Fluorescent chemosensors for copper(II) ion: Structure, mechanism and application

Accepted Manuscript Title: Fluorescent Chemosensors for Copper(II) Ion: Structure, Mechanism and Application Authors: Shuo Liu, Yan-Mei Wang, Jie Han PII: DOI: Reference:

S1389-5567(17)30028-X http://dx.doi.org/doi:10.1016/j.jphotochemrev.2017.06.002 JPR 270

To appear in: Reviews

Journal of Photochemistry and Photobiology C: Photochemistry

Received date: Revised date: Accepted date:

16-3-2017 30-5-2017 5-6-2017

Please cite this article as: Shuo Liu, Yan-Mei Wang, Jie Han, Fluorescent Chemosensors for Copper(II) Ion: Structure, Mechanism and Application, Journal of Photochemistry and Photobiology C:Photochemistry Reviewshttp://dx.doi.org/10.1016/j.jphotochemrev.2017.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Fluorescent Chemosensors for Copper(II) Ion: Structure, Mechanism and Application Shuo Liu, Yan-Mei Wang, Jie Han* (College of Chemistry and State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China) *Corresponding

author. E-mail:[email protected](J. Han). Tel./Fax: 86-22-23501520

Graphical abstarct

Highlights   

This review provides a comprehensive overview of fluorescent chemosensors for copper(II) ion. Three main types, namely, “on-off”, “off-on” and ratiometric fluorescence chemosensors for copper(II) ion are discussed systemically. Cu2+-promoted reaction based chemosensors are summarized briefly.

1

Abstract: Among the transition metal ions, copper is the third most abundant essential trace metal element in human body, and is also required by many living organisms for normal physiological processes, while excessive levels of Cu2+ are highly toxic to organisms and generate enormous quantities of pollution to our living environment. It is an essential and key issue to devise more sensitive and selective fluorescent chemosensors to efficiently evaluate the Cu2+ levels in environmental and biological systems. This review summarizes the important advances in fluorescent chemosensors for Cu2+, mainly made in the recent five years. Three types of chemosensors, namely ‘on-off’, ‘off-on’ and ‘ratiometric’, are categorized according to fluorescence signal changes, and each type is further classified into several sections according to the molecular structure features and/or recognition mechanisms. Additionally, the Cu2+-promoted reaction based chemosensors are also discussed by the different reactions like hydrolysis, oxidation and reduction. The molecular structures, recognition mechanism and applications of the fluorescent chemosensors are emphatically discussed, and the future perspective is overviewed briefly. Abbreviations: ACQ, aggregation-caused quenching; AIE, aggregation induced emission; APTES, 3-(aminopropyl)-triethoxysilane; AO, acridine orange; ATD, amino triphenylamine dendron; BODIPY, boron dipyrromethene; BSA, bovine serum albumin; CDs, carbon dots; CHEF, chelation enhance fluorescence; CQDs, carbon-based QDs; DFT, density functional theory; DMF, N,N-dimethyl formamide; DPA, bis(pyridine-2-ylmethyl)amine; EDTA, ethylenediaminetetraacetic acid; FRET, fluorescence resonance energy transfer; g-C3N4, graphitic carbon nitride; GQDs, graphene quantum dots; HEPES, 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid; hPEI-AgNCs, hyperbranched polyethyleneimine-protected silver nanoclusters; ICT, intramolecular charge transfer; IPA, 3-(1H-imidazol-1-yl)propan-1-amine; LOD, limit of detection; MPA, 3-mercaptopropionic acid; MSNs, mesoporous silica nanoparticles; NCs, nanoclusters; NDI, naphthalene diimide; NIR, near infrared; OXD, 1,3,4-oxadiazle; PAN, polyacrylonitrile; PEI, polyethyleneimine; PET, photoinduced electron transfer; PMOs, periodic mesoporous organosilica; Ptz, phenothiazine; QDs, quantum dots; RBITC, rhodamine B isothiocyanate; TBET, through-bond energy transfer; THF, tetrahydrofuran; WHO, world health organization.

Keywords: fluorescent chemosensors; copper(II) ion; structure; mechanism

Contents 1 Introduction 2. ‘On-off’ fluorescent chemosensors 2

2.1 Small molecular chemosensors 2.1.1 Intramolecular charge transfer (ICT) 2.1.2 Photoinduced electron transfer (PET) 2.1.3 Aggregation induced emission (AIE) 2.1.4 Miscellaneous mechanisms 2.2 Supramolecular chemosensors 2.3 Quantum dots (QDs) based chemosensors 2.4 Fluorescent nanomaterials based chemosensors 2.5 Miscellaneous chemosensors 3 ‘Off-on’ fluorescent chemosensors 3.1 Rhodamine based chemosensors 3.2 Coumarin based chemosensors 3.3 Boron dipyrromethene (BODIPY) based chemosensors 3.4 Miscellaneous chemosensors 4 Ratiometric fluorescent chemosensors 4.1 Pyrene based chemosensors 4.2 Fluorophore hybridization based chemosensors 4.3 Dual-emission fluorescent nanoparticles based chemosensors 5 Cu2+-promoted reaction based chemosensors 5.1 Cu2+-promoted hydrolysis 5.2 Cu2+-promoted oxidation reaction 5.3 Cu2+-based reduction reaction 6 Conclusions and perspectives 1 Introduction The term chemosensor is defined as a molecule of abiotic origin that signals the presence of matter or energy [1]. Now, chemosensors are generally understood to be devices that bind selectively and reversibly to the analyte with concomitant change in one or more properties of the system, such as fluorescence, color, or redox potential. Among many kinds of chemosensors, the development of fluorescent chemosensors 3

for the recognition and sensing of the biologically and environmentally important metal ions has drawn continuous interest in fields of chemistry, materials, biological and environmental sciences due to the low cost, simple operation, high sensitivity and specificity, real-time monitoring and short response time [2-7]. Upon interactions with the metal ions, the fluorescence intensity and/or fluorescence band shift of the chemosensors change and the metal ions may be detected qualitatively and quantitatively [8]. Development of new fluorescent chemosensors for transition and heavy metal ions have drawn continuous interest for many years because these ions play important roles in the fields of biological, environmental and chemical systems. As the third most abundant transition metal ion after zinc and iron in the human body, copper plays an important role in various biological processes [9-10]. Living cells must maintain optimal concentration of copper ions to keep the normal functioning of enzymes and intracellular metabolic balance. Deficient or excessive levels of Cu2+ ions may cause a series of severe diseases such as Menkes syndrome, Wilson’s disease, Alzheimer’s disease, etc., and long term exposure to Cu2+ ions can cause liver or kidney damage [11-13]. Commonly, the average concentration of Cu2+ in human blood is in the range of 15.723.6 μM, and the World Health Organization (WHO) have set the maximum allowable level of Cu2+ in drinking water at about 30 μM and the population mean intake of copper should not exceed 1012 mg per day for adults [14]. Therefore, the development of more sensitive and selective fluorescent chemosensors, that can be used to efficiently evaluate the Cu2+ levels in environmental and biological systems, is of great significance. Up to now, quite a lot of fluorescent chemosensors with various molecular structures and different recognition mechanisms have been developed for detection of copper ions. In this review, we will provide a comprehensive overview of the progress in fluorescent chemosensors for Cu2+ mainly in the recent five years, with focuses on the structures, photophysical characters, mechanisms, and applications. According to the recognition mechanism as well as the fluorescence response to Cu2+, the fluorescent chemosensors are classified into three categories: ‘on-off’, ‘off-on’ and 4

ratiometric chemosensors. Each category is further discussed in several sections according to the molecular structures and recognition mechanisms of the fluorescent chemosensors. As a special type of chemosensors, the Cu2+-promoted reaction based chemosensors are also reviewed according to the hydrolysis, oxidation and reduction reactions. 2. ‘On-off’ fluorescent chemosensors Upon irradiation with light, a molecule is often excited from the singlet ground state to the first or second electronic states, which are depicted by S0, S1, and S2, respectively. Fluorescence generally occurs when a thermally equilibrated excited state S1 returns to the ground state, in which an emission of a photon follows HOMO to LUMO excitation of an electron in the molecule. If the emission is efficient, the molecule may be termed a fluorophore. The intensity of fluorescence can be decreased by a wide variety of process. Such decreases in intensity are called quenching. Quenching can occur by different species. In the case of Cu2+, its dx2-y2 orbit only has one electron, and the energy of this orbital lies between those of the HOMO and LUMO of the excited fluorophore. Thus an electron transfer or energy transfer to the Cu2+ happens and leads to a rapid nonradiative decay of the excited fluorophore. Due to the intrinsic paramagnetic nature of Cu2+, quite a large number of fluorescent chemosensors for Cu2+ often show a fluorescence quenching to some extent. In other word, the free chemosensors are fluorescent, and their fluorescence is quenched upon interactions with Cu2+. This type of chemosensors is often called ‘on–off’ fluorescent chemosensor. In this section, the ‘on-off’ fluorescent chemosensors are classified into small molecules, supramolecules, quantum dots (QDs), nanomaterials and the miscellaneous according to their structural characters. 2.1 Small molecular chemosensors To date, a variety of fluorescent chemosensors for Cu2+ based on small molecules have been reported. Usually, a fluorescent chemosensor consists of a molecule incorporating an ion-binding site, a chromophore or fluorophore, and a mechanism for communism between the two [15]. Herein, the small molecular chemosensors are 5

discussed according to the recognition mechanisms including intramolecular charge transfer (ICT), photoinduced electron transfer (PET), aggregation induced emission (AIE), and so on. 2.1.1 Intramolecular charge transfer (ICT) based sensors Intramolecular charge transfer is an electron transfer process that occurs upon photoexcitation in molecules which are typically π-conjugated systems that feature an electron donor and an electron acceptor connected through a π-conjugated bridge [16]. In 2012, Xu and co-workers [17] designed and synthesized a series of new chemosensors 1a-1e, which were composed of two aminonaphthalimide fluorophores and 2,6-bis((N-aminoalkyl)aminocarboxy)pyridines. Fluorescence quenching was observed upon the addition of Cu2+ for 1c-1e in solution of THF, which was reasonably explained by the ICT mechanism. Based on the structures of 1a-1e, it was suggested that the length of the linkers between the aminonaphthalimides and 2,6-dicarboxypyridine was very crucial for sensitivity and selectivity for Cu2+, while the effect of substituents at the 4-position did not affect the fluorescent intensity changes. Recently, Li and co-workers [18] synthesized a naphthalene diimide (NDI) derivative 2, in which the NDI and 3-(1H-imidazol-1-yl)propan-1-amine (IPA) moieties acted as the receptor and the donor group, respectively. Since the strong electron donating ability of IPA unit and the double charge transfer between the NDI core and IPA moieties, 2 exhibited strong red emission. The strong red fluorescence of 2 could be quenched upon the addition of Cu2+, which was influenced remarkably by different solvent systems due to the different ICT and complexation ability. DMF, DMF/H2O, and DMF/HEPES were tested and a mixture solvent consisting of DMF and HEPES buffer with a volume ratio of 7:3 was defined to be the suitable solvent system. The results showed that 2 could not only serve as a practical fluorescence sensor by test strips and silica gel plates, but also be used for imaging of Cu2+ in living cells and in vivo. Di(2-pyridylmethyl)amine (DPA) could function as a binding site for metal ions. Its electron donating nature would be influenced by metal ion binding, hence optical properties would change. [19] Based on this strategy, Kim and co-workers [20] 6

synthesized a colorimetric and fluorescent chemosensor 3 for Cu2+. In the presence of Cu2+, the color of 3 changed from reddish orange to yellow. The addition of Cu2+ also resulted in a dramatic fluorescence quenching which was most probably attributed to an intramolecular charge transfer (ICT) with binding of Cu2+ at the DPA moiety of 3. In addition, the confocal microscopy experiment results showed 3 could be used for monitoring Cu2+ in living HepG2 cells due to its high water solubility and good cell-permeability. Nearly at the same time, Pang and co-workers [21] reported a chemosensor 4 with a flavonoid core as the fluorophore and a DPA moiety as the chelate group. 4 exhibited a sensitive and selective fluorescence response towards Cu2+ among other transition metal ions via the ICT mechanism. The cell experiments demonstrated that 4 is biocompatible and possesses an intracellular recognition of Cu2+. It’s noted that the complex 4-Cu2+ could be used for secondary sensing of pyrophosphate in living cells. In 2016, Choi and co-workers [22] reported a phenothiazine-based colorimetric and fluorescent probe 5 for Cu2+ and Hg2+, which is highly selective and sensitive over the competitive metal ions. Upon addition of Cu2+, a significant color change was observed from orange to blackish-blue. The UV-vis absorption studies revealed a 1:1 stoichiometry of 5-Cu2+ complex. The binding mode of 5 towards Cu2+ could be explained on soft-soft metal interactions between Cu2+ and the S and N atoms of the probe 5. The binding between Cu2+ and the probe 5 resulted in an overall decrease in the electron density from donor (phenothiazine) to acceptor, and consequently caused the fluorescence quenching. The probe 5 has been successfully applied as a solid state optical sensor, such as test paper and TLC plates with a detection limit of 0.3 μM.

7

The assembly of molecular logic gates based on organic receptors is an active area of research [23]. Recently, Kuwar and co-workers [24] reported a fluorescent sensor 6 which enabled highly selective and sensitive detection of Cu2+ and Zn2+. The addition of Cu2+ or Zn2+ to the solutions of 6 resulted in a dramatic color change from colorless to yellow, while there was no apparent color change in the presence of a large number of metal ions including transition metal ions, alkali metal ions and alkaline earth metal ions. The addition of Zn2+ to the solution of 6 resulted in a fluorescence enhancement, meanwhile the Cu2+ led to a fluorescence quenching, indicating that 6 may work as a two-input INHIBIT logic gate. As shown in Fig. 1, Zn2+ (input 1) and Cu2+ (input 2) were used as inputs, and the emission band at 450 nm was taken as the output in this system. The emission intensity at 450 nm was distinctly high only when the inputs were in a (1, 0) sequence, while the output was low when the inputs were (0, 1), (0, 0), and (1, 1). Thus, a two-input INHIBIT logic gate in molecular level was fabricated by using Zn2+ and Cu2+ as inputs and taking I450 as the output. As demonstrated above, compounds 1-6 are “on-off” fluorescent chemosensors for Cu2+ via an ICT mechanism, although their molecular structures are quite different. The photophysical properties, association or binding constant (Ka) and the limits of detection (LODs) of 1-6 for Cu2+ are summarized in Table 1. These chemosensors 8

display a maximum emission with a wide range from 450 nm to 647 nm, which are determined by the molecular structures, and may be further applied in different solvent systems. Notably, 2-6 could be used in semi-aqueous phases with a pH value of 7.0-7.4, and the LODs for Cu2+ are ranged from micromolar to nanomolar. Most of these sensors showed a 1:1 stoichiometry (sensor/ Cu2+) with a high binding constant, and could be used to detect Cu2+ quantitatively. 2.1.2 Photoinduced electron transfer (PET) based chemosensor PET is one of the most extensively adopted mechanisms for metal ion reorganization. A typical PET system often consists of an aromatic fluorophore, an aliphatic amine and a short methylene chain as the linker. When a lone electron pair is located in an orbit of the fluorophore and the energy of this orbital lies between those of the HOMO and LUMO, efficient electron transfer of one electron of the pair to the hole in the HOMO created by light absorption may occur, followed by the nonluminescent process returning to the ground state. The PET often causes a decrease in fluorescence intensity or quenching of the chemosensor [25-26]. Quite a lot of PET chemosensors for Cu2+ have been reported in literatures. Here, only two examples are selected to discuss. In 2013, He and co-workers [27] synthesized four bis-triazolyl indoleamine-based chemosensors 7a-7d for copper and fluorine. These sensors exhibited a markedly quenched fluorescence in the presence of Cu2+ with a simultaneous color change (yellow to green) over a range of metal cations. Among them, 7a and 7d showed less interference with Ni2+ and Hg2+ than 7b and 7c in fluorescence detection. What’s more, subsequent addition of F- led to fluorescence recovery of the sensors. A plausible mechanism of the specific and successive response of the sensors toward Cu2+ and then F- was proposed. First, a 2:1 complex with Cu2+ was formed due to the coordination of Cu2+ and the triazolyl binding sites, and the fluorescence quenched because of the electron transfer from the fluorophore to the receptor-Cu2+ motif. Then high-affinity interactions between F- and indole led to generation of the fluorescence of the sensors. In 2014, Zheng and co-workers [28] synthesized a BODIPY based colorimetric and fluorescent chemosensor 8 for Cu2+ detection. When 8 was titrated with Cu2+, the 9

fluorescence intensity decreased until fluorescence was completely quenched, with the color change from green to colorless, which were not observed by other metal ions. 8 showed fast response (~1 min) and high sensitivity for Cu2+ due to the PET from the excited state of fluorophore to the bipyridyl unit. Moreover, 8 could be used for sensing Cu2+ in living cell. Sulfide is known to react with Cu2+ to form CuS, which has a low solubility product constant of Ksp = 6.3 × 10−36 [29]. Therefore, the utilization of the higher affinity of Cu2+ towards S2− for designing chemosensors with a fluorescence response has received considerable attention. In 2015, Meng and co-workers [30] reported a selective and sensitive strategy for sequentially ‘on-off-on’ fluorescent detection of Cu2+ and S2- based on a fluorescein derivative 9. The specific binding of 9 towards Cu2+ in aqueous and biological media led to the intensive green fluorescence quenching. In the presence of S2-, the fluorescence of in situ generated 9-Cu2+ could be recovered by the S2--induced displacement approach. The fluorescence “on-off-on” circle could be repeated to a minimum of 5 times. In addition, the confocal microscopy imaging suggested that 9 was membrane permeable and potentially used as a powerful tool for the detection of Cu2+ and S2- in living cells. Recently, Paul and co-workers [31] synthesized a quinazoline functionalized benzimidazole 10, which acted as a highly selective colorimetric (colorless to light brown) and fluorescence sensor for Cu2+ ions. Reaction of 10 with CuCl2 formed a mononuclear Cu2+ complex, which could act as a metal based highly selective and sensitive chemosensor for S2−. The X-ray analysis showed that the complex was formed (on-off) through the interaction of Cu2+ with a phenolic oxygen of 10, and subsequent S2− recognition leading to decomplexation and to fluorescence revival of 10 (off-on). The propensity of 10 as a bio-imaging fluorescent probe for detection of Cu2+ and sequential detection of S2− by 10-Cu2+ in Dalton lymphoma cancer cells was also studied.

10

The properties of 7-10 are summarized in Table 2. All of the chemosensors display a fluorescence quenching upon interactions with Cu2+ via a PET mechanism. 7a, 7d and 8 exhibited a 2:1 stoichiometry with a high binding constant up to 107 M-2 with low LODs, however, these fluorescent chemosensors were used in organic solvents such DMSO and methanol, which might limit the application in detection of Cu2+ in aqueous media. In contrast, 9 and 10 showed a 1:1 stoichiometry with a binding constant from 3.8×104 to 6.4×104 M-1, and could be used in semi-aqueous phases with a pH value of 7.4. It’s worthy to note that they showed very high sensitivity towards Cu2+ with LODs of 1.6 ~ 8.8 nM. 2.1.3 Aggregation induced emission (AIE) based sensors Most fluorescent compounds suffer from the aggregation-caused quenching (ACQ) effect when dispersed in a poor solvent or fabricated into films in the solid state, which may limit their practical application. In contrast, the AIE phenomenon is precisely opposite to ACQ and provides a new strategy to broaden the application of fluorophores [32-33]. For example, Li and co-workers [34] synthesized a chiral luminogen 11, which is derived from (R)-1,10-binaphthol. As shown in Fig. 2, when dissolved in DMSO solution, 11 emitted weak emission, and emission intensity was gradually

enhanced

by

increasing

the 11

water

fraction.

The

functional

dicyanomethylene and hydroxyl groups may result in the restriction of intramolecular free motion, which should be responsible for the AIE phenomenon. Particularly, 11 displayed obvious decrease of the fluorescence and CD signals upon addition of Cu2+ with high selectivity and sensitivity in the aggregation state, because of the formation of complex between the pyridine unit and Cu2+. In addition, SEM images revealed that 11 could form nano-polyhedra in the aggregate state, and further self-assemble into micro-branches upon addition of Cu2+. 2.1.4 Miscellaneous mechanisms Besides the mechanisms stated above, there are still various “on-off” fluorescent chemosensors for Cu2+ with miscellaneous recognition mechanisms. These sensors often exhibit interesting properties and have practical applications in some special fields. Herein, several representative examples were chosen to discuss briefly. In 2015, Zhang and co-workers [35] reported a Zn2+ complex 12 as fluorescent chemosensor for Cu2+. 12 exhibited a very strong fluorescence because the coordination between the free ligand and Zn2+ inhibited the PET progress from N atom. Upon addition of Cu2+, the displacement of Zn2+ with Cu2+ occurred and the fluorescence was quenched owing to the paramagnetic properties of Cu2+ (Fig. 3). The metal complex rather than organic dyes as a luminescent probe for the detection of Cu2+ can effectively avoid the interference of other metal cations with weaker binding capability. As a result, the displacement approach may be used as a new strategy to devise Cu2+-responsive chemosensor with high selectivity. Kuwar and co-workers [36] synthesized a lawsone azo dye-based fluorescent chemosensor 13 with the fluorescent lawsone moiety itself as a recognition unit, which is different from the common structure feature of chemosensor. Compound 13 might form stable complex with Cu2+ and showed selective response to Cu2+ via fluorescence quenching. This ‘turn off’ fluorescence behavior could be explained on the basis of open shell effect of Cu2+, leading to donation of lone pair of electrons from 13 to empty d orbitals of the copper ions, and the ligand to metal charge transfer caused the sharp fluorescence quenching of 13 (Fig.4). Notably, this chemosensor has been successfully applied to examine the level of Cu2+ in drug supplements available 12

in the market in line with the data provided by the manufacturer. 2.2 Supramolecular chemosensors Supramolecular fluorescent chemosensors are abiotic devices that produce a change in fluorescence by binding analytes by noncovalent interactions (e.g. hydrogen bonds or π-interactions for a molecule; coordination interactions for a metal ion; electrostatic interactions for an anion) [37]. In view of molecular weight, most of the supramolecular fluorescent chemosensors are small molecular chemosensors, while they have outstanding structural features different from the common small molecules. To date, a wide range of molecular structures such as crown ethers, calixarenes, helicenes, metal complexes, porphyrins, cyclodextrin, etc. have been used as host skeleton to devise various fluorescent chemosensors [38]. In this section, the progress in fluorescent chemosensors for Cu2+ of the representative supramolecules such as perazamacrocycle, cyclodextrin and calixarene are briefly discussed. As an important kind of host molecules, perazamacrocycles have been widely applied in coordination chemistry, metal catalysis, material chemistry, and ion recognition [39]. In 2011, Zhu and co-workers reported a chiral perazamacrocycle 14 [40]. It could serve as a fluorescent ‘on-off’ sensor with high selectivity toward Cu2+ to form a 1:1 complex. Furthermore, the in situ generated complex Cu2+-14 was the first

metal-containing

perazamacrocycle

exhibiting

remarkable

fluorescent

enhancement responses and considerable enantioselectivities toward unmodified α-amino acids in protic solutions via a ligand displacement mechanism, but the free 14 exhibited no enantioselectivity for α-amino acids. Thus, a cascade recognition of Cu2+ and unmodified R-amino acids has been achieved, which made 14 work as bifunctional chemosensor. Most of the reported supramolecular chemosensors are typical organic compounds and have poor solubility in water, which limited their practical applications. As a result, water solubility is one of important factor to consider in devising new chemosensors. Recently, Geng and co-workers [41] synthesized a water soluble fluorescent sensor 15 constructed by using 7-nitrobenz-2-oxa-1,3-diazole as the electron donor and 3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-triene as the 13

acceptor. 15 showed better selectivity and sensitivity to Cu2+ compared with Ca2+, Na+ and Mg2+. Specifically, 15 could be successfully applied to visualize and monitor Cu2+ in the lysosomes of Hela cells.

As a class of cyclic oligosaccharides, cyclodextrins can encapsulate various organic guests inside their hydrophobic cavities, which enables them to be used in design of chemosensors. In 2013, Pitchumani and co-workers [42] synthesized 7-aminoflavone modified β-cyclodextrin with a hydrazinecarbothioamide linker 16 as a highly selective and efficient fluorescent chemosensor for Cu2+. The NOESY and emission spectra suggested the self-inclusion of phenyl ring of flavone moiety inside the cyclodextrin cavity. When Cu2+ binds to the C=S bond, the flavone moiety would move outside the cavity of the β-cyclodextrin. Meanwhile the PET from C=S bond to the flavone unit is inhibited and resulted in remarkable fluorescence quenching. Interestingly, the addition of histidine, among other amino acids, recovered the fluorescence, which was rationalized by displacing Cu2+ from 16-Cu2+ complex with the histidine (Fig.5). Compound 16 is not only a fluorescent chemosensor for Cu2+, it can also be used as a specific sensor for histidine. Calix[4]arene is one of the most attractive synthetic macrocycle for the design of fluorescent receptors as it allows introduction of appropriate binding cores suitable for ion recognition [43-44]. Chawla and co-workers [45] synthesized a calix[4]arene based molecular receptor 17 for sensitive and selective recognition of F- among anion ions and Cu2+ among cation ions. Simultaneous binding studies of 17 with F- and Cu2+ by UV–vis method showed that 17 exhibited a negative allosteric effect towards 14

Cu2+/F-, which could be attributed to the weak binding of ions to the host molecule and strong ion-pairing equilibrium between these two types of ions. 1,3,4-Oxadiazole (OXD) derivatives have been paid much attention because of the electron-deficient nature, high photoluminescence quantum yield and excellent chemical stability, and have found many practical applications in the areas of organic light-emitting diodes [46] and liquid crystals [47-48]. Furthermore, the OXD unit has potential coordination sites (N and O) with metal ions and could be also used as a signaling component in fluorescent chemosensors [49-50]. By combining the unique features of calix[4]arene and OXD units, our research group reported a new type of fluorescent chemosensors 18, which displayed a specific selectivity for Cu2+ recognition over other transition-metal ions including Mn2+, Cd2+, Ni2+, Pb2+, and Zn2+ by the fluorescence quenching [51]. The configurations of the chemosensors have significant effects on the fluorescent recognition for Cu2+, and the 1,3-alternate conformer showed much better sensitivity for Cu2+ than the cone counterpart. As the OXD unit work as both an ion-binding site and a fluorophore, it’s possible to increase the selectivity by appending more OXD units. So, we synthesized a chemosensor 19 based on 1,3-alternate calix[4]arene with four OXD units [52]. As expected, 19 displayed a more selective recognition of Cu2+ than 18 by the fluorescence quenching. In order to develop molecular switch, we further reported a fluorescent chemosensors 20 by appending two OXD units on a calix[4]crown skeleton [53]. The recognition behaviors of 20 in CH2Cl2 solution to alkali metal ions, alkaline earth metal ions and transition metal ions have been investigated by UV-Vis spectrum and fluorescence spectrum. The results showed that Na+ enhanced the fluorescence intensity of 20 significantly, while all the measured transition metal ions may quench the fluorescence greatly due to the PET mechanism. The photophysical properties of the supramolecular fluorescent chemosensors 1420 are summarized in Table 3. As the structures of supramolecular compounds are quite different from each other, it is difficult to get a comprehensive conclusion. Generally, quite a number of host supramolecules have been successfully used to devise fluorescent chemosensors for Cu2+. Among them, 14, 16 and 20 exhibited 15

bifunctional recognition for Cu2+ and α-amino acids or other analytes through a cascade process, while 15, 17, 18 and 19 showed specific recognition for Cu2+. In future, there are still some challenges such as improving the water solubility of this kind of chemosensors and expanding their practical applications in living organism and environmental samples.

2.3 QDs based chemosensors Quantum dots (QDs) are semiconductor nanoparticles that have physical dimensions close to or smaller than the exciton Bohr radius [54]. The spatial confinement of intrinsic electron and hole carriers leads to an increased band-gap energy and to a splitting of the continuous energy bands in discrete energy levels, which makes QDs to an intermediate between bulk materials and molecules [55]. Recently, QD-based fluorescent chemosensors have been widely used in biology, pharmacology, and environmental science due to their universal advantages such as tunable absorption and emission spectra, spectrally broad and strong absorption, narrow emission bands, and high photostability [56]. 16

In 2014, Han and Jin [57] reported a hexadecyl trimethylammonium bromide modified CdSe/ZnS QDs 21 as a fluorescent probe for Cu2+. The possible sensing mechanism of Cu2+ detection is shown in Fig. 6. When 21 directly interacts with Cu2+, the Cd2+ ions may be replaced and parts of Cu2+ are reduced to Cu+/Cu0, and CuxSe (x = 1, 2) are formed on the surface of 21, leading to the quenching of the emission. It was found that the presence of thiosulfate could decrease the interference of Ag+ and Hg2+. When thiosulfate was added in the QDs solution, the thiosulfate could generate a passivation layer on the surface of the QDs. The Cu2+ ions might replace Cd2+ ions while Ag+ and Hg2+ were resisted outside of the QDs by thiosulfate. The CdSe/ZnS QDs 21 could be used to detect Cu2+ in deionised water with good selectivity and ultrahigh sensitivity in the presence of thiosulfate. The LODs for Cu2+ in the deionised water and in tap water are 0.15 and 0.14 nM, respectively. This work provided a good potential chemosensor for Cu2+ ions detection in aqueous solution with simplicity, rapidity, ultrahigh sensitivity, and excellent selectivity. To date, quite a lot of QDs have also been applied in chemical and biological chemosensors, however, most of them are based on the visible light emitting. The visible light emitting QDs cannot meet the requirements of biosensing and bioimaging in vivo for human beings because visible light has a limited penetration depth resulting from the scattering and fluorescent background signal. To address this issue, Tao and co-workers synthesized a NIR-emitting CdTe/CdS QDs 22 with 3-mercaptopropionic acid (MPA) as a stabilizer (Fig. 7) [58]. Aggregation of 22 was observed by dynamic light scattering and the fluorescence quenched after addition of Cu2+, which might be caused by the competitive binding between the MPA of the surface of 22 and the Cu2+ present in the solution. In other words, the Cu-S bond has a much lower Ksp value than that of Cd-S bond. 22 has been used to detect the Cu2+ and monitor the change of Cu2+ concentration in living cells and animals, and is expected to pave the way for developing novel bio-imaging nano-reagent for future medical applications. As mentioned above, most conventional QDs are based on semiconductors containing heavy metals, such as Cd [57-58], Hg [59], and Pb [60], which made the 17

applications to be limited due to the well-known toxicity and potential environmental hazard of the heavy metals. Carbon-based QDs (CQDs), mainly including graphite nanoparticles less than 10 nm in size and graphene nanosheets less than 100 nm in width [61], are proposed to be promising substitutes of the heavy-metal-containing QDs. More and more attention has been paid to CQDs due to their many advantages, such as low cytoxicity, good stability, easy preparation, and environmental friendliness [62]. In 2014, Muster and co-workers [63] reported a selective approach detection of Cu2+ and L-cysteine by using unmodified carbon dots (CDs) 23 as fluorescent probes. The free 23 in aqueous solution emitted strong fluorescence, which could be quenched greatly by adding of Cu2+ owing to the binding of Cu2+ to the surface of 23. The fluorescence could be recovered by addition of L-cysteine into 23-Cu2+, because the thiol group of L-cysteine could bind the Cu2+ ions and remove them from the surface of CDs (Fig. 8). Although the competitive transition metal ions such as Co2+, Fe2+, and Ni2+ might interrupt slightly the recognition of Cu2+, this report provided a facile and environmentally benign method to detect Cu2+ and L-cysteine in real sample. Silica coating is one of the most popular strategies for nanoparticle surface modification with the assistance of organosilane self-assembly. Lin and co-workers [64] reported silica shell coated citric acid derived CDs based fluorescence probe 24 (Fig. 9) with enhanced selectivity for monitoring Cu2+. The fabrication of 24 was based on the efficient hybridization of 3-(aminopropyl)-triethoxysilane (APTES) with CDs. 24 showed cooperative properties and synergistic effects of APTES and CDs, and its fluorescent properties were tunable through varying the ratio of CDs and APTES. The probable mechanism was attribute to the stronger interaction including chelation and electrostatic attraction between Cu2+ and N and O atoms-containing as well as negatively charged silica-coated CDs than other interference. The color change from colorless to deep yellow and the Tyndall effect could also distinguish the concentration of Cu2+. The fluorescent chemosensor 24 has been successfully applied to monitor the alteration of striatum Cu2+ in rat brain during the cerebral calm/sepsis process. 18

Polyethylenimine (PEI) has been demonstrated the ability of selectively capture trace-level free Cu2+ [65]. Recently, Chi and co-workers [66] prepared a new kind of polyamine functionalized CQD 25 with branched PEI as fluorescent chemosensor. The fluorescent quenching mechanism was attributed to an inner filter effect. The amino groups at the surface of the CQDs could bind Cu2+ forming cupric amine, and thus resulted in a selective and strong quenching of the CQDs’ fluorescence (Fig. 10). Notably, the chemosensor 25 could be applied in the detection of Cu2+ in river water sample. As a kind of typical CDs, graphene quantum dots (GQDs) contain a graphene structure which endows them with some of the unusual properties of graphene [67-68]. However, GQDs often show a comparatively low quantum yield (2.5%). To overcome this problem, Qu and co-workers [69] reported amino-functionalized GQDs 26 with a high quantum yield (16.4%) by hydrothermal treatment of GQDs in ammonia. This strategy is simple in design and economic in operation in that it does not require dye modified oligonucleotides or complex chemical modification. Because Cu2+ has a higher binding affinity and faster chelating kinetics with N and O on the surface of 26 than other transition metal ions, the selectivity of 26 for Cu2+ is much higher than that of GQDs (Fig. 11). In addition, 26 is biocompatible and eco-friendly, and the positively charged 26 can be easily taken up by cells, which make it possible to sense Cu2+ in living cells. Table 4 shows the photophysical properties of the QDs based chemosensors. In summary, all of the QDs based chemosensors 21-26 could be applied in aqueous phase with low detection limits. Most of them exhibit biocompatibility as the optimized pH values are close to neutral. Compared to the small molecular chemosensors, the disassociation constant can’t be calculated as the quantitative structure-activity relationship is not clear, but this does not affect the practical applications of the QDs based chemosensors. 2.4 Fluorescent nanomaterials based chemosensors Fluorescent nanomaterials have attracted a great deal of interest due to their low cytotoxicity, easy surface functionalization, and high price competitiveness [70]. Such 19

kind of materials can also be used to devise various fluorescent chemosensors for Cu2+. In 2011, Lu and co-workers [71] reported a dual-emission fluorescent silica nanoparticle-based probe 27 for rapid and ultrasensitive detection of Cu2+. The chemosensor 27 is prepared according the following procedures. The water soluble PEI was covalently grafted onto the surface of the fluorescein isothiocyanate-doped silica nanoparticles by hyperbranching surface polymerization, then rhodamine B isothiocyanate (RBITC) was covalently linked by the reaction of primary amine group of PEI and the thiocyanate group present on RBITC. The dye-doped silica core served as a reference signal and provided a built-in correction for environmental effects, while PEI worked as both chelating reagent for selective binding of Cu2+ and the linking groups for covalent linking of RBITC. The fluorescence of 27 could be selectively quenched in the presence of Cu2+ with a detect limit of 10 nM within 20 s, accompanied by a visual orange-to-green color switch, and the change could be fully reversible by the addition of EDTA. Two factors are proposed for the high sensitivity of 27. Firstly, PEI is a strong chelating reagent for Cu2+ even at low concentrations. Secondly, the large amount of PEI/RBITC units on an individual nanoparticle enables the realization of a signal amplification effect. The nanoprobe 27 has been used to detect Cu2+ in industrial waste water and lake water. It can also be used efficiently in monitoring Cu2+, because the long-wavelength emission of the response dye can avoid the interference of the autofluorescence of the biosystems. The outstanding properties endow 27 with a great promise for real-world sensor applications.

20

In 2014, Gu and co-workers [72] reported a fluorescent ‘on-off’ chemosensor 28 for Cu2+ via labelling mesoporous silica nanoparticles (MSNs) with maleimide. As shown in Fig. 12, the non-fluorescent 2-bromomaleimide was converted to 2-aminomaleimide by a nucleophilic addition-elimination reaction with pre-grafted amino groups in the MSNs. Although the free maleimide molecule is non-fluorescent, the introduction of this small molecule into the mesochannels of MSNs makes them fluorescent, since the nucleophilic amino groups can form a conjugation structure with maleimide. The fluorescence of 28 could be selectively quenched by aqueous Cu2+ with detection limit as low as 0.28 mM. The fact that the strong interactions between amino groups of 2-aminomaleimides and Cu2+ restricted the lone electron pairs of N atoms to conjugate with the maleimide ring might explain the recognition mechanism reasonably. Chemosensor 28 could also be used for the detection of Cu2+ in intercellular environments and water-quality monitoring. By taking the advantage of magnetic feature of Fe3O4, Pina-Luis and co-workers [73] reported a fluorescent magnetic chemosensor 29 based on Fe3O4@SiO2 core-shell nanoparticles. 29 was prepared by coating Fe3O4 with amino-functionalized silica shell and modified with morin. Via the phenomenon of fluorescence, 29 had been used as sensor for the recognition of Cu2+ with excellent selectivity and sensitivity in the presence of other metal ions and biological compounds. Additionally, the fluorescent magnetic nanoparticles could be magnetically separated by external 21

magnetic fields, and consequently reduce the contamination of the analyzed samples. Due to the multifunctional properties such as biocompatible, magnetic and fluorescent, 29 can be manipulated to develop prospective applications in therapy, diagnostic, drug delivery, bioseparation and biosensors.

Recently, the development of ion imprinted polymers as sensors has received great interest, since they have excellent recognition ability with selective binding sites [74]. In 2015, Zheng and co-workers [75] reported an imprinted polymer based nanoprobe 30, which was prepared by doping highly monodisperse silica spheres with an Eu(III) complex and coating them with a nanoshell of a copper-imprinted polymer. Compared to the corresponding non-imprinted sensor, 30 showed higher fluorescent response to Cu2+. The possible reason is that the surface of 30 could adsorb Cu2+ by a process of ion imprinting, while non-imprinted sensor did not have the specific recognition cavities (Fig. 13). The nanoprobe 30 could be applied to the detection of Cu2+ in aqueous solution, however the detection limits (10-100 μM) are higher than other nanomaterials based chemosensors stated above, and the fluorescence of 30 was only partly quenched by Cu2+, which may hamper the practical applications. As a kind of nitrogen-containing nanomaterials, graphitic carbon nitride (g-C3N4) is the most stable allotrope of carbon nitride and has recently attracted great interest because of its high fluorescence, excellent biocompatibility and nontoxicity [76-77]. In 2013, Sun and co-workers developed new applications of g-C3N4 in fluorosensor, they prepared ultrathin g-C3N4 nanosheets 31 comprised of only about three C−N layers by ultrasonication-assisted liquid exfoliation of bulk C3N4 [78]. The nanosheets exhibit high fluorescence, which might be quenched obviously by Cu2+. As shown in Fig. 14, as the redox potential of Cu2+/Cu+ lies between the conduction band (CB) and 22

valence band (VB) of g-C3N4, the photoinduced electron transfer from the CB to the complexed Cu2+ might occur and lead to fluorescence quenching. 31 exhibited high selectivity towards Cu2+ with a detection limit as low as 0.5 nM, and has been used in determination of Cu2+ in real water samples. However, the whole detection process needs a long time up to 10 min, which might limit its practical applications. Polyacrylonitrile nanoparticles (PAN NPs) are another kind of nitrogen-containing nanomaterials with many advantages such as blue fluorescence, low cytotoxicity, and abundant surface functional groups, which have been further modified with various moieties by Jang and co-workers [79-80]. In 2014, they [81] fabricated amidine/Schiff base dual-modified PAN nanoparticles (tPAN NPs, 32), which exhibited excellent selectivity for Cu2+ sensing in aqueous solution based on fluorescence quenching (Fig. 15). 32 also showed good permeability to cells and low toxicity, offering a new fluorescence sensor for Cu2+ in living cells. Due to excellent photostability, good biocompatibility and large Stokes shifts, Noble metal (e.g., Au, Ag, Pt) nanoclusters (NCs) have become a powerful alternative to fluorescent dye molecules, and attracted wide interest in fields of chemosensors in recent years [82-84]. For example, Yang and co-workers [85] reported a new kind of highly fluorescent lysine-stabilized Au nanoclusters (AuNCs@Lys, 33). By cooperating with bovine serum albumin stabilized Au nanoclusters (AuNCs@BSA), the water soluble nanoclusters 33 could be used for the determination of Cu2+ with a lower detection limit of 0.8 × 10-12 M. In the presence of Cu2+, the fluorescence was readily quenched with the color changed from faint yellow to light brown, since Cu2+ can coordinate with the –COOH and –NH2 of both AuNCs@BSA and AuNCs@Lys (Fig. 16). Notably, 33 could be used to determine the concentrations of Cu2+ in lake water, running water and human urine samples with high sensitivity and excellent selectivity. . Table 5 shows the properties of fluorescent nanomaterials based sensors. Similar to the QDs based sensors, most of this kind of sensors can be used in aqueous phase and exhibit very low detection limits. The most outstanding feature is that some of them 23

exhibit high sensitivity and excellent selectivity for Cu2+ with great photostability, good biocompatibility and large Stokes shifts, which make them to be used in qualitative and quantitative detection of Cu2+ in environmental water and living cells. This will draw continuous interest in fields of chemosensors and material sciences. 2.5 Miscellaneous sensors To date, various peptide based sensors have been reported to detect metal ions [86], however, multianalyte recognition using a single sensor remains a challenge. In order to develop multifunctional chemosensors, Wu and co-workers [87] synthesized a fluorescent chemosensor 34 with a lysine backbone and double sides conjugated with histidine and dansyl groups. 34 could selectively and sensitively detect Zn2+ with fluorescence enhancement and Cu2+ with fluorescence quenching in 100% aqueous solutions. Upon addition of S2- to the solution of the complex 34-Cu2+, CuS was precipitated and the free sensor 34 was released. As a result, the fluorescence was recovered (Fig. 17). Indeed, 34 is a multifunctional sensor for Zn2+, Cu2+, and S2-, which make it find potential applications in environmental and biological systems. 3 Off-on type Although various ‘on-off’ fluorescent chemosensors for Cu2+ have been reported owing to the paramagnetic nature of Cu2+, the ‘on-off’ fluorescence quenching might occur in intracellular environment by artefacts other than metal complexation and could give rise to false positive results. Thus, ‘off-on’ fluorescent Cu2+ chemosensors are favored over the ‘on-off’ ones and have been developed in recent years. Compared to the ‘on-off’ fluorescent chemosensor, the ‘off-on’ fluorescent Cu2+ chemosensor is non-fluorescent or its fluorescence is very weak in absence of Cu2+. Upon binding with Cu2+, the intensity of fluorescence increases greatly due to several mechanisms such as the chelation-enhanced fluorescence [43] and the yield of new fluorophore. In this section, the ‘off-on’ fluorescence chemosensors are classified into rhodamine, coumarin, bodipy, and miscellaneous chemosensors according to the functional group. 3.1 Rhodamine-based sensors Rhodamine dyes have excellent photophysical properties such as high molar 24

extinction coefficient, high fluorescence quantum yields, long absorption and emission wavelength, and remarkable photostabilities. They are nonfluorescent and colorless in visible range. However, the spirocyclic structure of rhodamine derivative molecules can transform into ring-open forms by complexations with specific metal ions, and give rise to strong fluorescence emission and color changes of solutions. Rhodamine dyes have become the most important synthons to devise ‘off-on’ fluorescent sensors [88]. Since Czarnik [89] firstly used rhodamine B hydrazide as a chemosensor for Cu2+ detection in 1997, a lot of rhodamine B based chemosensors have been designed to detect Cu2+ via ring-opening processes of spirolactam amidesor hydrazides. In 2012, Kumar and co-workers [90] synthesized a rhodamine B derivative 35 as a highly selective fluorescence off-on chemosensor for Cu2+detection. 35 exhibited different fluorescence change upon addition of Cu2+ in acetonitrile and aqueous acetonitrile solution. Free 35 in acetonitrile exhibits very weak charge transfer emission at 508 nm with a shoulder at 430 nm attributed to the locally excited emission when excited at λex = 380 nm. The addition of Cu2+ results in the fluorescence enhancement at 508 nm along with appearance of a new emission band at 586 nm. The fluorescence intensity at different wavelength could be tuned by the concentration of Cu2+, which was explained reasonably by the resonance energy transfer mechanism operating between the dimethylaminovinyl-benzene and rhodamine moieties. The addition of EDTA to the 35-Cu2+ complex in acetonitrile could recover the fluorescence signal of 35 to its original level. In contrast, the Cu2+ in aqueous acetonitrile solution promoted the hydrolysis of 35 irreversibly, generating highly fluorescent products, a hydrazide derivative and ring-opened form of rhodamine (Fig. 18). This is the first report in which catalytic hydrolysis of a receptor by Cu2+ ions produced fluorescence turn-on changes at two different wavelengths. Nearly at the same time, Yin and co-workers synthesized an (UV−Vis)-reversible but fluorescence-irreversible chemosensor 36 by reaction fluorescein hydrazine with picolinaldehyde in methanol containing acetic acid [91]. The introduction of pyridyl unit may increase the coordination site with Cu2+, and 36 could recognize Cu2+ via a 25

simple coordination action with a color change from colorless to yellow. 36 could be regenerated by P2O74- or C2O42- as they could coordinate with Cu2+ and remove it from the 36-Cu2+ complex. However, the storage of the complex resulted in hydrolytic cleavage of the N=C bond, which released the ring-opened fluorescein hydrazine and resulted in irreversible fluorescence (Fig. 19). Interestingly, the reaction time can be controlled, so the probe is reversible and multifunctional. In 2016, Wang and co-workers [92] reported a rhodamine B derivative 37 as a fluorescent chemosensor for Cu2+. The spirolactam ring-opening of 37 induced by Cu2+ led to a highly selective fluorescence ‘off-on’ response toward Cu2+ over other metal ions with the color change from colorless to intense pink within 20 min. Compared to 36, the free 37 could be released from the complex 37-Cu2+ by the addition of excess EDTA (Fig. 20), indicating that the chemosensor could be used reversibly. Notably, 37 could be successfully used for the determination of Cu2+ in neutral water and the imaging of Cu2+ in living cells. Cyclen (1,4,7,10-tetraazacyclododecane) has been demonstrated to coordinate strongly with many transition metal ions [93]. In 2013, Ye and co-workers [94] synthesized 38 by combining rhodamine B and cyclen, which exhibited prominent fluorescence enhancements upon addition of Cu2+ over the other coexistent metal ions with the color change from colorless to pink. Similar to 37, the chemosensor 38 showed a reversible recognition toward Cu2+ by addition of EDTA. A stoichiometry (38/Cu2+) of 1:2 suggested that one Cu2+ ion coordinated with the cyclen and the other induced the N atom of spirolactam and got a ring opened rhodamine (Fig. 21). Recently, the electrospinning has become an effective and simple method for preparing various composite nanofibers, which are potential to provide high sensitivity and fast response time in sensing application [95-96]. In 2013, Song and co-workers [97] reported a novel surface modification strategy for an electrospun nanofibrous film, in which the surfaces of polymer nanofibers were modified with rhodamine derivatives to form a colorimetric and fluorescence sensor 39 for Cu2+. 39 could effectively avoid the aggregation and self-quenching of molecular fluorophores, and exhibited high fluorescence sensitivity and very short response with an 26

observable color change from colorless to pink. Furthermore, 39 could be utilized as an adsorbent to remove Cu2+ in aqueous solution and reused by washing with EDTA solution. (Fig. 22) Periodic mesoporous organosilicas (PMOs) are a new class of functional inorganic-organic hybrid materials with long-range porous order, in which the organic fragments are covalently attached [98]. In 2014, Han and co-workers [99] synthesized a novel PMOs 40 bridged by a bis(rhodamine Schiff-base derivative) unit. 40 exhibited mesoscopic and molecular scale periodicities with high selectivity towards Cu2+, due to the strong chelation of “N” atoms of the Schiff base units to Cu2+. Moreover, the complex Cu2+-40 showed high optical stability under intensive laser irradiation over 1 h, indicating the potential applications in biomarkers and solid-state optical emitters.

Table 6 showed the properties of rhodamine-based sensors. The on/off fluorescence switching of these sensors is based on structure change of the rhodamine moiety between spirocyclic and open ring forms. The clear mechanism and visible color change make rhodamine derivatives become an important kind of sensors. However, the nanomaterial-supported rhodamine derivatives usually showed high detection limits, which is still a challenge for researchers. Another drawback of this kind of chemosensor is that most of them are irreversible, which might limit their practical applications. So the development of reversible chemosensors is one of the most important issues to be solved in the future. 3.2 Coumarin-based sensors Coumarin derivatives can be used as fluorescent probes for metal ions because of 27

their high fluorescence quantum yield, hydrophobicity, chelation and long-wavelength emission [100]. Here two typical coumarin-based sensors with distinctive features are chose to comment briefly. In 2011, Lee and Kim [101] reported a coumarin-based fluorescent sensor 41, which displayed high selectivity for Cu2+ over a variety of competing metal ions in aqueous solution with a significant fluorescent increase. DFT/TDDFT calculations suggested that the off-on fluorescence of 41 was caused by blocking the electron transfer of the nitrogen lone pair upon complexation with Cu2+, which is similar to the mechanism proposed by Wu and co-workers in 2007 [102]. 41 has been applied to the microscopic imaging for detection of Cu2+ in LLC-MK2 cells in vitro. In 2015, Mahapatra and co-workers [103] synthesized a coumarin-appended thioimidazole-linked imine conjugate 42 by combining two different fluorogenic ligands. 42 could recognize Cu2+ selectively among a wide range of biologically relevant metal ions, with a color change from light yellow to colorless. The fluorescence enhancement upon addition of Cu2+ was attributed to the chelation of Cu2+ through the deprotonated phenolic oxygen, the imine and thiazole N atoms, and the lactone carbonyl oxygen, which led to the suppression of C=N bond isomerization to attain a conjugated coplanar structure as well as the excited-state intramolecular proton transfer. Especially, 42 exhibited low cytotoxicity and good membrane permeability for the detection of Cu2+.

3.3 BODIPY-based sensors The first BODIPY-based fluorescent sensor for Cu2+ was reported by Bentley and co-workers in 2006 [104]. Since then such kind of chemosensors have drawn continuously interest because of their outstanding advantages such as strong 28

absorption in the near-infrared (NIR) region, high fluorescence quantum yield, high solubility and stability in many solvent systems [105]. In recent years, a lot of chemosensors have been synthesized by combining BODIPY unit and various chelator ligands. In 2012, Ng and co-workers [106] reported a highly selective colorimetric and fluorescent probe 43 based on a distyryl BODIPY with two bis(1,2,3-triazole)amino substituents. 43 could selectively bind to Cu2+ to give remarkably fluorescent and color change as a result of inhibition of the intramolecular charge transfer process. Namely, the emission band of 43 in CH3CN/H2O (11 v/v) was blueshifted by 82 nm and become stronger upon addition of Cu2+, with a color change from green to deep blue. However, the competition experiments showed that excess Hg2+ could interfere with Cu2+, which may limit its practical applications. In 2013, Wu and co-workers [107] synthesized a BODIPY-based fluorescent chemosensor 44 with NSe2 moiety as a chelator for the metal ion. 44 exhibited significant fluorescence enhancement upon addition of Cu2+, while a large range of other transition metal ions only caused minimal changes in fluorescence emission. It’s worthy to note that 44 could detect Cu2+ in a wide pH range of 5.0-9.0, and showed reversibility as an excess amount of S2- could release the chemosensor from the complex 44-Cu2+. Additionally, 44 has low cytotoxicity and therefore can be used as an effective fluorescent probe for detecting Cu2+ in living cells. Very recently, Qin and co-workers

[108]

reported

a

novel

BODIPY

derivative

45

with

a

1-(furan-2-yl)-N-((pyridin-2-yl)methyl)methanamine (FPA) unit as receptor. Similar to 44, 45 also exhibited a high affinity and selectivity for Cu2+ over a large range of competing metal ions with large fluorescence enhancement and visible color change from light yellow to pink due to the formation of 45-Cu2+ complex, but the coordination modes are different. For 45-Cu2+, both the nitrogen atom and the oxygen atom of the FPA unit provided coordination sites, while the NSe2 moiety works as a chelator in 44-Cu2+. Moreover, the visible light excitable, fluorescent chemosensor 45 showed potential for imaging and sensing of Cu2+ in living cells. 29

3.4 Miscellaneous sensors In 2014, Shankarling and co-workers [109] synthesized a thio-β-enaminone analog 46, which showed excellent sensitivity and selectivity for Cu2+. As shown in Fig. 23, 46 exhibited pronounced fluorescence enhancement for Cu2+ ions, which remained nearly unaffected in presence of the other competitive metal ions. The remarkable fluorescence enhancement was due to the chelation enhance fluorescence effect. The low detection limit in micromolar range with a wide pH range (3.0–10) made 46 a suitable candidate for detection of Cu2+ in tap water and human serum samples. Schiff bases can also be used in analytical and pharmacological area as they are good ligands for metal ions [110]. In 2016, Wu and co-workers [111] synthesized a p-dimethylaminobenzamide-based Schiff base derivative 47 as an off-on fluorescent chemosensor for Cu2+. The possible sensing mechanism is shown in Fig. 25. Upon the addition of Cu2+, the formation of complex showed a strong fluorescence enhancement, as the complexation could restrict the rotation of O−C=N bonds and lead to the suppression of -O−C=N isomerization (Fig. 24). 47 can be used to quantify Cu2+ in aqueous phase with a detection limit of 0.32 nM, it is also a simple and visible fluorescent probe for quantitative detection of Cu2+ as low as 10 M on the paper-made test strips. Importantly, 47 may be one of the most favorable chemosensor 30

for the detection of Cu2+ in living cells due to the water solubility and membrane permeability. Hydrogel is a cross-linked hydrophilic polymer that has been widely exploited in biochemical applications, such as hydrogel-based sensors [112]. Recently, Wang and co-workers [113] reported a strip-like functional hydrogel 48 for visual and portable detection of Cu2+. As shown in Fig. 25, the chemosensor 48 was prepared by caging the nonfluorescent hydrogel with poly(thymine), which could effectively template the formation of fluorescent copper nanoparticles in the presence of the ascorbate and Cu2+. The strategy integrated sample-injection, reaction and indication with fast signal response, and provided an add-and-read manner for visual and portable detection of Cu2+. The impressive advantages such as detection ability with a detectable minimum concentration of 20 μM, resistance to environmental interference, good constancy and recoverable function made the hydrogel-based sensor great potential for practical detection of Cu2+. 4 Ratiometric fluorescent chemosensors ‘On-off’ and ‘off-on’ fluorescent chemosensors are based on the changes in emission intensity at a single wave-length, which tend to be affected by a variety of factors such as the instrumental efficiency, the concentration of chemosensor, and the micro-environment. [114] In contrast, the ratiometric fluorescent chemosensors exhibit changes in the ratio of the intensities of emission at two different wavelengths, and can be used to evaluate the analyte concentration and provide a build-in correction for environmental effects [115]. 4.1 Pyrene based chemosensors Among many kinds of fluorophores, pyrene is a well-known aromatic hydrocarbon with unique photophysical properties that has been widely used as fluorophore for synthesis of ratiometric fluorescent chemosensors [116-118]. In 2012, Kumar and co-workers [119] synthesized a ditopic fluorescent chemosensor 49 in the 1,3-alternate conformation of thiacalix[4]arene possessing a crown-4 moiety and an amino moiety appended with pyrenyl groups. Only in the presence of Cu2+, 49 31

exhibited fluorescence enhancement at 378 nm and fluorescence quenching at 466 nm, respectively, which was attributed to the conformational change that occurred during the binding of the Cu2+ to the nitrogen atoms. The addition of Li+ resulted in fluorescence enhancement due to the binding of a Li+ ion to the crown-4 ring, which inhibited the photoinduced electron transfer to the photoexcited pyrene dimer. Sequential additions of Cu2+ and Li+ triggered a Cu2+/Li+ switchable fluorescent chemosensor with negative allosteric behavior between these ions. Then, in 2015, Yamato and co-workers [120] reported a thiacalix[4]arene based fluorescent chemosensor 50 bearing two pyrenyl groups in the same conformation as 49. Fluorescence titration experiments showed that the fluorescence intensity of the excimer emission gradually decreased with an enhancement of the monomer emission at the low concentration of Cu2+. However, when the concentration of Cu2+ was beyond 4 equiv. of 50, the fluorescence intensity exhibited a dramatic decrease, which may be attributed to the heavy atom effect at high ionic strength. Very recently, Li and co-workers [121] synthesized a simple pyrene compound 51 containing thiophene and used it as ratiometric fluorescent chemosensor to recognize Cu2+. On the contrary to the thiacalix[4]arene derivatives 49 and 50, the monomer emission at 375 nm decreased while the excimer emission at 460 nm increased upon addition of Cu2+, suggesting the skeleton of thiacalix[4]arene play a key role on the photophysical properties of the pyrene based chemosensors.

32

4.2 Fluorophore hybridization chemosensors Besides the strategy using a single fluorophore to obtain ratiometric changes, fluorophore hybridization approach is the commonly exploited sensing method for designing of ratiometric fluorescent chemosensors. This kind of ratiometric chemosensors normally consists of two fluorophores linked by a spacer: one is an energy donor, and the other is an energy acceptor. The structural feature of the fluorophore hybridization can achieve large pseudo-Stokes shifts, meanwhile affording simultaneously recorded ratio signals of two emission intensities at different wavelengths, which could provide a built-in correction for the environmental effects [122]. Fluorophore hybridization chemosensors mainly work on two mechanism, Förster resonance energy transfer (FRET) [123-125] or through-bond energy transfer (TBET) [126]. Normally, the chemosensors based on FRET processes are usually linked by a nonconjugated spacer, and the energy transfer occurs through the spacer. For example, Guo and co-workers [127] reported a reversible ratiometric sensor 52 for Cu2+ detection, which was constructed by two fluorophores, i.e. coumarin and 4-amino-7-sulfamoyl benzoxadiazole. The fluorescent ratiometric sensor 52 exhibits a specific Cu2+-induced blue shift from 555 to 460 nm, since the coordination may decrease the FRET between the two fluorophores. It’s worthy to note that the metal coordination signaling mode made the sensing response very rapid and reversible, which are especially appreciated for the tracking of quick intracellular Cu2+ fluctuation. Ratiometric chemosensors based on TBET (through-bond energy transfer) are the ones which have a donor connected to an acceptor via electronically conjugated linkers which prevent the donor and acceptor fragments from forming planar, and the energy transfer occurs through a bond. TBET-based chemosensors often exhibit fast energy transfer rates, large pseudo-Stokes shifts, and flexibility in fluorophores [128]. To date, the examples of this kind of chemosensors are quite limited. Recently, Fan and co-workers [126] synthesized a rhodamine-naphthalimide based fluorescence ratiometric chemosensor 53 linked by 4-ethynylaniline at the naphthalic anhydride position. In the absence of Cu2+, the excited energy of the naphthalimide donor could 33

not be transferred to the rhodamine acceptor, and only the emission of the naphthalimide (535 nm) was observed. Upon addition of Cu2+, the emission maximum of the system changed from 535 nm to 577 nm, with the color change from yellow-green to pink. The detection of Cu2+ was nearly not interfered by a large range of metal ions and anions in environmental and biological settings, and the sensor 53 could be applied for ratiometric fluorescence imaging of Cu2+ in living cells.

4.3 Dual-emission fluorescent nanoparticles Compared with the conventional organic chemosensors, dual-emission fluorescent nanoparticles based ratiometric fluorescent chemosensors do not need elaborate molecular design and complicated synthesis. They are simply obtained by combining two different fluorophores in one nanoparticle, one fluorophore as reference and another as a signal report unit. Thus this kind of ratiometric fluorescent chemosensors has attracted significant attention in recent years [129-130]. In 2014, Shangguan and co-workers [131] developed a simple method to prepare dual emission nanoparticles 54 for ratiometric detection of Cu2+. As shown in Fig. 26, the dye-doped silica nanoparticles (red) were firstly prepared with rhodamine B isothiocyanate (RBITC), aminopropyltriethoxysilane (APTES), and tetraethyl orthosilicate (TEOS) by a Stöber method. Then a thin silica shell was deposited on the silica core by capping TEOS. Finally, the CDs were coupled on the surface of the dye-doped silica nanoparticles through the silylation reaction affording the dual-emission fluorescent chemosensor 54, which could exhibit characteristic fluorescence emissions of rhodamine B (red) and CDs (blue) under a single excitation wavelength. As the surface of CDs is appended with large amount of ethylenediamine units, Cu2+ can selectively bind to the surface of CDs and result in the quenching of the blue fluorescence, whereas the red fluorescence still remained, thereby realizing 34

the ratiometric fluorescence response to Cu2+. It’s worthy to note 54 exhibited good selectivity to Cu2+ over other metal ions, and could be used in the determination of spiked Cu2+ in water samples and in living cells. Recently, Pitchumani and co-workers [132] reported a silver nanoparticles-based ratiometric chemosensor 55, which was prepared by a simpler method. First, thiol stabilized silver nanoparticles were prepared by the reduction of silver nitrate with 2-mercaptoethanol. Then the thiol stabilized silver nanoparticles were treated with an ethanolic solution of 2-(2-aminophenylthio)acetyl bromide and dansyl chloride in the presence of triethylamine affording the chemosensor 55. A decrease in the fluorescence at 497 nm and an increase in the fluorescence at 410 nm upon the addition of Cu2+ to the solution of 55 in aqueous acetonitrile were observed, which were attributed to the formation of Cu2+ complex and energy transfer occurred from the dansyl moiety to the copper complex (Fig. 27). The facile preparation, excellent sensitivity and selectivity for Cu2+, and low detection limit up to 5.0×10-10 M made 55 to be a potential ratiometric sensor in practical applications. Most of the reported fluorescent chemosensors require one-photon excitation using short-wavelength UV−vis light (350-500 nm). However, the utilization of UV−vis excitation may bring some problems such as background fluorescence, scattering light, photodamage to biological samples, and photobleaching of fluorophores. As a new technique, the two-photon microscopy (TPM) utilizes two photons of lower energy for excitation, and exhibits several advantages including increased penetration depth, localized excitation, and low phototoxicity. In 2013, Tian and co-workers [133] developed a two-photon fluorescent probe 56, namely, ATD@QD-E2Zn2SOD (ATD = amino triphenylamine dendron, QD = CdSe/ZnSe quantum dot, E2Zn2SOD = Cu-free derivative of bovine liver copper−zinc superoxide dismutase). The probe features two independent emission peaks at 515 nm (green) and 650 nm (red), respectively, under two-photon excitation at the wavelength of 800 nm. As shown in Fig. 28, Cu2+ might quench the red fluorescence of QDs, whereas the green fluorescence of ATD stays constant, resulting in a two-photon ratiometric fluorescent sensor for Cu2+ in live cells with high sensitivity and selectivity. This is the first report of QD-based two-photon 35

ratiometric fluorescence probe suitable for detection of Cu2+ in live cells. As shown in Table 7, the ratiometric fluorescent chemosensors 49-56 all display two emission bands, which are determined by the structures of chemosensors. One emission was dependent on the concentration of the Cu2+, while the other one was not affected by the Cu2+ and could be corrected for using the ratio between the constant and varying emission intensities. The outstanding advantage of this kind of chemosensors is that most of them can be used to detect the Cu2+ in biological system. The key factors such as the cytotoxicity and water solubility should be considered in the design of this kind of chemosensors in future. 5 Cu2+-promoted reaction based chemosensors In a broad sense, all of the chemosensors are involved in a special reaction during the recognition process of Cu2+. Generally, most of the reactions are the coordination between the chemosensor and Cu2+. Especially, the reactivity-based Cu2+ detection refers to the irreversible chemical reactions to transform nonemissive precursors to fluorescent products. 5.1 Cu2+-promoted hydrolysis Cu2+-promoted hydrolysis has become one of important strategy to devise fluorescent chemosensors for Cu2+, and drawn several research groups’ attention [134-137]. Generally, such kind of chemosensor itself is non-fluorescent, while a fluorophore can be released via the Cu2+-promote hydrolysis of the chemsensor. So, one of outstanding advantage of these chemosensors is that they are applicable for the determination of Cu2+ in aqueous samples as well as in living cells. In 2016, Zheng and co-workers [138] prepared a semicarbazide-based naphthalimide 57 as a simple and effective fluorescent probe for Cu2+. Upon addition of Cu2+, 57 exhibited color change from colorless to jade-green with remarkable fluorescence enhancement, which was attributed to the Cu2+-promoted hydrolysis of the semicarbazide moiety leading to the release of the green fluorescent 4-amino-1,8-naphthalimide fluorophore (Fig. 29). 5.2 Cu2+-promoted oxidation reaction 36

As we know, Cu2+-promoted oxidation reaction has been used widely in organic synthesis due to the redox-active nature of Cu2+ [139-140]. This reaction can also be used to devise chemosensors for Cu2+ [141-142]. In 2013, Kim and co-workers [143] reported a new naphtol derivative 58, which could detect Cu2+ in CH3CN via an ion-promoted oxidation reaction. A selective color change from yellow to dark blue and a fluorescence quenching was observed after Cu2+ was added. As shown in Fig. 30, the naphthol moiety of 58 being oxidized by Cu2+ to a quinine moiety led to the color change. However, 58 could trigger a color change from yellow to colorless and quench the fluorescence upon binding Cu2+ in 10% aqueous CH3CN solution, because the oxidative activation of 58 by Cu2+ did not happen in the aqueous solution. In 2014, Zhou and co-workers [144] reported a coumarin-based colorimetric and fluorescence off–on chemosensor 59 containing a diaminomaleonitrile unit. The interactions among 59 and Cu2+ were completed in less than 3 min with the color change from purple to yellow green, suggesting 59 could detect Cu2+ with high sensitivity and could be used for real-time tracking of Cu2+. Notably, the single crystal structure of the complex 59-Cu2+ explained reasonably the mechanism for recognition of Cu2+. As shown in Fig. 31, Cu2+ played dual roles of coordination center and catalyst that catalyzed the ring-closing of diaminomaleonitrile moiety in the recognition process. Cu2+-promoted oxidation reaction can also been used to yield organic radical cations, which has been actively studied as organic magnets, mixed-valence materials, biomedicines [145] and chemosensors [146]. Zhu and co-workers [147] designed a donor-acceptor system of indoline-benzothiadiazole 60 as a chemosensor for Cu2+. Upon addition of Cu2+, a rapid color change from red violet to blue and the NIR fluorescent quenching could be observed, as the radical cations were formed by oxidation of 60 in concomitance with a reduction of Cu2+ to Cu+. (Fig. 32) 5.3 Cu2+-based reduction reaction To our best knowledge, there are only two examples that Cu2+-based reduction reaction was used to devise fluorescent chemosensors for Cu2+. In 2013, Peng and co-workers [148] reported the first example of such kind of chemosensor 61, which 37

consisted of a bis-rhodamine as the fluorophore and a tridentate sulfur ligand as coordination sites for Cu2+. 61 showed excellent specificity for Cu2+ over other cations and the sensing process could be completed within 3 min with the color change from colorless to purple. The detection mechanism was proposed to the coordination of Cu2+ by the tridentate ligand, which promoted ring-opening of the rhodamine groups following by a spontaneous reduction reaction (Cu2+ to Cu+), and led to the formation of a fluorescent 61-Cu+ complex (Fig. 33). This is a rarely reported mechanism related with the reduction reaction. 61 could be made into test papers for the practical detection of Cu2+ in the environment. The typical click chemistry reaction, Cu+-catalyzed azide and alkynecycloaddition reaction, has also been used to detect Cu2+ [149]. In 2016, by combining the metal-enhanced fluorescence technology [150] and click chemistry reaction, Ma and Zhou [151] reported a novel strategy (Fig. 34) for Cu2+ detection, which was based on the reduction of Cu2+ to Cu+ by sodium ascorbate to get a cycloaddition reaction between 4-azidobenzoic acid-tagged Au@SiO2 and propiolic acid-tagged carbon dots (CDs). The strategy not only possesses a good selectivity, but also has a linear relationship between the fluorescence intensity and the concentrations of Cu2+ in the range of 0.1-100 nM with a detection limit of 0.08 nM. Additionally, the standard deviation in the river sample ranges from 97.6% to 101.8%, indicating the high precision of this method. As it needs a long time up to about 3 h to complete the click chemistry reaction, and the sample should be centrifuged and washed to remove the unattached CDs. Furthermore, the as-formed sample should be dispersed in deionized water before the fluorescence measurement. The procedure seems so complicated that it is not suitable for practical applications. 6 Conclusions and future perspectives The literature retrieval about the title research topic was carried out via SciFinder Academic by using “fluorescent chemosensors for copper(II) ions” as key words. Up to date, 277 literatures including journal paper, patents, conference abstracts, etc. have been published, since the first paper was published in 1997 by Corradini and 38

co-authors [152]. As seen in Fig. 35, in the initial stage from 1997 to 2006, there were only a handful of publications every year, and most of the fluorescent chemosensors were the on-off type basically due to the paramagnetic nature of Cu2+. Since 2007, this research field has gradually drawn much attention from many chemists, and a lot of great achievements have been obtained in recent years. At present, there have been a large number of novel chemosensors for Cu2+ based on Quantum dots, nanomaterials, and periodic mesoporous organosilicas. Moreover, several new techniques including near infrared light emitting and two-photon microscopy have been developed to devise fluorescent chemosensors for Cu2+, and some of them have been successfully applied for detection of Cu2+ both in biological and in environmental samples. The research topic in fluorescent chemosensors is still in the developing stage, there are many challenges to be solved in the future. For the practical applications, an ideal chemosensor should have many features such as high sensitivity and selectivity, fast response time, ease of preparation, low toxicity, water solubility, and so on. Although many fluorescent chemosensors for Cu2+ have been reported, they are still limited in practical applications to some extent. Specific devices of fluorescent chemosensors are quite scarce, which might be one of the major tasks in fields of chemistry and materials sciences. In addition to further improvements of these properties, other important scientific issues to pursue in this field include: (1) To develop fluorescent chemosensors for Cu2+ in living system. The Cu2+ ions in biology include two general pools: a static pool where Cu2+ ions are tightly bound by proteins and other macromolecules, and a labile pool where Cu2+ ions are bound weakly to cellular ligands.[153] Exchange can occur between the static and labile metal pools, indicating the Cu2+ in biology keep in a dynamic equilibrium, and thus bring more difficulties to detect the Cu2+ accurately. Currently, all of reported fluorescent chemosensors still can’t meet the practical demand. It’s a key task to improve the sensitivity, the binding ability with competing ligands, toxicity, water-compatibility, and distribution in biological systems. (2) To study the relationship between the molecular structures and properties. 39

Although the research in fluorescent chemosensors for Cu2+ has been carried out for more than two decades, it still hasn’t a definite rule to follow in design of new chemosensors. To some extent, the scientists are random in developing new chemosensors and often get negative results. Thus, theoretical studies should be strengthened to identify systematically the relationship between the structures and physical properties, especially the factors to determine the selectivity of the chemosensors for Cu2+ should be explored intensively. (3) To develop Cu2+-promoted reaction based chemosensors. This is a quite new interdiscipline related with chemistry, biology and material sciences, and needs close cooperation among different subjects. The reaction based chemosensors for Cu2+ often exhibit unique advantage over the others, which make it possible to find special applications in biological conditions and environmental systems as aforementioned. In summary, the fluorescent chemosensors for Cu2+ have an enough room to be explored, and more important achievements are expected to obtain in the future. Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 21272130) and Beijing National Laboratory for Molecular Science. We are grateful to the reviewers for their valuable comments and suggestions. Reference [1] A. W. Czarnik, in Advance in Supramolecular Chemistry, ed. G. W. Gokel, JAI Press, Greenwich, Connecticut, 1993, vol. 3, pp. 131-157. [2] D. T. Quang, J. S. Kim. Fluoro- and chromogenic chemodosimeters for heavy metal ion detection

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Shuo Liu received his Master’s degree in pharmaceutical engineering from Tianjin University in 2011. Currently he is working as a research associate in college of chemistry, Nankai University, Tianjin, China. His research interests mainly include fluorescent nanomaterial based chemosensors for heavy metal ions.

Yan-Mei Wang received her B.Sc in metallurgy from Shenyang College of Metallurgy, Shenyang, China in 1995 and M.Sc in chemistry from the college of chemistry, Nankai University, Tianjin, China in 2009. She is currently a senior experimentalist in college of chemistry, Nankai University, Tianjin, China. Her major research interest focuses on the chemosensors for H2S, NO2 and transition metal ions.

Dr. Jie Han is an associate professor in the college of chemistry, Nankai University, Tianjin, China. He received his Ph.D. in chemistry in 2003 from Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences with Professor Liang-Fu Zhang. Then, he worked as a research assistant from 2004 to 2005, with Professor Chi-Ming Che, at the University of Hong Kong, Hong Kong, China, and worked as a visiting professor from 2013 to 2014 with Professor Fraser Stoddart, at Northwestern University, IL, USA. His major research interest lies in the synthesis and the relationship between the structures and properties of photochromic organic materials, light-emitting liquid crystals and fluorescent chemosensors for heavy transition metal ions. He has published more than 60 research paper in peer-reviewed international journals.

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Shuo Liu

Yan-Mei Wang

Dr. Jie Han

57

Fig.1 Fluorescence intensity at 450 nm in the absence and presence of Zn2+ and Cu2+. Reproduced from Ref [24] with permission of Elsevier.

A

B

Fig. 2 (A) Emission spectra of 11 (10 mM) in DMSO and DMSO–water mixtures with different water fractions (fw). (B) Plots of emission intensity versus the composition of the aqueous mixtures of 11. Inset: Photo of 11 in DMSO and DMSO–water mixtures with fw values of 0 and 99 vol% under 365 nm UV lamp illumination. Reproduced from Ref [34] with permission of The Royal Society of Chemistry.

Fig.3 Proposed sensing mechanism for Cu2+ detection.

58

Intens

ity/a.

u.

Cu

2+

Fig. 4 Changes in the fluorescence spectra of 13 with varying concentrations of Cu2+. Reproduced from Ref [36] with permission of Copyright 2016, Elsevier.

Fig. 5 Mechanism of Cu2+ and l-histidine sensing by 16.

Fig.6 Schematic illustration of the sensing mechanism of CdSe/ZnS QDs 21 for the detection of Cu2+.Reproduced from Ref [57] with permission of The American Chemical Society.

59

Fig. 7 Schematic illustration of the NIR QDs 22 for detection of Cu2+. Reproduced from Ref [58] with permission of Copyright 2016, Elsevier.

Fig.8 Schematic illustration of CDs 23 for detection of Cu2+ and L-cysteine detection. Reproduced from Ref [63] with permission of Copyright 2014, Elsevier.

Fig. 9 Schematic representation of the preparation route for silica coated CDs 24 and the detection for Cu2+.Reproduced from Ref [64] with permission of The American Chemical Society.

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Fig. 10 Schematic diagram for the fluorescence of 25 quenched by Cu2+. Reproduced from Ref [66] with permission of The American Chemical Society.

Fig. 11 Schematic representation of the preparation route for 26 and its quenching by Cu2+. Reproduced from Ref [69] with permission of Copyright 2013, Wiley-VCH.

Fig.12 Schematic representation of the proposed synthetic routes for 28, and the illustration of the fluorescence emission and quenching mechanisms. Reproduced from Ref [72] with permission of The Royal Society of Chemistry.

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Fig. 13 Schematic illustration of the fabrication of 30. Reproduced from Ref [75] with permission of Copyright 2015, Elsevier.

Fig. 14 The sensing principle of 31 for Cu2+. Reproduced from Ref [78] with permission of The American Chemical Society.

Fig. 15 Possible sensing mechanism of 32 for Cu2+. Reproduced from Ref [81] with permission of The American Chemical Society.

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Fig. 16 A schematic illustration of the synthesis of 33 (A) and the strategy for Cu2+ detection (B). Reproduced from Ref [85] with permission of The Royal Society of Chemistry

Fig. 17 A schematic representation of the detection systems of 34. Reproduced from Ref [87] with permission of Copyright 2015, Elsevier.

Fig. 18 Cu2+ induced catalytic hydrolysis of 35.

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Fig. 19 The proposed determination mechanism of 36.

Fig. 20 The proposed determination mechanism of 37.

Fig. 21 Proposed possible binding mode of 38 with Cu2+.

Fig. 22 Chemical and schematic illustration of the preparation of 39 for Cu2+.

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Fig. 23 Fluorescence response (excitation  = 467 nm) of 46 (1 × 10−5 M) for various metal ions in ACN-HEPES buffer (pH = 7, 10 mM, 9:1, v/v) solutions. Reproduced from Ref [109] with permission of Copyright 2014, Elsevier.

Fig. 24 A possible sensing mechanism of 47 to Cu2+.

Fig. 25 Visual and Portable detection of Cu2+based on 48. Reproduced from Ref [113] with permission of The American Chemical Society.

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Fig. 26 Schematic illustration of the preparation of 54 and its sensing mechanism to Cu2+. Reproduced from Ref [131] with permission of The American Chemical Society.

Fig. 27 Proposed binding mechanisms for 55 with Cu2+.

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Fig. 28 Schematic illustration for the working principle of two-photon ratiometric imaging and sensing of Cu2+. Reproduced from Ref [133] with permission of The American Chemical Society.

Fig. 29 The reaction mechanism of 57 with Cu2+.

Fig. 30 Oxidation of 58 by Cu2+.

Fig. 31 The proposed mechanism of ring-closing of diaminomaleonitrile moiety and the process of coordination between 59 and Cu2+. Reproduced from Ref [144] with permission of Copyright 2014, Elsevier.

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Fig. 32 NIR fluorescent Cu2+ sensors based on indoline-benzothiadiazole derivatives via formation of radical cations.

Fig. 33 Proposed sensing mechanism of 61 for Cu2+.

Fig. 34 Fluorescence sensing of Cu2+ based on click chemistry. Reproduced from Ref [151] with permission of Copyright 2016, Elsevier.

Fig. 35 Number of publications on fluorescent chemosensors for copper(II) ions versus year (Information retrieval from Sci-Finder Academic on Feb.9, 2017)

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Table 1 Properties of chemosensors 1-6 Sensor

Solvent

pH

Stoichiometry (Sensor/Cu2+)

Ka M−1

λex, nm

λem, nm

LODs (nM)

1e 2 3 4 5 6

THF DMF/HEPES (7:3) DMSO/PBS (1:9) DMSO/PBS (9/1) THF/HEPES (8:2) MeOH/H2O (6:4)

7.0 7.3 7.4 7.4 -

1:1 1:1 1:1 1:1

1.5×106 3.5×106 2.33×105

440 600 400 400 450 398

513 647 567 510 628 450

400 189 100 97 5

Table 2 Properties of chemosensors 7-10 Sensor

Solvent

pH

Stoichiometry (Sensor/Cu2+)

Ka

λex, nm

λem, nm

LODs (nM)

7a 7d 8 9 10

DMSO DMSO MeOH DMSO/H2O (3:7) DMF/HEPES (1:1)

7.4 7.4

2:1 2:1 2:1 1:1 1:1

2.1×107 M−2 7.5×107 M−2 6.4×104 M−1 3.8×104 M−1

282 282 480 470 365

350 350 518 524 425

8.8 4.9 3 1.6

Table 3 Properties of the supramolecular fluorescent chemosensors 14- 20. Probe

Solvent

pH

Stoichiometry (Sensor/Cu2+)

Ka

λex, nm

λem, nm

LODs (μM)

14 15 16 17 18 19 20

MeOH/ H2O HEPES buffer DMSO/ H2O THF CH3CN/CH2Cl2 CH2Cl2 CH2Cl2

7.3 7.4 7.4 7.3 7.3 7.3

1:1 1:1 1:1 1:1 1:1 1:2

1.25×106 M−1 2.09×104 M−1 6×103 M−1 1.16×104 M−1 -

331 470 320 350 315 280 300

380 530 481 455 403 354 367

0.84 0.5 -

Table 4 Properties of QDs based chemosensors. Probe

Solvent

pH

λex, nm

λem, nm

LODs(nM)

21 22 23 24 25 26

H2O Tris-HCl buffer H2O PBS PBS Tris-HNO3 buffer

8.5 7.0 7.4 4.0 -

380 320 358 365 320

620 810 460 446 450 405

0.15 50 23 300 6 6.9

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Table 5 Properties of fluorescent nanomaterials based chemosensors. Probe 27 28 29 30 31 32 33

Solvent

Ka, M−1

pH

EtOH/ H2O (2:1) HEPES buffer MeOH/H2O (4:1) distilled water Tris-HCl H2O H2O

λex, nm

λem, nm, free(Cu2+)

LODs (nM)

365 371 417 347 355 290 367

580 505 500 615 455 410(370) 440

10 280 7.5 8000 0.5 10 0.0008

6

HNO3 7.4 -

1.3×10 2.6×104 -

7.4 4

-

Table 6 Properties of rhodamine-based sensors. Probe

Solvent

pH

Stoichiometry (Sensor /Cu2+)

Ka, M−1

λex, nm

λem, nm

LODs (nM)

35 36 37 38 39 40

CH3CN/H2O(4:1) HEPES CH3CN/H2O(2:3) MeOH/H2O (1:1) EtOH/ H2O (1:1) EtOH/ H2O (4:1)

7.0 7.2 6-7 7.2 6.8

2:1 1:1 1:2 1:1 1:1

9.32×104 -

380 325 515 552 520 500

534,575 518 585 580 557 ~550

20 110 2000 1500 1.0×104

Table 7 Properties of ratiometric fluorescent chemosensors. Probe 49 50 51 52 53 54 55 56

Solvent EtOH/HEPES(4:1) EtOH Tris-HNO3 CH3CN/Tris-HCl (9:1) CH3CN/Tris-HCl (20:1) PB CH3CN/PB (1:1) PBS

pH 7.0 7.0 7.4 7.4 7.4 7.4 7.4

Ka 11

−2

3.39×10 M 3.5×105 M−1 2.18×104 M−1 7.14×104 M−1 -

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λex, nm

λem, nm (Cu2+)

LODs (nM)

340 344 342 405 420 360 260 800

378, 466 379, 484 375, 460 460, 555 535, 577 467, 585 410, 497 515, 650

40 144 20 3000 388 35.2 0.5 10