATP and ADP (Figure 72).157 A pyrene−adenine−pyrene sandwich-like

Figure 72. Molecular structures of complexes 100 and 101.

ensemble was formed in the case of complex 100 with ATP or ADP, leading to increased monomer fluorescence. However, other NTPs, i.e., CTP, GTP, UTP, and TTP, did not form sandwich-like ensembles, resulting in modulation of the monomer−excimer emission. The different binding modes of various nucleosides with the pyrene−pyrene ensemble 100 enable selective determinations of ATP and ADP. Introduction of ATP to a solution of 101 produced a strong excimer emission, whereas ADP only led to a distinct monomer increase, indicating

Figure 70. Molecular structure of complex 97. 7918

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3.2.1.8. Other Phosphate-Related Species, Inositol 1,4,5Trisphosphate. FRET-based receptors 104 and 105 were coordinated with Zn2+ to form ensembles, providing a ratiometric emission signal for determination of nucleoside polyphosphates (Figure 75).160 Receptor 104 shows a dual

that the complex 101 enables efficient discrimination between ATP and ADP. The functionalized BODIPY-based receptor 102 was used for selective sensing of Cd2+ and P2O74− (Figure 73).158 Receptor

Figure 73. Molecular structure of receptor 102.

102 shows two absorption bands peaked at 614 and 665 nm in Tris buffer solution. The addition of Cd2+ to a solution of 102 led to gradual decrease at 665 nm and produced two blue-shifted bands, at 580 and 627 nm, whereas the corresponding emission centered at 638 nm increased significantly. Receptor 102 and Cd2+ can form an ensemble complex with a 1:4 ratio. The addition of PPi to the complex 102−Cd2+ diminished the absorbance, with a distinct red shift and a decreased fluorescence intensity at 637 nm. Negligible changes in its fluorescence intensity were found with other anions (i.e., F−, Cl−, Br−, I−, HPO4−, HSO4−, NO3−, HCO3−, CF3SO3−, AcO−, SO42−, ATP, and ADP), indicating selective detection of PPi. Receptor 103 interacts with the fluorescent indicator (alizarin red S, ARS) to form an ensemble complex in buffered solution at pH 7.4. The resultant ensemble shows two emission bands peaked at 554 and 619 nm, respectively. Receptor 103 provides two binding sites for sensing; both metal center and boronic acid units are used to capture the phosphate species (Figure 74).159

Figure 75. Molecular structures of receptors 104 and 105.

emission signal, resulting from FRET from the coumarin at 454 nm (donor) to the xanthene at 525 nm (acceptor). Addition of Zn2+ induces a significant fluorescence increase at 454 nm with the gradual expense of acceptor emission at 525 nm, because the resultant 104−Zn2+ destroys the conjugated structure of the xanthene unit and decreases FRET. The ensemble 104−Zn2+ was further utilized for ratiometric sensing of nucleoside polyphosphates. P2O74−, ADP, ATP, GTP, CTP, and UDP induced intense quenching at 454 nm and a concomitant increase at 525 nm, as a result of recovery of FRET to give a three-component ensemble between the nucleotide and 104− Zn2+. However, AMP, c-AMP, ADP-Glu, c-GMP, UDP-Gal, AcO−, HPO4−, SO42−, NO3−, and HCO3− induced negligible emission changes for 104−Zn2+. Similar sensing results were found with the receptor 105. Both 104−Zn2+ and 105−Zn2+ were utilized for real-time determination of enzyme-activated sensing and for ratiometric visualization detection of nucleoside polyphosphate in live cells. A Zn2+−glucose-based ensemble complex containing a naphthylimino conjugate was reported for the sensing of phosphates species, including DNA (Figure 76).161 The addition of Zn2+ to an aqueous solution of 106 produced distinct enhancement in the emission intensity, with a limit of detection of 2.4 mM. In situ-generated 106−Zn2+ was used as an ensemble to test 16 different anions. It was found that only phosphatebased species could quench the emission of 106−Zn2+ with the quenching order as follows, DNA > (Bu4N)H2PO4 > ATP > NaH2PO4 > ADP ∼ Na2HPO4 > AMP.

Figure 74. Molecular structure of receptor 103.

Addition of a phosphosugar (ribose 5-phosphate) to a solution of 103−ARS results in concomitant diminishes in both fluorescence bands, because they can bind two coordination sites. However, on introduction of a phosphate-free sugar (i.e., ribose or fructose), only a slight emission enhancement at 619 nm was found, as a result of partial indicator replacement from the ensemble, leading to different signals. In addition, introduction of P2O74− to 103−ARS increases the emission intensity of both bands. 7919

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Figure 78. Molecular structure of receptor 108. 2+

Figure 76. Molecular structure of 106−Zn .

The biscyclen tweezer receptor 107 and Zn2+ form a complex ensemble 107−2Zn2+ that senses InsP3 (Figure 77).162 Two Zn(II)/cyclen groups are preorganized into a binding cleft to connect with a rigid acridine backbone. Click chemistry was used to produce two triazole moieties that facilitate structural rigidity and recognition. Receptor 107 displays a maximum absorption band peaked at 355 nm and an emission band at 440 nm. When various phosphates were added to a solution of 107−2Zn2+, a decrease (20−25%) in the emission signal was observed. The order of the binding affinities was barium cyanoethyl phosphate > InsP3 > trisodium D-fructose-1,6-bisphosphate > sodium pyrophosphate > dihydrogen phosphate. In addition, phosphorylated guests with more phosphate units (i.e., InsP3) produced greater fluorescence changes than did analytes with a single phosphate unit (i.e., dihydrogen phosphate). 3.2.1.9. Oxalate. Receptor 108, based on alkyne-conjugated carboxamidoquinolines and Zn2+, forms an ensemble complex with a ratiometric sensing of oxalate in aqueous solution and living cells.163 On addition of Zn2+, receptor 108 in ethanol− H2O solution shows a remarkable fluorescent decrease at 470 nm and an enhancement at 512 nm as a result of a 1:2 complex 108− 2Zn2+ (Figure 78). The addition of oxalate produces an 80% emission decrease and a 20 nm blue shift, with a limit of detection down to 3.0 μM. It was also found that 108−2Zn2+ and oxalate can form a three-component ensemble. However, other monoand dicarboxylates (i.e., AcO−, formate, propionate, malonate, butanoate, succinate, sebacate, adipate, o-phthalate, and pphthalate) and phosphates (i.e., PO43−, HPO42−, and H2PO4−) only induced fluorescence quenching of about 20% for 108− 2Zn2+. This ensemble adduct was also utilized for biological imaging of oxalate in HeLa cells. 3.2.2. Sensing of Neutral Molecules. An azamacrocyclic− Cu2+ complex ensemble, 109−Cu2+, was used as a fluorescent probe for H2S (Figure 79).164 Complex 109−Cu2+ in HEPES buffer at pH 7.4 displayed an absorption band peaked at 491 nm

Figure 79. Molecular structures of complex 109−Cu2+ and its diacetylated derivative 110−Cu2+.

and a fluorescence band peaked at 516 nm. The addition of H2S to a solution of 109−Cu2+ immediately produced a considerable 50-fold fluorescence enhancement, whereas negligible fluorescence variations were found on introduction of excess GSH. The complex 109−Cu2+ also displayed high selectivity for H2S over other thiols (i.e., Cys, Hcy, DTT, 2-ME, SCN−, SO32−, S2O32−, and sodium ascorbate) and other reactive oxygen or nitrogen species (i.e., H2O2, •OH, ONOO−, ClO−, O2−, 1O2, and •NO). The complex 109−Cu2+ is highly hydrophilic and membrane impermeable; therefore, the diacetylated derivative 110−Cu2+ was prepared to enhance its cell permeability. On addition of Na2S, HeLa cells incubated with 110−Cu2+ produced a substantial intracellular fluorescence enhancement, with no cytotoxicity, even at high concentrations. 3.2.3. Biomolecule Sensing. 3.2.3.1. Sensing of Cys. The rhodamine−Au+ complex 111 was used for fluorescent determination of mercapto amino acids (Figure 80).165 A solution of 111 in H2O−methanol (99:1 v/v) is weakly emissive at 560 nm; its intensity increases on addition of Cys and Hcy, whereas other amino acids examined including GSH, Glu, Asp, Met, Pro, Leu, Try, Phe, Gly, Asn, Ser, Gln, Lys, Tyr, His, Ala, Arg, Thr, and Val did not produce obvious emission responses of

Figure 77. Molecular structure of receptors 107 and its Zn2+ complex. 7920

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Figure 80. Formation of ensemble complex between rhodamine−Au+ 111 and Cys.

Figure 81. Molecular structures of calixarene-based receptor 112 and its Zn2+ complex 112−Zn2+.

111. Emission enhancement is ascribed to formation of a threecomponent ensemble between 111 and Cys. The triazole-linked calix[4]arene conjugate 112−Zn2+ was used as an ensemble complex for the selective recognition of Cys in proteins (Figure 81).166 Receptor 112 shows fluorescence enhancement on addition of Zn2+, as a result of PET inhibition. Ensemble 112−Zn2+ in HEPES buffer at pH 7.4 shows an emission band peaked at 454 nm, with a gradual decrease in the intensity on titration with Cys; this is caused by replacement of Zn2+ in 112−Zn2+. Negligible fluorescence changes were found with other competitive mercapto biomolecules (i.e., mercaptopropionic acid, Cys, Hcy, and GSH). 112−Zn2+ was also applied for the determination of Cys in blood serum samples, with a limit of detection down to 846 ppb. 3.2.3.2. Sensing of AMP, ADP, and ATP. The 113−Cu2+ complex was used as an ensemble for the sensing of AMP, ATP, and ADP in DMSO−H2O solution (Figure 82).167 AMP addition resulted in a distinct shift in the absorbance in the UV−vis spectrum from 325 to 413 nm. ADP and ATP produced similar spectral responses, resulting from the interaction of 113 with nucleotides to form a three-component ensemble via both coordination between Cu2+ and phosphate groups, and π−π stacking between adenine groups with seven-membered amide cycles. The order of the binding constants of the nucleotides with 113 was AMP > ADP > ATP; this is because the shorter chain of AMP matches well with receptor 113. As a result, the present ensemble system can successfully distinguish AMP from ADP and ATP.

Figure 82. Molecular structure of complex 113−Cu2+.

A cyclam-based colorimetric complex, 114−Zn2+, and its pseudorotaxane adduct with α-cyclodextrin (α-CD-115) were reported to recognize ATP arisen from in situ metabolism in HEPES buffer (pH 7.2) solution and in living organisms (Figure 83).168 On binding with ATP, 114 displayed a 40 nm red shift in its absorption spectrum. CTP caused a 9 nm red shift, but other competitive species, i.e., ADP, AMP, P2O74−, H2PO4−, SO42−, F−, Cl−, Br−, I−, AcO−, CN−, SCN−, NO3−, and NO2−, caused less significant changes. ATP was found to display the highest affinity for 114 among various competitive anions. The α-CD inclusion complex (α-CD-114) gave a more intensive color change on binding to ATP. α-CD-114 was also successfully used for the 7921

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Figure 83. Molecular structures of complexs 114−Zn2+ and 115−Zn2+.

PO43−. Among these anions, ATP and ADP caused the largest emission increases at 535 nm and gave detection concentrations at the micromolar level. The proposed mechanism involves binding of ATP (or ADP) with Zn2+−DPA, which diminishes Zn2+−NH interactions, and results in significantly increased emission. An ion-sensitive fluorescent unit was incorporated into a hydrophilic copolymer, poly(HEMA-co-DCPDP) to give 117 (Figure 85). A polymer ensemble was formed with Cu2+ ions, and can be developed as a sensing film for the determination of PPi.171 Copolymer 117 gave rise to an intense emission peak at 605 nm, and complete fluorescence quenching was found on addition of Cu2+, because of formation of the polymer ensemble complex 117−Cu2+. The formed complex produced PET from the fluorophore to Cu2+, resulting in emission quenching. The addition of P2O74− produced a 4.8-fold fluorescence enhancement, because of electrostatic interactions between P2O74− and the Cu2+ center in 117−Cu2+; this suppressed PET. However, the other tested anions (F−, Cl−, Br−, H2PO4−, I−, HCO3−, AcO−, HSO4−, NO3−, HPO42−, SO42−, CO32−, AMP, ADP, ATP, and PO43−) did not induce distinct emission enhancements. A thin film of 117−Cu2+ on quartz slides displayed a sensitive response to P2O74−, with a turn-on fluorescence enhancement. Shortly, the formation of a three-component ensemble (A− B−C) undergoes two consecutive equilibria, in which the third component C (guest species) is not required to be capable of replacing the component A or B but should be bound together to A and B. That is to say, both A and B have a suitable affinity to C, that is distinctly different from the two-component ensemble in which B has a stronger affinity with C to replace A. As such, the sensing system based on the design of three-component ensemble gives rise to drastically different emission changes with the indicator not only in the intensity but also in the wavelength, which can be utilized as a ratiometric sensor. Following this line, a variety of three-component ensemble systems emerged in recent years for a variety of target analytes, including anions (i.e., F−, Cl−, I−, CN−, ClO4−, H2PO4−, pyrophosphate, InsP3, and oxalate) and biomolecules (ATP, ADP, AMP, GMP, Cys, Hcy, GSH, etc.) have been reviewed. The breadth of examples above enables us to believe that it is a convenient and efficient strategy to design optical sensors for different requirements. However, it is involved in two consecutive balances and is necessary to further understand the supramolecular interactions between A−B, A−C, B−C, and A− B−C. In addition, the three-component ensemble cannot be reversibly reusable due to its own property.

sensing of ATP in live Saccharomyces cerevisiae cells under physiological conditions. The ensemble complex 115−Zn2+ shows an intense excimer emission at 520 nm, because of the spatial proximity of two anthracene units (Figure 83).169 The addition of ATP produced a decrease in the excimer emission and a simultaneous 13.7-fold increase in the monomer emission at 420 nm. ADP and P2O74− also produced similar spectral behaviors, but with lower enhancements, whereas AMP, HPO42−, and AcO− did not induce any obvious emission changes. The proposed mechanisms for such changes are based on coordination of ATP with Zn2+ and with the secondary amines, which will repulse both anthracene fluorophores and reduce their π−π interactions. 115−Zn2+ shows clearly different fluorescence responses to PPi and ATP in water, indicating that the ensemble 115−Zn2+ can be applied as a selectively fluorescent chemosensor for PPi and ATP. A naphthalimide−DPA-based receptor was bound to Zn2+ to form a complex ensemble, 116−Zn2+, which is water-soluble and can selectively sense ATP (Figure 84).170 When Zn2+ is added to

Figure 84. Molecular structure of complex 116−Zn2+.

a buffer solution of receptor 116, it gives rise to a hypsochromic shift from 450 to 441 nm in the absorption spectrum. Correspondingly, the emission spectrum of 116 at 535 nm is increased, because of suppression of PET from the tertiary amine to the fluorophore via Zn2+ complexation. The resultant ensemble complex 116−Zn2+ was tested in the presence of various anions, i.e., ADP, ATP, citrate, P2O74−, GTP, NO3−, and 7922

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Figure 85. Hydrophilic copolymer-based fluorescent receptor 117 and its Cu2+ adduct for ppi sensing.

3.3. Multicomponent Ensembles

of intramolecular free rotation in aggregates. This means that the unrestricted intramolecular rotation in AIE molecules can suppress nonradiative decay in the excited states; therefore, they are nonfluorescent. However, intramolecular rotation is hindered in their aggregated forms, and emissions are accordingly greatly increased. Based on their unusual emission properties, AIE-active molecules have been successfully used to develop selective bio/chemosensors. Such AIE behavior can also be seen in multicomponent ensemble systems. Appropriate structural modification of AIE-active molecules enables their aggregation to be mediated by guest molecules via electrostatic, coordinationdriven, steric hindrance, hydrophobic, and hydrophilic interactions and the influence of polarity and viscosity. Accordingly, various AIE-based fluorescent bio/chemosensors with appropriate functional groups have been designed for various guest species, including cations (Hg2+ and Ag+), anions (CN−), gases and explosives (CO2, TNT, and picric acid), and biomolecules (proteins, ATP, heparin, and DNA), as well as assays for nuclease activities. Because of their different existing states of the single molecule and aggregate, enormous photophysical changes can be observed upon aggregation or deaggregation. Accordingly, AIEbased sensors generally have more sensitivity to analytes. In this section, a number of AIE-based sensors based on multicomponent ensemble systems have been summarized. 3.3.1. Cation Sensing. Tetraphenylethylene shows a good AIE activity, and its derivatives 121 and 122 were designed as a multicomponent ensemble to display fluorescence turn-on for Ag+ and Hg2+, respectively (Figure 87).173 Compound 121 bears two adenine moieties as metal receptors for selective binding with Ag+ ions. The addition of Ag+ ions to 121 causes aggregation in aqueous solution, which inhibits the intramolecular free rotation of tetraphenylethylene, thus resulting in significant fluorescence enhancement. Similar results are found when 122 bearing two thymine moieties is utilized to detect Hg2+ with negligible interferences from competitive ions. The TPE derivative 123 and aptamer DNA form an ensemble adduct, which was reported as a label-free fluorescent sensor for alternate detection of Hg2+ and GSH (Figure 88).174 This muticomponent ensemble is based on a combinational use of the AIE effect and conformational variations in the aptamer DNA on reversible interaction with substrates, giving a simple, convenient, and rapid method for alternating detection of Hg2+ and GSH. The positive TPE derivative 123 is water-soluble and does not form aggregates in water media; therefore, it is non-

Self-assembly of organic molecules to form organized aggregates provides an efficient strategy for easily producing and optimizing fluorescent chemosensors. Aggregation via supramolecular selfassembly under appropriate conditions forms multicomponent ensemble systems. Multiple fluorescent or potentially fluorescent molecules can form aggregates induced by guest molecules; the optical properties change significantly, because of aggregateinduced fluorescence enhancement. Alternatively, multiple fluorescent or potentially fluorescent molecules can form aggregates by supramolecular self-assembly. The interactions between the aggregate and the guest species deaggregate the sensing system, and the aggregated-induced fluorescence decreases accordingly. Generally, the aggregates involved in this system induce enormous changes in the absorption and/or emission spectra via interactions with guest species because of the distinct difference between the single molecule and aggregate. Aggregation- or deaggregation-related fluorescence changes, which can be caused by guest-induced supramolecular binding, are summarized in this section as multicomponent ensembles. Generally, the emission of an organic fluorophore is quenched if it exists in its aggregated form, and this restricts the applications of many dyes in organic light-emitting diodes (OLED) and chemical and biological sensing. In contrast, some organic molecules are almost nonfluorescent in solutions but become strongly fluorescent on aggregation. This unusual and abnormal emission behavior was noticed by Tang et al. in 2001, from a solution of 1-methyl-1,2,3,4,5-pentaphenylsilole (118), and they named it AIE.172 Various AIE-active fluorophores, including tetraphenylethene (119), diphenyldibenzofulvene (120), substituted olefins, and pyran derivatives, have been reported (Figure 86).33,34 Tang and coauthors ascribed AIE to inhibition

Figure 86. Structures of AIE-active molecules 118−120. 7923

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Figure 87. Ag+- or Hg2+-induced AIE effect and molecular structures of tetraphenylethylene derivatives 121 and 122.

3.3.2. Anion Sensing. Silole derivative 124, which contains a positively charged ammonium salt, shows good AIE. A combination of amphiphilic silole 124 and hydrophobic compound 125 produces an intermolecular ensemble system, which can be used as a fluorescence sensor with turn-on response to cyanide in aqueous solution, as shown in Figure 89.175 Compound 125 containing an −NHCOCF3 unit is strongly hydrophobic due to its long alkyl chain. The addition of CN− to 125 results in a CN−-induced nucleophilic addition, yielding an amphiphilic species. Such species induce the aggregation of amphiphilic 124 in aqueous solution via electrostatic and hydrophobic interactions. As a result, a mixture of 124 and 125 shows very weak emission, which increases on addition of cyanide, whereas other anions (i.e., AcO−, Br−, Cl−, F−, H2PO4−, HSO4−, N3−, and NO3−) induce negligible fluorescence changes. The limit of detection for cyanide was estimated to be 7.74 mM, based on this ensemble system, which meets the concentration requirement for cyanide in the blood of poisoning victims. The same group also used the silole derivative 124 in an ensemble system for selective sensing of ATP over ADP, AMP, and other adenosines.176 It was also found that the hydrolysis targets (AMP or ADP) do not disturb ATP determination. The selective identification of ATP was used in situ to monitor ATP consumption in some biologically important processes. ATP hydrolysis induced by calf intestinal alkaline phosphatase has been tested based on gradual fluorescence increases of 124. 3.3.3. Sensing of Neutral Molecules. Hexaphenylsilole 126 is almost nonfluorescent in solution but highly fluorescent when aggregated.177 This is ascribed to its good AIE effect; this arises from the propeller-like molecular conformation of 126, which restricts intramolecular rotation of the hexaphenyl rotors in the nonaggregated states. Based on the AIE phenomenon, a convenient assay for the quantitative sensing of CO2 was constructed, as shown in Figure 90.178 In this ensemble strategy, a carbamate ionic liquid (CIL) is formed by bubbling CO2 gas into a solution of dipropylamine. The formed CIL increases the polarity and viscosity of the solution, which inhibits free rotation of the AIE-active molecule 126 (Figure 90). As a result, the

Figure 88. Sensing mechanism of TPE derivative 123 for reversible detection of Hg2+ and GSH.

fluorescent. When the aptamer ssDNA was added to 123, fluorescence enhancements were observed, as a result of electrostatic interactions. Subsequent addition of Hg2+ ions caused the aptamer ssDNA to undergo a conformational change, giving rise to a hairpin-like conformation, because of the specific interactions between the aptamer DNA and Hg2+. The formed multicomponent ensemble adduct 123/Hg2+−aptamer ssDNA produced a pronounced fluorescence enhancement, whereas other metal ions cannot induce such fluorescence changes, because of their nonspecific interactions; this can be used for selective sensing of Hg2+. If the thiol-containing biomolecule GSH is introduced into the ensemble complex, it leads to a displacement assay of Hg2+ from the T−Hg2+−T complex and destroys the compact ensemble of the 123/Hg2+−ssDNA complex. The decreased fluorescence can be used as the basis of sensitive determination of GSH. 7924

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Figure 89. Multicomponent ensemble system, based on combination of AIE-active silole 124 and hydrophobic 125, for CN− sensing.

qualification, which suffer from the interference from moisture and CO.179 The nitro explosive 2,4,6-trinitrophenol (TNP) is widely used in products such as fireworks, dyes, and matches, and the direct release of TNP into the environment produces serious contamination of soil and aquatic systems.180,181 The development of efficient TNP-selective sensors is therefore highly desirable. Ir(III) complexes 127 and 128, which exhibit phosphorescent AIE properties, have been used for the selective sensing of nitro explosives.182 The complex 127 is nonemissive in acetone but exhibits intense emission in the aggregated state. The quantum yields of 127 in acetone and the solid state are about 0% and 15%, respectively, with a lifetime of ∼0.20 μs. Complex 127 in acetone is faintly emissive, and the phosphorus emission is significantly enhanced (60-fold) with increasing water fraction up to 90%, indicating that 127 displays a clear AIE effect. Nanoaggregates of 127 as ensembles in aqueous solution can sense trace quantities of nitro explosives at concentrations of 0.5 ppm, with distinct emissive quenching. Such a quenching process can be ascribed to PET from phosphorus in 127 to the electrondeficient TNP. A structurally similar complex, 128, was used to study this sensing mechanism (Figure 91).

Figure 90. Formation of CIL via interaction of dipropylamine and absorbed CO2 gas, induced by aggregation of hexaphenylsilole 126.

fluorescence enhancement of the ensemble solution is found as the absorbed volume of CO2 increases, enabling a quantitative assay of CO2. This method is superior to other methods for CO2

Figure 91. Molecular structures of Ir complexes 127 and 128. 7925

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3.3.4. Biomolecule Sensing. The TPE derivatives 129 and 130, which contain ammonium units, have been used to form aggregates as multicomponent ensembles to determine biomolecules, i.e., calf thymus (ct) DNA and bovine serum albumin (BSA) (Figure 92).183,184 Compounds 129 and 130 have similar

Figure 93. Conversion of 133 to deacetoxylated product 134, using lysosomal esterase. Figure 92. Molecular structures of tetraphenylethene derivatives 129− 132.

aggregation at high concentrations, which provides the advantages of antioxidant and antibleaching effects, and the disadvantage of higher sensor concentration.14d

molecular structures; they each contain two ammonium groups, but the alkyl chain lengths differ. They are weakly emissive but become strongly emissive on addition of negative biomolecules. Both 129 and 130 can be utilized for the detection of ct DNA and BSA, but 130 produces a more remarkable result. This result implies that the sensitivity can be controlled by structural modification of AIE molecules. The same group also developed a four positively charged TPE derivative, 131, using as a fluorescence label free probe to study DNA conformations. Compound 131 can be applied to monitor the folding process of guanine-rich DNA strands and screen G-quadruplex stabilizers.185 The negatively charged TPE derivative 132 was developed to explore the unfolding of BSA protein on addition of surfactants.186 The potentially AIE-active molecule 133 was reported as a fluorescence turn-on sensor for in situ imaging of the activity of lysosomal esterase.187 The salicyladazine fluorogen in 133 is attached to two lysosome-target morpholine units and esterasereactive acetoxyl groups and is poorly fluorescent because of the destruction of hydrogen bonding and the free rotation of the nitrogen−nitrogen bond. The deacetoxylated product 134 is weakly fluorescent at 532 nm in THF, but its fluorescence progressively increases on gradual addition of an aqueous fraction, because of its poor water solubility and aggregation in aqueous solution. It was found that 134 displays the dual characteristics of both AIE and ESIPT. The masked AIE-active 133 was applied for monitoring of the activity of lysosomal esterase in situ and tracking lysosomal in living cells; this is very important for the clinical diagnosis of Wolman’s disease, induced by a deficiency of lysosomal esterase (Figure 93). To summarize, AIE-based sensors, because of their specific molecular structures, form aggregates that can be recognized as multicomponent ensembles and are widely used as bio/ chemosensors for a variety of target species. Many AIE-based systems are designed with positive charges and aggregate via a variety of supramolecular interactions to form an ensemble, based on factors such as electrostatic and hydrophobic interactions. Many negatively charged biomolecules can induce aggregation, which inhibits highly selective sensing of specific biomolecules. The selectivity of AIE sensors need to be further improved. It should be noted that the AIE effect requires

3.4. Organic−Inorganic Hybrid Ensembles

This section describes the use of functionalized preorganized nanomaterials as organic−inorganic hybrid ensemble in the sensing of various guest species. Inorganic and organic components combined in unique nanocomposites give rise to limitless possibilities to open a versatile access for chemosensors/ biosensors.188 In most cases, the combinational use of these systems with a supramolecular ensemble results in new probing strategies that are very difficult to realize based on simple organicmolecule-based systems. Addition of a guest species to a solution of a hybrid ensemble results in aggregation, which significantly changes the optical features. Intermolecular preorganization into a supramolecular ensemble might lead to new properties and functions, thus possibly producing important applications. The use of nanomaterial supports for sensing has received considerable attention in recent years, and a large number of organic−inorganic hybrid materials have been developed and reviewed for the sensing of various substrates.189 In this section, only a couple of representative examples based on Au, Ag, and Si nanoparticles and quantum dots have been summarized. 3.4.1. Au, Ag, and Si NP-Based Ensembles. Au-functionalized NPs (AuNPs) and organic molecules can form ensemble systems via supramolecular interactions. AuNPs have several interesting properties, for example, well-dispersed AuNPs are red but become blue when aggregated. This aggregation-induced color change of AuNPs provides a number of colorimetric sensors for various guest species. AuNP-based colorimetric sensors display high sensitivity and have been applied for the determination of a variety of substances, including DNA and proteins, because of their extremely high extinction coefficients.190,191 AuNPs have been used to detect cyanide, because cyanide can etch Au to produce a water-soluble metal−cyanide complex. An ensemble system consisting of polysorbate 40-stabilized AuNPs (135−AuNPs) was used for the sensitive and selective sensing of CN− (Figure 94).192 Compound 135 is a neutral surfactant and can stabilize citrate-modified AuNPs from high ionic strength. When CN− is added to 135−AuNPs, it causes the aggregate of AuCN(s) on the surfaces and a soluble complex Au(CN)2− in water media, producing a color change from red to violet, with a 7926

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Figure 94. Schematic diagram of positively charged cysteaminestabilized 135-AuNPs for CN− detection.

Figure 96. Schematic diagram of bifunctional Au−Fe3O4 NPs for CN− sensing.

limit of detection as low as 5.0 × 10−7 mol L−1. Other metal cations and anions exhibited negligible effects on CN− detection. A colorimetric ensemble system consisting of ATP-stabilized AuNPs and a Cu2+−phenanthroline complex 136 as a receptor was applied for the colorimetric detection of CN− in water media (Figure 95).193 The addition of CN− to a solution of Cu2+− phenanthroline complex 136 and ATP-stabilized AuNPs induces a release of the phenanthroline ligand from the complex. The resultant free phenanthroline causes the ATP-stabilized AuNPs to aggregate, producing a visual change from red to blue of the AuNPs solution. The ensemble system can detect cyanide in aqueous solution at physiological pH and enables a quantitative assay of cyanide at concentrations as low as 10−5 M. Bifunctional Au−Fe3O4 NPs combined with rhodamine B to form inorganic−organic hybrid materials were reported as a turnon fluorescent sensor for the selective and sensitive determination of CN− (Figure 96).194 Rhodamine dye gives an intense emission band peaked at 577 nm in PBS at pH 10.5. The addition of Au−Fe3O4 to rhodamine induces distinct fluorescence quenching, because of the strong overlap between the absorption band of the Au−Fe3O4 NPs and the emission band of rhodamine. The addition of CN− to the Au−Fe3O4−rhodamine ensemble causes dissolution of Au from the Au−Fe3O4 NPs, with formation of Au(CN)2− complexes. As a result, the absorption band peaked at 548 nm decreased, whereas the emission band peaked at 577 nm restored, because of erosion of Au. This ensemble system can be used to determine the concentration of CN−, with a limit of detection down to 2.0 × 10−13 mol L−1. This method has been successfully applied to test CN− in tap water, lake water, and groundwater.

Polymer-based AuNPs organic−inorganic hybrid materials have been applied for the selective and sensitive detection of CN− (Figure 97).195 The sensing strategy was designed on the basis of the CN−-induced dissolution of Au from polymer−Au nanocomposites. The Au surface has good affinity to N atoms of the imidazole units in 137; therefore, the hybrid polymer ensemble 137−AuNPs is formed; it is brown and nonfluorescent in aqueous solution, because of the Au-promoted emission quenching of 137 at 402 nm. The addition of CN− induces the dissolution of AuNPs to form a soluble and stable [Au(CN)2]− complex, with blue fluorescence and a distinct visual change from brown to colorless. This ensemble system can detect cyanide anions with a limit of detection of 0.3 μM, and other common anions (i.e., F−, Cl−, HCO3−, Br−, I−, AcO−, CO32−, NO2−, SCN−, EDTA2−, SO32−, NO3−, SO42−, S2O82−, C2O42−, P2O74−, PO43−, and HPO42−) do not induce any distinct fluorescence changes. Using this strategy, several water samples, i.e., boiled water, local groundwater, tap water, and lake water, were tested with satisfactory results. DNA-functionalized AuNPs can act as an ensemble system for the reversible determination of Ag+ and Cys, with on−off switches (Figure 98).196 AuNPs were functionalized with two different oligonucleotide sequences to form the ensembles 138 and 139. Two complementary DNA single strands were used in 138 and 139, except that cytosine is replaced by other nucleotides at four sites. There are no interactions when 138 and 139 are suspended in PBS buffer solution, because of the mismatched non C−C strands. However, addition of Ag+ ions produces aggregation between 138 and 139, with a visual change from red to blue. Negligible color changes are found upon addition of other competitive ions, i.e., K+, Li+, Zn2+, Ca2+, Mn2+,

Figure 95. ATP-stabilized AuNPs and a Cu2+−phenanthroline complex (136) for detection of CN−. 7927

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Figure 97. Schematic diagram of polymer-based 137-AuNPs for CN− sensing.

Figure 99. Molecular structure of Zn2+−DPA complex 140.

cross-linking of BPPs in the presence of the 140−AuNP ensemble. Positively charged cysteamine-stabilized AuNPs 141 were used as a hybrid ensemble for the visual and sensitive determination of heparin (Figure 100).198 The cysteamine-

Figure 98. Schematic diagram of DNA-functionalized AuNPs for reversible determination of Ag+ and Cys.

Cu2+, Pb2+, Ni2+, Ba2+, Co2+, Fe2+, Fe3+, Mg2+, and Cr3+. This is ascribed to the interconnection of duplex DNA induced by the thiophilicity between Ag+ ions and non C−C mismatched strands. Subsequent addition of Cys to the ensemble system leads to the formation of a Cys−Ag+−Cys adduct, producing aggregate dispersion with signal turn-off again. Such disaggregation process was observed to selectively detect Cys and the limits of detection for Ag+ ions and Cys were found to be 50 and 5 nM, respectively. The Zn2+−DPA complex 140 was appended to AuNPs to form an organic−inorganic hybrid ensemble system, which was utilized for the colorimetric determination of bisphosphorylated peptides (BPPs; Figure 99).197 On gradual addition of BPPs, the absorption intensity at 521 nm progressively diminished, and a new peak appeared at 680 nm, with a color change from red to blue. The addition of BPPs clearly produces aggregation of the functionalized AuNPs. However, non- and monophosphorylated controls did not produce such aggregation and color changes. The sensing mechanism is attributed to aggregation induced by

Figure 100. Schematic diagram of positively charged cysteaminestabilized AuNPs 141 for heparin detection.

modified AuNPs are with positive charges, and the electrostatic interactions between polyanionic heparin and the positively charged AuNPs result in aggregation of the AuNPs with a color change from red to blue. The addition of heparin to a solution of cysteamine-capped 141 caused an absorbance decrease at 520 nm and an enhancement at 670 nm, with a limit of detection of 0.03 μg mL−1. However, physiological concentrations of Na+, K+, 7928

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Mg2+, Ca2+, Cl−, CO32−, PO43−, Cys, lactic acid, glucose, BSA, and biopolymers, i.e., DNA, chitosan, protamine, hyaluronic acid, and polylysine, did not produce obvious color changes. Reversible aggregation and deaggregation of citrate-stabilized AuNPs 142 were used in a simple and efficient method for the colorimetric determination of biologically important polyionic protamine and heparin (Figure 101).199 Negatively charged

Figure 101. Schematic diagram of protamine-induced aggregation of citrate-stabilized AuNPs 142 to form ensemble 143 for heparin detection.

citrate-stabilized AuNPs 142 were aggregated to give an organic−inorganic hybrid ensemble 143 on addition of polycationic protamine, with a distinct colorimetric change from red to blue, together with a signal shift in the surface plasmon. Subsequent introduction of polyanionic heparin to the ensemble system dissipates the aggregated AuNPs, because of their strong affinity with protamine, and the color changes from blue to red. The aggregation and deaggregation are proportional to the concentration of protamine and heparin, providing a quantitative detection, with limits of detection of 0.1 and 0.6 μg mL−1 for protamine and heparin, respectively. Modified AgNPs were also used to design ensemble systems. Water-soluble 4,4-bipyridine-functionalized AgNPs (4-DPDAgNPs, 144) were prepared as an ensemble material for selective colorimetric detection of tryptophan (Figure 102).200 An aqueous solution of 4-DPD-AgNPs is yellow, whereas on addition of tryptophan, it changes to red with a distinct surface plasmon absorption signal at 556 nm. This ensemble system provides a rapid assay for quantification of tryptophan, with a limit of detection of 2 × 10−5 M. Other amino acids including Leu, Thr, Pro, Pyr, Val, Phe, Ser, and Cys induce negligible absorption changes. The proposed mechanism involves aggregation via supramolecular interactions between the Trp and the pyridine ring of bipyridine, through hydrogen bonding and π−π stacking interactions between the carboxylic group of Trp and pyridine. Silica NPs (SiNPs) functionalized with terpyridines to coordinate with metal ions and sulforhodamine B as a fluorescent indicator were utilized to probe anions (Figure 103).201 The addition of metal ions (Cu2+, Fe3+, Hg2+, Ni2+, and Pb2+) to a CH3CN suspension of the hybrid NPs induced fluorescence quenching of the grafted sulforhodamine unit via an electron transfer or energy transfer from the terpyridine to the excited sulforhodamine. The addition of F−, Cl−, Br−, I−, H2PO4−, HSO4−, and NO3−) produced partial revival of the sulforhodamine emission, as a result of electrostatic interactions. In the case of Pb2+, only H2PO4− could result in revival of the sulforhodamine B emission. It was found that different anions produced different changes, i.e., addition of H2PO4− and F− induced significant emission increases; Cl−, Br−, and HSO4− produced moderate enhancements, whereas I− and NO3− led to minimal emission changes. 3.4.2. Carbon Dot (CD)-Based Ensembles. Quantum dots (QDs) have been receiving general attention for their potential

Figure 102. Tryptophan sensing using 4,4-bipyridine-functionalized AgNPs 144.

applications in sensors/biosensor and imaging because of their unique size-reliable spectral properties such as broard and strong absorption spectrum and narrow emission spectrum with tunable wavelength.202 Their functionalization in the surface using organic molecules is a basic method to realized QDs-modified sensors/biosensors, because surface modification increased the stability of QDs and provides the desired binding receptors for substrates.203 In this case, carboxylate-modified CDs complexed with Eu3+ ions to form an ensemble were developed as an off−on fluorescent probe to detect HPO42− (Figure 104).204 The CDs showed an intrinsic and intense emission at 420 nm. The introduction of Eu3+ produced a significant emission decrease, as a result of aggregation of the CDs on association of Eu3+ with the carboxylate units on the CDs surfaces. When HPO42− was added to the ensemble, it induced revival of the emission band, via disruption of the preferential coordination of Eu3+ with HPO42−. The ensemble shows a limit of detection as low as 51 nM and much higher selectivity for HPO42− than for other tested anions (i.e., F−, Cl−, Br−,SO42−, I−, SO32−, NO3−, NO2−, ClO3−, ClO−, BrO3−, S2−, S2O32−, Ser, Glu, Hcy, and Arg). 3.4.3. Other Hybrid Ensembles. As well as various NPs and quantum dots, rGO was also used as a carrier to form organic− inorganic hybrid ensembles (Figure 105). A sensitive and labelfree method for the fluorescent determination of tartrazine (Tz) was reported, using an ensemble complex of rGO and Fl dye (145−Fl).205 Introduction of 145 to a buffer solution of Fl at pH 5.03 results in significant fluorescence quenching, as a result of FRET between Fl and 145. On gradual addition of Tz to 145−Fl, fluorescence enhancement was clearly observed, as a result of competitive binding of 145 to Tz against Fl. Similar behaviors 7929

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Figure 103. Schematic diagram of terpyridine-linked SiNP interactions with metal ions and sulforhodamine B, used as ensemble system for anion sensing.

Figure 104. Schematic diagram of carboxylate-modified CDs coordinated with Eu3+, to form an ensemble for HPO42− sensing.

4. APPLICATIONS

were observed when 2,7-dichlorofluorescein or EY was used. Fluorescent recovery on desorption of Fl from rGO provides a quantitative analysis for Tz, with a limit of detection of 0.53 ng mL−1. Shortly, organic−inorganic hybrid ensembles have been widely used for the design of chemosensors and biosensors toward a variety of substrates. Nanoparticles, quantum dots, polymer dots, graphene oxides, and other inorganic carriers have been well modified with different organic components, exhibiting excellent sensing properties. Since these contents have been widely developed and well summarized, only a couple of representative examples have been selected for illustration in this section.

4.1. Single-Analyte Sensing

Hundreds of ensemble systems have been designed based on the strategies described in this review, and used for the detection of single-target analytes such as organic or inorganic anions (e.g., F−, Cl−, I−, AcO−, CN−, HS−, S2−, ClO−, SCN−, citrate, oxalate, H2PO4−, PPi, and phosphonoformate), cations (e.g., Hg2+, Cu2+, and Ag+), neutral molecules (e.g., CO2 and trinitrophenol), and biomolecules (e.g., ATP, ADP, AMP, GMP, Cys, Hcy, GSH, folate, amino acids, short peptides, and heparin). The convenient in situ sensing of biologically important species is particularly useful, because these generally need tedious and stepwise syntheses. 7930

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Figure 105. Schematic diagram of hybrid ensemble system 145 consisting of rGO and Fl dye for Tz sensing.

4.2. Multiple-Analyte Sensing for Complex Samples

As shown in Figure 108, N-heteroaromatic receptors 164−170 and their corresponding lanthanide complexes (Eu3+, Tb3+, Nd3+, and Yb3+) were used to construct a combinatorial library to recognize 7 amino acids (Ala, Asp, Val, Phe, Gln, Glu, and Lys).208 Different emission responses induced by the supramolecular interactions of one amino acid with 28 possible combinational complexes were explored. In general, introduction of amino acids to an aqueous solution of the ensemble complexes led to visible and near-IR luminescent enhancements, to different extents. A summary of the 196 combinational tests showed that 164−Yb3+ gave rise to a selective change with zwitterionic amino acids, while 164−Tb3+ selectively interacted with Glu. Although a number of colorimetric and/or fluorescent sensors for heparin have been developed, based on design of boronic acids,209,210 specific peptides,211 labeled proteins,212 polymer conformational changes,213 and fluorophore aggregation,214,215 no methods provide a tunable design enabling the facile realization, optimization, and differentiation of negatively charged polymers, i.e., unfractionated heparin (UFH), lowmolecular-weight heparin (LMWH), oversulfated chondroitin sulfate (OSCS), heparan sulfate (HS), chondroitin sulfate A (CS), poly(glutamic acid) (PGA), dermatan sulfate (DS), and poly(acrylic acid) (PAA). However, a unique diagnostic pattern based on an ensemble-based array of receptors with broad specificities has been designed for the rapid determination of heparin.216 The modular nature of the ensemble strategy provides many specific receptors to be developed rapidly in a simple synthetic step. Functionalized CD and quinoliniumlabeled lithocholic acid (LCA) were designed as modular receptors with high affinities for heparin, in which CD efficiently yielded a stable inclusive complex with LCA. Functionalized CD provides amide or guanidino derivatives as polycationic receptors. The different recognition manners between CDs and polyanionic biopolymers provide various specific recognization patterns for each substrate. Different CD receptors (170−175) and LCA−fluorophore conjugates (176−178) in 96-well plates were used to illustrate the pattern-based discrimination for UFH, LMWH, HS, DS, CS A, OSCS, PGA, and PAA (Figure 109). Analyses of various arrays were illustrated via accurate recognition of heparin from commonly potential contaminants using this important drug. A supramolecular ensemble based a dynamic mixture of a Fe2+ complex was prepared as a colorimetric sensor for negatively

Multiple-analyte sensing for complex samples and pattern recognition based on chromogenic differential receptors have been receiving considerable interest in the past decade, because these methods provide powerful tools for analyzing diverse components in complex mixtures.7 In this design strategy, the receptor need not have a specific or selective affinity for a substrate. Receptors in the array only need to show different affinities for various analytes, which can produce various patterns for an analyte. Various receptors and indicators combined with pattern recognition tools have been used to develop an array of receptor−dye ensembles for the determination of various carboxylates.206 Ensemble arrays were produced by combining receptors 146−154 and metal salts (ZnCl2, CuCl2, CdCl2, MnSO4, and LaCl3; Figure 106). These complexes were further interacted with various indicators, i.e., alizarin (155 and 156), PV (157), xylenol orange tetrasodium salt (158 and 159), Fl (160), arsenazo III (161), and gallocyanine (162) to produce the related ensemble array. The formed ensembles were utilized in the assays of pattern recognition of certain α-hydroxycarboxylic acids, α-amino acids, and phenolic acids in a wine sample. Principal component analysis (PCA) was applied for data analyses and discrimination of the target substrates. The same research group used the concept of ensemble array sensing to differentiate small peptides and their phosphorylated analogs (Figure 107).207 A series of receptors were designed through the introduction of random peptides to a C 3v conformational scaffold (163), which can interact with phosphomonoesters in which 5 specific peptides were used based on a screen procedure. Five peptide sequences (hosts), three metal ions (Ni2+, Co2+, and Cu2+), and three dyes (PV, celestine blue, and gallocyanine) were selected to produce an ensemble sensing array with 45 different metal−receptor− indicator ensembles, based on combinatorial chemistry. These combinatorial ensemble arrays were designed for a pattern recognition of different sequence, i.e., Pro-pSer-Glu, Pro-SerGlu, Ser-Glu-Glu, and pSer-Glu-Glu tripeptides. The colorimetric data were selected from 45 test ensembles in a 96-well plate reader, and linear discrimination analysis produced a pattern manner producing 100% discrimination of these peptides. This approach illustrates the general principle for creating pattern recognition for complex substrates. 7931

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Figure 106. Molecular structures of receptors 146−154 and indicators 156−162. Pattern recognition: Reprinted with permission from ref 206. Copyright 2009, American Chemical Society.

charged polysulfated sugars. The ensemble complex included a mixture of FeCl2, a functionalized bipyridyl ligand (179), DPA, and the dye EB in buffered aqueous solution (Figure 110).217 LMWH, UFH, DS, CS, and HS were used to evaluate the sensing

performance of negatively charged polysulfate sugars with a dynamic equilibration time of 90 min. On the basis of UV−vis analysis at six different wavelengths, i.e., 431, 545, 585, 612, 632, and 669 nm, a mixture of UFH and HS can be discriminated with 7932

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Figure 107. Molecular structure of receptor 163 and corresponding pattern for discrimination of small peptides. Reprinted with permission from ref 207. Copyright 2009, American Chemical Society.

Ni2+ or Co2+ and zircon−Zn2+. Among these, the murexide−Ni2+ ensemble complex 180 showed the most remarkable sensitivity to CN− with a limit of detection as low as 7.7 μM, whereas zircon−Zn2+ was highly selective for CN−, although it showed less sensitivity for CN− (limit of detection 65 μM). The murexide−Ni2+ (180) and zircon−Zn2+ ensembles were also utilized for the sensing of endogenous CN− in crushed flax seeds and pickled bamboo shoots. A colorimetric sensing array was constructed for the sensitive sensing of the drug, γ-hydroxybutyric acid (GHB) on the basis of supramolecular interactions between organic capsules cucurbiturils 182 and 183, and six positively charged dyes (MB, TH, OX, AO, PYY, and PF; Figure 112).219 The sensing mechanism for the color changes was due to the formation of a ternary ensemble adduct (CB−dye−GHB). Combinational use of several dyes enables a wider range of concentrations to be covered than with a single dye. It was found that the dye PF was useful for distinguishing GHB in dilute solution, whereas the PYY dye was better for quantifying concentrated GHB. The ensemble was able to recognize GHB from some analogues such as 1,4-butanediol, γ-butyric lactone, propionic acid, and butyric acid. The same research group developed a similar colorimetric array on the basis of cucurbiturils (182 and 183) and tricyclic basic indicators. By simple visual imaging, this ensemble array can recognize α-amino acids from similar amines and acids, without the help of enzyme activation (Figure 113).220 The ensemble array was composed of four tricyclic indicators (OX, PYY, AO, and PF) and two organic capsules 182 and 183, because the capsules can interact with these amino acids by means of strong hydrogen bonding interactions. Different

Figure 108. Molecular structures of receptors 164−170.

a good selectivity. LMWH, UFH, and DS caused reequilibration, giving a decreased emission of complex [Fe(DPA)2]2+ at 431 nm and increased emissions of the other wavelength. DS showed a remarkable response at 545 nm, but almost no responses of other bands. CS, DS, and HS produced lower overall changes, because of their lower charge densities. As a result, such a multicomponent ensemble system could be utilized to recognize and differentiate UFH and HS with high resolution. 4.3. Biological Screening

A naked-eye, two-step procedure for the rapid screening of metal-complex-based ensembles was developed to detect biologically important anions, i.e., CN−, PO43−, and oxalate (Figure 111).218 Starting from 12 possible ensemble complexes, obtained by combining five indicators (pyrocatechol, murexide, eriochrom black T, zircon, and alizarin) and equimolar metal ions (Fe2+, Fe3+, Co2+, Ni2+, or Zn2+), three ensemble systems that gave pronounced color changes were screened: murexide− 7933

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Figure 109. Molecular structures of CD receptors 170−175 and LCA−fluorophore conjugates 176−178.

Figure 110. Ensemble system composed of a bipyridyl ligand 179, FeCl2, DPA, and dye EB for the sensing of polysulfated sugars.

ternary complexes formed, i.e., organic capsule−dye−amino acid, are responsible for the relevant color changes. In short, multiple ensemble array and pattern recognition have been widely applied for the sensing of complex mixtures, which cannot be realized in the traditional sensing method. Moreover, the receptor need not show a specific or selective affinity to analyte. Using this method, many analogues with very similar molecular structures have been well discriminated based on the array and pattern recognition.

5. CONCLUDING REMARKS As described above, the chemosensing ensemble emerges with the supramolecular chemistry and continuous progress has been

Figure 111. Conversion of CN−-selective receptor 180 to 181.

Figure 112. Molecular structures of capsules 182 and 183. 7934

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Figure 113. Molecular structures of four dyes and corresponding patterns for discriminating amino acids. Reprinted with permission from ref 220. Copyright 2010, American Chemical Society.

the highly selective determination and meet the specific requirement. (iii) Recyclable use: The ensemble system is inconvenient for the application in flow analysis, even using supported systems, because the released indicator is also brought away by the sample flow. Recently, receptors can be grafted on resin beans to realize the sensing devices in which the dyes can be recycled and reloaded for many times. In summary, the ensemble system has been growing in an important and promising way to construct chemosensors and biosensors. With the exception of design strategies in this review, other methods for ensembles will be explored that give new insights into this fascinating field. With the development of principal component analysis (PCA), it is therefore expected that more and more new ensemble-based sensors will come in the near future.

made in the past two decades. Now it is growing into a vibrant and active research field. Early work involves an indicator displacement assay in which the indicator and substrate complete for the receptor, followed by a conceptional extension that the indicator is not necessary to release from the receptor. As a result, in a broad sense, it can be systematically divided into twocomponent, three-component, multicomponent, and organic− inorganic hybrid ensembles. Along with this classification, hundreds of ensemble examples sensing for a variety of chemical guests and biological substrates have been summarized. The breadth of ensemble examples involved in various ions, neutral molecules, and biomolecules enables us to believe that it is a convenient and useful strategy to constitute chromogenic/ fluorogenic sensors. Compared to the conventional fluorophore−spacer−receptor structure, the ensemble−based chemosensor has displayed sufficient merits, i.e., it does not need a tremendous and laborious procedure for stepwise synthesis; it can be operated in solutions in situ that is essential for biologically important substrates; it only requires a rational combination of the receptor, indicator, and the substrate; it can be designed as a sensing array for screening of different analytes. A database of various indicators and receptors can be available that are readily combined together to optimize the suitable ensemble system for the desired substrate. Such a versatility of supramolecular ensembles open new perspectives to meet practical requirements. The ensemble systems, however, have some intrinsic disadvantages and face some problems that need to be solved as follows. (i) Stability: The ensemble system is designed via a variety of weak noncovalent suparmolecular interactions, and it is not thermodynamically stable enough compared to the covalent bound molecule. The ensemble system involves an equilibrium process that reliably changes with temperature, concentration, pH, polarity, and viscosity. Such a reliable equilibrium process makes the ensemble system unsuitable for the intracellular sensing of substrates because, once the ensemble-based supramolecules enter the cell, the associate constants of the complex remarkably changes. Fortunately, introduction of inorganic component (i.e., quantum dots and nanoparticles) to form organic−inorganic hybrid ensembles can well realize intracellular sensing and fluorescence imaging. (ii) Selectivity: Generally, only one receptor is included in an ensemble system, in which the electrostatic interaction or hydrogen bonding interaction, but not a cooperative interaction, is used for the driving force. Such a single force readily gives interferences in the presence of analogues. To improve selectivity, more than one receptor can be used in one ensemble system, in which two complementary receptors with different ratios can capture the substrate and tune its selectivity, just like different functional monomers in copolymers. Such an ensemble system is expected to realize

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Jiasheng Wu received his Ph.D. in 2006 from Technical Institute of Physics and Chemistry, Chinese Academy of Sciences (TIPC, CAS). After working in Korea and Hong Kong as a postdoctoral researcher for nearly three years, he joined TIPC in 2009. Now he is an Associate Professor at TIPC, and his current research interests include design and synthesis of fluorescent chemosensors/biosenors. 7935

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Pengfei Wang is a professor at TIPC. He received his Ph.D. in organic chemistry from Institute of Photographic Chemistry, Chinese Academy of Sciences (CAS) in 1993. He joined Technical Institute of Physics and Chemistry, Chinese Academy of Sciences (TIPC, CAS) in 2005 as a professor. His current research interests include carbon nanomaterials, chemosensors/biosensors, and organic electroluminescent materials and devices.

Bomi Kwon was born in Incheon, Korea in 1989. She received her B.S. from the Department of Chemistry at Korea University in 2013. Currently she is working towards a Master degree under the guidance of Professor Jong Seung Kim. Her current research focuses on hypoxia triggered drug delivery systems.

Weimin Liu is an Associate Professor at Technical Institute of Physics and Chemistry, Chinese Academy of Sciences (TIPC, CAS). She received her Ph.D. in organic chemistry from TIPC in 2008 and then joined the TIPC. Her current research interests focus on the design of luminescent materials and their application in biosensor and bioimaging.

Jong Seung Kim obtained a Ph.D. from the Department of Chemistry and Biochemistry at Texas Tech University. Then he had 1 year research experience as a postdoc at the University of Houston. He is currently a Professor in Department of Chemistry at Korea University in Seoul. To date, he has published over 330 scientific publications. He is also an inventor on over 50 Korean and international patents.

ACKNOWLEDGMENTS This work was supported by Major State Basic Research Development Program of China (No. 2014CB932600), the NNSF of China (Grant Nos. 21173244, 21373250, and 61227008), and the Creative Research Initiative program (No. 2009-0081566) of the National Research Foundation of Korea (J.S.K.). ABBREVATIONS ADP adenosine diphosphate AIE aggregation-induced enhanced fluorescence Ala alanine AMP adenosine monophosphate AO acridine orange Arg arginine ARS alizarin red S Asn asparagine Asp aspartic acid ATP adenosine triphosphate

Eric V. Anslyn received his B.S. in chemistry from the California State University Northridge, followed by a Ph.D. degree from Caltech under the tutelage of Robert Grubbs. His postdoctoral work was performed at Columbia University with Dr. Ronald Breslow. He has been a Professor at the University of Texas since 1989. His work is primarily focused on the creation of optical sensors, sensing protocols, and sensing arrays, for use in real-life applications. 7936

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Chemical Reviews BODIPY BPPs BSA CAPS CD CDP CF CHEF CHEQ CIL CS CTA CTP Cys DCPDP DMAP DMSO DPA DPD DS DTT EB EDTA EET ESIPT EY FI FRET Gal GHB Gln Glu Gly GMP GSH GTP Hcy HEMA HEPES His HS ICT IDP Ilc IMP ITP LCA Leu LMWH Lys MB MCB ME Met NMP NTPs OSCS OX PAA PBS PCA PET PF

Review

PGA Phe PPi Pro PV Pyr PYY Ser TH Thr TNP TNT Trp TTP Tyr Tz UDP UFH UMP UTP Val

boron dipyrromethene difluoride bisphosphorylated peptides bovine serum albumin N-cyclohexyl-3-aminopropanesulfonic acid cyclodextrin cytidine diphosphate 6-carboxyfluorescein chelation-enhanced fluorescence chelation-enhanced fluorescence quenching effect carbamate ionic liquid chondroitin sulfate A cetyltrimethylammonium cytidine triphosphate cysteine dicyclopentadiene polymer dimethylaminopyridine dimethyl sulfoxide dipicolylamine dihydropyrimidine dehydrogenase dermatan sulfate dithiothreitol Evans blue ethylenediaminetetraacetic acid electron energy transfer excited-state intramolecular proton transfer eosine Y fluorescein fluorescence resonance energy transfer galanin γ-hydroxybutyric acid glutamine glutamic acid glycine guanosine monophosphate glutathione guanosine triphosphate homocysteine (hydroxyethyl)methacrylate 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid histidine heparan sulfate intramolecular charge transfer inosine diphosphate isoleucine inosine monophosphate inosine triphosphate lithocholic acid leucine low-molecular-weight heparin lysine methylene blue methylcalcein blue methylcoumarin methionine nucleoside monophospates nucleoside triphosphates oversulfated chondroitin sulfate oxonine poly(acrylic acid) phosphate buffer solution Principal component analysis photoinduced electron transfer proflavine

poly(glutamic acid) phenylalanine pyrophosphate proline pyrocatechol violet pyruvic acid pyronine Y serine thionine threonine 2,4,6-trinitrophenol trinitrotoluene tryptophan thymidine triphosphate tyrosine tartrazine uridine diphosphate unfractionated hearin uridine monophosphate uridine 5′-triphosphate valine

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DOI: 10.1021/cr500553d Chem. Rev. 2015, 115, 7893−7943