Chinese Chemical Letters  2018, Vol. 29 Issue (10): 1465-1474   PDF    
Recent advances in click-derived macrocycles for ions recognition
Rongpeng Peng1, Youliang Xu1, Qianyong Cao    
Chemical College, Nanchang University, Nanchang 330031, China
Abstract: The Cu(Ⅰ)-catalyzed azide-alkyne 1, 3-dipolar cycloaddition (CuAAC) reaction, popularly known as the "click reaction", have been widely used in chemosensor field. This reaction gives a mild and efficient coupling reaction between the binding site and the reporter. In addition, the formation 1, 4-disubstituted 1, 2, 3-triazole linker shows a high binding affinity toward both anions and metal ions. Recently researches revealed this reaction is also an efficient tool to form rigid or shape-persistent, preorganized macrocyclic species. This review summarized the recent advances in click derived macrocyclic receptors for recognition of anion, metal ion and ions pair.
Keywords: Macrocycle     Click reaction     Anion recognition     Metal ion recognition     Ions pair receptor    
1. Introduction

Macrocyclic receptors bearing preorganized cavities and multivalent binding sites are the major hot topic in supramolecular chemistry [1-6]. Functionalized macrocycles are not only used in molecular recognition and sensing, but also found applications in molecular machines and devices, supramolecular polymers, stimuli-responsive materials and drug-delivery systems. However, the design and synthesis of novel macrocyclic hosts with good host-guest properties still remains a challenge.

The Cu(Ⅰ) catalyzed azide-alkyne cycloaddition (CuAAC) reaction, also known as "click reaction", has had an enormous impact on the field of organic chemistry due to its high efficiency, mild reaction conditions, and technical simplicity [7-10]. Recently, this reaction has also been widely used in chemosensor filed for it's effectively coupling method, and can be acted as a linker between the binding site and the reporter [11-13]. Importantly, the formation 1, 4-disubstituted 1, 2, 3-triazole is a good donor for both anion and canion via different binding mechanisms (Fig. 1). The heterocycle ring can coordinate with cation via the N2 or N3 atom of the triazole, while the acidic C5-H proton can bind with anion via the C5-H… anions hydrogen bonding interaction, which can be further enhanced by converting the 1, 2, 3-triazole unit into a 1, 2, 3- triazolium cation. The latter is expected to be an even-more efficient anion captor using anion-π interaction as an alternative binding mechanism. In addition, when the C5-H proton of triazole/ triazolium was displaced by a halogen atom like iodine or bromine, a halogen bond interaction mechanism will be applied in selective anion detection.

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Fig. 1. The click-derived click ring as multiple binding donor for metal ions and anions.

Due to its mild reaction conditions and technical simplicity, click reaction is viewed as an efficient and flexible strategy for preparing macrocycles with different purposes. There are two main strategies for the synthesis of cyclic triazole receptors (Fig. 2). The first involves the macrocyclization of a bifunctional acyclic monomer containing a free acetylene and a free azide termini (method A), while the second strategy is achieved by cyclization between a diazole and a dialkyne monomers (method B). To avoid the linear oligomers byproducts, the macrocyclization is usually conducted under high dilution conditions. The reported yield of the macrocyclization is about 40%–50%. Better product yields could be realized when the acetylene and azide groups inside the monomers are preorganized to reduce the entropy loss [14-16], or the macrocycle product shows low solubility in the reaction solution [17], which crash it out of the reaction mixture.

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Fig. 2. Formation of cyclic triazoles higher oligomers via different methods.

In this review, we would like to focus our attention on macrocyclic receptors with using the click reaction as the macrocyclization method, in which the triazole ring is used as both anion and cation binding site forionsrecognition. The alkylation triazolium macrocycles alsobelong to this catalog. Macrocycles like cyclam, calixarenes, cyclodextrins bearing pendant triazole ligands for recognition are excluded from the present review. The review is structured in several sections according to the recognition guests(anions, metalions and ions pair), thesensing mechanism and the structural characteristics of host.

2. Recognition of anions

Anions have a major role in industry, the environment, and biology. The research of anion recognition has attracted more and more attention over the last few decades [18-22]. Despite numerous anion receptors have been developed in thisfield, it continues to be a real challenge for selective anion recognition, especially inwater and biological media [23, 24]. To gain the desired selectivity, many research groups have developed different approaches. Effective anion receptors are often constructed from a combination of strong hydrogen-bond donors, positively charged moieties, and Lewis acid metal ions. Recently, the 1, 2, 3-triazole moiety has been shown to play an important role as an anion binding motif through multiple weak C-H hydrogen bonds to stabilize anions.

2.1. Recognition of halides

In 2008, the pioneering work by Flood and co-workers reported a rigid and preorganization [34]triazolophane 1 (Fig. 3) [25]. This macrocycle has a diameter of about 3.8 Å, and the four triazoles and four phenylene CH groups direct into the cavity. Triazolophane 1 displays a high affinity toward Cl- via multiple triazole C–H…anion and phenyl C–H…anion hydrogen bonding interaction as shown in Fig. 3, followed by Br- >> F- >> I-. In CH2Cl2 solution, the association constant of 1-Cl- was calculated to be Ka = (130, 000 ± 30, 000) L/mol; △G = -7.0 kcal/mol (CH2Cl2, 298 K), which approaches the traditional NH donors from pyrrole.

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Fig. 3. Representative [34]triazolophanes 1–3 reported by Flood et al.

Continue this work, more [34]triazolophanes (2a–c) (Fig. 3) with different substituents on the phenylene linkers were designed and prepared [26]. The halide anions binding affinity of 2a–c were determined by UV–vis and 1H NMR titrations. All these triazolophanes show a high selectivity toward size comparable Cl- and Br- anions (Cl- > Br-), which is about 1.5 and 3 orders of magnitude larger than the smaller F- and larger I- anions, respectively. Compared with 1, the anions binding affinity of 2a–c reduced for replacing the t-butyl groups with strong electron donation OTg groups. It also can be envisioned that the triazolophane 3 [27], inwhich one phenyl linker is replaced bya methylenebased (CH2) one, will show a weaker halide anions binding affinity for the flexible cavity and the weak CH hydrogen bond of propylene.

The triazolium cation is known to be more strong anion affinity than the neutral triazole donor. Thus, a bis-triazolium bile acidbased macrocycle 4 (Fig. 4) was designed by Pandey et al. using click reaction [28]. The 1H NMR titration results reveal that this receptor exhibits selectivity for binding of chloride ion, followed by HSO4- > H2PO4- > F- > Br- > CH3COO- > I-. The binding constant of 4-Cl- was calculated to be 3700 L/mol with a 1:1 complexation in CDCl3 solution. In contrast, the neutral analog 5 (Fig. 4) reported by Pasini and co-workers exhibits a unique fluoride coordination property with the formation of a 1:2 complex [29], according to the 1H NMR titration results.

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Fig. 4. Chemical structures of macrocycles 4–8.

Halogen bonding has been used in anion receptors due to the advantages of halogen-bonding. Halogen bond has high directionality and strength, which often cause anions binding more efficiently than the corresponding hydrogen bonding analogue. Kubik et al. reported a cyclic pseudopeptides 6a (Fig. 4) containing three 5-iodo-1, 2, 3-triazole subunits as a novel macrocyclic halogen bonding receptor [30]. Qualitative 1H NMR spectroscopic binding studies were performed to test anion affinity. The results showed that the receptor has a high binding affinity and selectivity toward halides, in particular with chloride, in 2.5 vol% H2O/DMSO. However, non-halogenated compound 6b (Fig. 4) just binds oxoanions such as dihydrogenphosphate and sulfate anions in 2.5 vol% H2O/DMSO solution, but not halides. This result indicates that the introduction of iodine atoms in 6a really can increase affinity for halides, especially for chloride.

The indolocarbazole-based anion receptors have strong anion binding ability. To increase the size and complexity of the anion, larger structures were designed and synthesized. Li and coworkers reported two indolocarbazole-containing macrocycles 7 and 8 by click reaction (Fig. 4) [31]. The single crystal X-ray diffraction analysis reveals both macrocycles form folded structures by the intramolecular hydrogen bonding and π-π stacking. The 1H NMR and UV–vis titrations revealed that macrocycles 7 and 8 show affinity toward halide anions in the order of F- > Cl- > Br- > I-. However, the association constants of 8 with anion are much smaller than that of 7 due to the greater rigidity in 7.

The porphyrin macrocycle has inherent optical and redox properties that can be developed for anion sensors with easy detectable signal change. Beer et al. reported tetratriazole- and tetratriazolium- containing zinc(Ⅱ) metalloporphyrin-cages, 9 and 10 (Fig. 5), for anion sensing [32]. Because of combining C– H…anion hydrogen bonding and Lewis acidity, these two zinc(Ⅱ) metalloporphyrin cages can strongly bind anions with a distinctive naked-eye colorimetric response in polar organic and organicaqueous solvent mixtures. The UV–vis titrations reveal both 9 and 10 form 1:1 stoichiometric complexes with a range of halides and oxoanions, with the tetra-triazolium cage showing stronger affinity toward anions than that of the neutral tetra-triazole host.

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Fig. 5. Chemical structures of compounds 9 and 10, and color of receptor 9 before (left) and after addition of 10 equiv. of anions in acetone. Copied with permission [32]. Copyright 2012, Royal Society of Chemistry.

Gale et al. reported a series of triazole-strapped calix[4]pyrroles 11 and 12 (Fig. 6) for lipid bilayer chloride transport [33]. These calix[4]pyrrole cages bind Cl- via pyrrole NH…Cl- and triazole CH…Cl- hydrogen bond interaction, which can be confirmed by the 1H NMR titration techniques and isothermal titration calorimetry. Further evidence can be proved by the single crystal X-ray crystal analysis of 12b-Cl- and 12c-Cl- complexes. All the triazolestrapped calix[4]pyrroles show a higher affinity for chloride than the parent macrocycle, and the two triazole capped calix[4]pyrrole transporters 12a–c surpass the chloride transport efficiency of 11.

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Fig. 6. Chemical structures of compounds 11–14.

Macrocycles 13a–f (Fig. 6) containing triazole and thiourea hybrid donors were also reported by the same group [34]. The cycles show a good affinity toward Cl- even in competitive DMSOH2O (100:0.5, v/v) solution. These receptors can mediate both Cl-/ NO3- antiport and H+/Cl- symport. So they were able to function as anion carriers, and the transport activity of these hosts were dominated by their lipophilicity.

A chiroptical bitriazole macrocycle 14 (Fig. 6) incorporation the axially chiral binaphthalene unit was reported by Pasini et al. [35]. It was able to selectively bind I-, Br- and Cl- over F- and AcO-, via the CH…X hydrogen bonding. Important, the anions binding causes a large chiroptical response originating from the conformational change of the free host, with changing its dihedral angle in the circular dichroism (CD) spectroscopy.

Rotaxane-based molecular shuttle can be used as mechanically interlocked molecules. It has drawn much attention in the field of nanoscale molecular machines and switches. Anion recognition can serve as a stimulus for rotary motion in rotaxane structure. Examples of anion controlled rotations of interlocked rings in rotaxanes are developed. A series of click derived rotaxane have been reported by Beer et al. [36-41]. A mixed halogen and hydrogen bonding hetero-[2]catenane 15 (Fig. 7) was synthesized via an anion templated Grubbs' Ⅱ-catalysed RCM clipping mechanical bond forming methodology [39]. The 1H NMR titration experiment gives the evidence for interpenetrative pseudorotaxane formation. It was capable of binding and sensing of anion, in particular forming strong associations (Ka > 104 L/mol) with acetate and dihydrogen phosphate, which is demonstrated by the 1H NMR spectroscopy and the fluorescence titration experiments.

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Fig. 7. Chemical structures of compounds 15 and 16.

Electron-deficient heavy chalcogen atoms contain Lewis acidic σ-holes known as chalcogen bonding (ChB) are able to form attractive supramolecular interactions with Lewis bases. They have been used in solution-phase anion binding in simple acyclic systems. Beer's group prepared a mechanically interlocked [2] rotaxane 16 (Fig. 7) as a ChB donor for anion binding [40]. The 1H NMR binding studies performed in organic and aqueous solvent mixtures reveal that ChB-anion binding affinity can rival, and even exceed, that of hydrogen bonding exhibited by all hydrogen bonding receptor analogues. Charge-assisted ChB-mediated halide anion binding favors large halides, followed by I- > Br- > Cl-, which is due to the larger degree of covalency with the heavier halides, as well as the smaller degree of hydration of the anion binding site. The 77Se NMR spectroscopy shows that the chemical shifts of the chalcogen atoms are highly sensitive to anion binding.

Perylene diimide (PDI) has become increasingly popular in the construction of supramolecular materials due to its excellent chromophoric, emissive, and redox properties. Thus, a PDIcontaining dynamic [3]catenane 17 (Fig. 8) was designed [41]. The addition of tetrabutylammonium (TBA) chloride to a solution of 17 in CHCl3:CH3OH (3:1, v/v) solution causes a significant naked-eye detectable color change from red to orange. Fluorescence spectroscopy shows a notable increase in the PDI emission intensity (quantum yield enhancement factor of 57%). The [3]catenane 17 can recognize anions at a low concentration (10-5 mol/L) in a competitive aqueous-organic CHCl3-CH3OH-H2O mixture (45:45:10, v/v/v). Fluorescence emission spectroscopies together with molecular dynamics simulations demonstrated that anions binding, including chloride and other oxoanion salts, induced circumrotatory motion of the smaller macrocyclic rings from the core-substituted PDI motif to the two triazolium groups. The anions binding strength correlates with their basicity, followed by AcO- > H2PO4- > Cl- > SO42- >NO3-.

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Fig. 8. Anion-induced circumrotatory motion in the hetero [3]catenane 17 and the colors associated with each anion. Reproduced with permission [41]. Copyright 2010, American Chemical Society.

2.2. Recognition of phosphate ion

Pyrophosphate detection has aroused interest in the scientific community not only because pyrophosphate is the product of ATP hydrolysis under cellular conditions but also because it could afford a means of effecting real-time DNA sequencing. Sessler et al. reported a pyrrolyl-based triazolophane 18 (Fig. 9), incorporating CH and NH donor groups [42], acts as a receptor for the pyrophosphate anion in chloroform solution. It shows selectivity for trianion HP2O73-, followed by HSO4- > H2PO4- > Cl- > Br-, with N–H…anion interactions being more important than C– H…anion interaction, which can be confirmed by the 1H NMR titration and the single crystal X-ray analyses of 18-HP2O73- complex. The association constants between receptor 18 and HP2O73- was calculated to be (2.30 ± 0.40) × 106 L/mol with a 1:1 binding stoichiometry in CHCl3 solution. Continuing this work, methylation 18 gives a tetracationic triazolium macrocycle 19 (Fig. 9) [43]. Unlike its precursor, which shows anions binding affinity only in apolar media, 19 displays a high selectivity for tetrahedral oxyanions (HP2O73-, HSO4-, H2PO4-) over various monoanions and trigonal planar anions in a mixed polar organicaqueous media. The single crystal X-ray diffraction analyses reveal that 19 can bind pyrophosphate and phosphate anions in the solid state, with the 1:1 and 1:2 complexation, respectively.

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Fig. 9. Chemical structures of macrocycles 18 and 19, and the X-ray single crystal structures of 18 and its HP2O73- complex (bottom). Reproduced with permission [42], Copyright 2010, American Chemical Society.

Two new tetratriazole macrocycles 20 and 21 (Fig. 10) were reported by Lin et al. [44]. The X-ray crystal structures reveal that both receptors have an oblique-pillar cavity with the chair-like conformation in the solid state. In macrocycle 20, the four triazole protons point outside of the cavity and involve in intramolecular hydrogen bond with the adjacent n-hexyloxy oxygen atoms. However, those protons in 21 direct into the cavity, and give intramolecular hydrogen bond with the pyridine nitrogen atom. The 1H NMR titration studies indicated that only macrocyle 21 shows a good anions affinity, with selectively and strongly binding HSO4-, H2PO4- and HP2O73- to form 1:2 host-guest complexes in CDCl3 solution.

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Fig. 10. Chemical structures of compounds 20-24.

A ferrocene-containing marcrocycle 22 (Fig. 10), bearing bistriazole/amide hybrid donors was reported by our group [45]. This receptor shows a high affinity toward H2PO4- in a 1:1 stoichiometry binding model. The association constant of 22-H2PO4- was reported to be 2.28 × 102 L/mol in DMSO-CDCl3 (2:8, v/v) solution. The 1H NMR titration and density functional theory (DFT) calculation results reveal that the amide NH, the triazole CH and the inner phenyl CH are involved hydrogen bonding with the H2PO4- anions, with the anions binding ability amide NH > triazole CH > inner phenyl CH. Owing to the incorporation of redox active ferrocene moiety, marcrocycle 22 shows about -60 mV potential shift upon binding with H2PO4- anion.

Similarly, two ferrocene-containing bis-triazoles marcrocycles 23 and 24 (Fig. 10) were also designed and synthesized [46]. In CH2Cl2 solution, both cycles showed an exclusive electrochemical sensing of H2PO4-, with a cathodic shift in the ferrocene half-redox peak (△E1/2) by 220 mV and 80 mV, respectively. The 1H NMR titrations and the DFT calculations revealed that the triazole C–H, and even the cyclopentadienyl α-position C–H play a key role in the interaction with H2PO4-.

2.3. Recognition of sulfate ion

Li et al. reported a chiral macrocyclic binaphthalene 25 (Fig. 11) containing amide and triazole hybrid donors via click reaction [47]. The results of 1H NMR titration in CD3CN solution reveal that this receptor prefers to bind sulfate over other anions through amide NH…anion and triazole NH…anion hydrogen bonding interaction, with the formation of first a 1:1 host-guest complex, and then a sandwich 2:3 binding stoichiometry complexation. The macrocycle 25 also show CD signal response toward sulfate anion for incorporation the axially chiral binaphthalene unit.

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Fig. 11. Chemical structures of compounds 25 and 26, and the binding model of 25 toward SO42-. Copied with permission [47]. Copyright 2014, Royal Society of Chemistry.

A tetra-triazolium macrocycle 26 (Fig. 11) was reported by Beer et al. [48]. In a 1:1 DMSO-water competitive mixture, this tetracationic receptor exhibits a high preference for sulfate dianion with the associating constant >104 L/mol. In addition, moderated binding ability was also found for the larger halides like bromide and iodide, more strongly than the oxoanion acetate.

3. Recognition of metal ions

Metal ions are widely spread in environment and human body [49-51]. Some metal ions such as Fe3+, Cu2+, Ca2+ and Zn2+ are fundamental element in natural biological systems, while some heavy metal ions (Pb2+, Hg2+, Cd2+) are well-known high toxic substances. Thus, the design and synthesis of new receptors for metal ions is of great interest in supramolecular chemistry. In the past few years, large numbers of newchemosensors for the binding of metal ions have been synthesized via the click reaction due to its simplicity and the good metal ions binding ability of the 1, 2, 3- triazole ring [52-54].

3.1. Recognition of Hg2+

Hg(Ⅱ) is a well-know toxic metal ion, thus a huge amount probes for sensing and detection of Hg(Ⅱ) have been reported. Ju et al. have reported a click derived glycyrrhetinic acid-based macrocycle 27 (Fig. 12) [55]. The 1H NMR, 13C NMR and UV–vis titrations results revealed that this probe can selectively recognize Hg(Ⅱ) in a 1:2 complexation in CD3Cl-CD3OD (7:3, v/v) solution. The triazole ring and carbonyl group in 27 play a significant role for Hg(Ⅱ) ions binding. In addition, compound 27 also exhibited a good affinity toward F- ion through C–H…F- interaction.

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Fig. 12. Chemical structures of compounds 27-29 and schematic representation of the recognition behavior of 28 for Hg2+ ion, and its applications in cascade enantioselective recognition of amino acids. Copied with permission [56]. Copyright 2017, Elsevier.

The same group also reported a fluorescent macrocycle 28 (Fig. 12) by clicking binaphthalene unit onto a deoxycholic acid scaffold to create two tirazole binding sites [56]. In MeOH solution, the binaphthalene-based fluorescence of 28 was quenched by Hg(Ⅱ) for the PET and/or heaven atom effect, and can be recovered by addition of amino acids. Importantly, owing to the chiral scaffold of deoxycholic acid and the macrocylic structure, the formation [28·Hg2+] complex exhibited different fluorescence sensitively toward D-amino acids and L-amino acids. Thus, [28·Hg2+] can be used as an efficient fluorescent turn-on sensor for the enantioselective recognition of amino acids.

Calixarene is a common motif in suprachemistry field. The oxygen atoms in the calixarene pocket are good donors for metal ions, which the binding sensitivity and selectivity can be enhanced by incorporated other metal donors. Some acyclic and cyclic clickbased calixarene sensors have been designed for metal ions recognition. Pandey and coworkers created a hybrid macrocyclic receptor 29 (Fig. 12) based on clicking bile acid and calix[4]arene scaffold [57]. With the bis-triazole motif and oxygen atoms as the binding donors, probe 29 showed a high binding affinity toward Hg2+ with a 1:1 stoichiometry, followed by Cd2+ > Zn2+ > Pb2+ > Li+ > Mn2+ > Cu2+, which was confirmed by the UV–vis titration in CH3CN solution.

We have reported a naphthalene-containing macrocyclic triazole 30 (Fig. 13) and its acyclic analog for Hg(Ⅱ) recognition [58]. Both receptors show a fluorescence sensing of Hg2+ in acetonitrile and acetonitrile/aqueous (8:2, v/v) solutions over other test metal ions, with the fluorescence intensity of receptors a largely quenching. The emission titration results revealed that the cyclic probe 30 exhibits larger binding constants than the acyclic analog, which can be attributed to the macrocyclic effect. The binding mechanism between receptors and Hg(Ⅱ) was investigated by 1H NMR titrations and DFT calculation, revealing that the triazole ring and the ether group shows a key role for complexation with Hg2+.

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Fig. 13. Structures of compounds 30-33.

Similarly, an anthracene containing bis-triazole macrocycle 31 (Fig. 13) and its acyclic analog were also reported [59]. In CH3CN-H2O (9:1, v/v) solution, cyclic receptor 31 showed an excusive turnoff fluorescent sensing of Hg2+. However, the analog responded towards Zn2+, Hg2+ and Cu2+ with different fluorescence changes. The addition of Zn2+ make the fluorescence of receptor a large enhancement, while the addition of Hg2+ and Cu2+ leads a fluorescence quenching effect. The emission titration, 1H NMR spectra and DFT calculation confirmed that the triazole and the ether groups play a key role to form a 1:1 stoichiometry complex.

3.2. Recognition of Fe3+

Fe(Ⅲ) is one of the most essential metals and plays a crucial role in physiological processes. Georghiou and coworkers reported four naphthyl "capped" triazole-linked calix[4]arene macrocyles, 32a-d (Fig. 13) [60]. Among twelve tested metal ions (Mn2+, Ca2+, Co2+, Zn2+, Pb2+, Ni2+, Fe3+, Hg2+, Cu2+, Cd2+, Fe2+ and Ag+), the four new macrocyclyes exhibit fluorescence quenching response toward Fe3+ and Hg2+, in particular for Fe3+ ions, in CH3CN:CHCl3 (9:1, v/v) mixture solution. The 1H NMR spectroscopic analysis and the DFT computational calculations revealed that the 3-postion N atoms form the triazole ring and oxygen atoms of the calixarene take part in binding with the metal ions.

Similar bis(naphthyl)methane "capped" triazole-linked calix[4] arene macrocyles, 33a and b (Fig. 13) were also reported [61]. Unlike 32a-d, which show fluorescence interfere form Hg(Ⅱ), macrocyles 33a and b show fluorescence quenching response toward Fe3+ without interference from other metal ions, with the binding model between 33 and Fe3+ in a 1:1 stoichiometry. According the emission titration data in CH3CN: CHCl3 (9:1, v/v) mixture solution, the binding constants of 33a-Fe(Ⅱ) and 33b-Fe(Ⅱ) were obtained to be 1.28 × 105L/mol and 1.13 ×105 L/mol respectively, using the non-linear global analysis.

Rhodamine dyes are widely employed as fluorescent probes for their desirable photophysical properties, including good photostability, high extinction coefficient and high fluorescence. Particularly, their emission can be easily modulated by the spirolactam ring-opening transformation. A rhodamine containing macrocycle 34 (Fig. 14) was recently synthesized by the Cu(Ⅰ)- catalyzed 1, 3-dipolar cycloaddition between steroidal diazides and rhodamine terminal dialkynes [62]. The cyclic steroid-rhodamine conjugate shows fluorescent and colorimetric dual signal sensing of Fe3+, with the color changing from colorless to pink, and the emission from no fluorescence to orange fluorescence. This unique change can be attributed to the complexation triggering spirolactam ring-opening in the presence of Fe3+. In addition, the spirolactam ring-opening state of 34-Fe3+ can be reclosed with the fluorescence quenching in the presence of pyrophosphate for the displacement mechanism. Thus, probe 34 can fluorescent OFF-ONOFF detect of Fe(Ⅲ) and pyrophosphate. Notably, this bi-functional probe was successfully used for monitoring Fe3+ and PPi on silica gel plates, in water samples and living cells.

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Fig. 14. Proposed mechanism of probe 34 for fluorescent, colorimetric detection of Fe3+ and PPi.

3.3. Recognition of Cu2+

Cu2+ is the third most abundant essential metal trace element in the human body, and plays an important role in biosystem processes. Chemosensors for monitoring Cu2+ in living cells and environment have attracted much attention in recent years. Wu et al. reported a fluorescent bis-triazole macrocycle by clicking diazo functionlized anthracene with the dialkyne substituted sugar-aza-crown ether (Fig. 15) [63]. The macrocycle can tightly bind with Cu2+ via the four nitrogen donors from triazole and sugar-aza-crown ether groups, which make the fluorescence of 35 a large enhancement in MeOH solution. The addition of other metal ions leads little fluorescence change. The association constant of 35 Cu2+ was calculated to be 2.5 ×104 L/mol. In addition, they also reported that this probe shows fluorescent sensing of HSO4- over other test anions (H2PO4-, F-, Br-, CH3COO-, I-, NO3-) in MeOH solution [64].

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Fig. 15. Schematic representation of 35 and 36 binding Cu2+ and sulfate anion (for 35).

Li et al. synthesized a chiral 1, 1-bi-2-naphthol-derived calix[4] arene 36 via a click reaction [65]. The receptor can highly bind Cu (Ⅱ) in a 1:1 stoichiometry in CH3CN solution, with the fluorescence of 36 at 361 nm a significant quenching. The binding constant of 36-Cu(Ⅱ) was calculated to be 7.38 × 105 L/mol. Important, the in situ generated 36-Cu(Ⅱ) complex exhibited excellent enantioselective recognition of R- and S- mandelic acid, using both the dynamic light-scattering technique and fluorescent methods.

An enlongated tetra-triazole macrocycle 37 (Fig. 16) appended the calixarene scaffold was reported by Shah and co-workers [66]. This probe showed a blue emission with the maximum emission wavelength at 485 nm in DMSO-H2O (1:1, v/v) solution. When Cu2+ was added into the solution, the blue emission of probe 37 deceased largely for the paramagnetic quenching effect of the Cu2+ ion. The MALDI-TOF-MS analysis and the emission job plot showed that probe 37 binds Cu2+ in a 1:3 stoichiometry. The Cu2+ limit of detection was found to be 40nmol/L. Further more, macrocycle 37 showed a low cytotoxicity and has been elegantly used for detection of Cu2+ in living cells.

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Fig. 16. Chemical structures of compounds 37-41.

3.4. Recognition of other metal ions

Kim and co-workers clicked anthraquinone dye with 1, 2-bis(2- azidoethoxy)ethane to generate the bis-triazole macrocycle 38 (Fig. 16) [67]. Probe 38 showed a weak emission for the PET quenching from the triazole and/or ether donor in CH3CN solution. Upon the addition of Al3+, a large fluorescence enhancement was observed for suppressing the PET process. The addition of other metal ions gave a little fluorescence change. A proposed 2:1 sandwich-like complexation was obtained according to the emission titration and the 1H NMR spectroscopy. Since the anthraquinone is a redox active group, macrocycle 38 also showed an electrochemical respond toward Al3+, with the differential pulse voltammetry (DPV) a large change.

A bis-triazole macrocycle 39 incorporating two Binol fluorophores was synthesized for detection of Ag+ (Fig. 16) [68]. This macrocycle displayed a selective fluorescence quenching effect toward Ag+ over other various metal ions in MeOH solution. A 1:1 binding mode of 39-Ag+ was confirmed from the emission titration and the 1H NMR spectroscopy. The association constant of 38-Ag+ was calculated to be 2.2 × 104 L/mol.

We reported a bis-triazole marcrocyle 40 (Fig. 16) containing a binaphthol fluorophore and a ferrocene redox active unit [69]. In CH3CN solution, compound 40 showed fluorescent and electrochemical dual signal sensing of Zn2+ over other metal ions. The binding Zn2+ makes the fluorescence of 40 a significant enhancement with a red shift from 380 nm to 428 nm. In addition, the Fe (Ⅲ)/Fe(Ⅱ) reversible redox potential of 40 was shifted from 430 mV to 480 mV. Fluorescence titration, 1H NMR titrations and DFT calculation results reveal that the N atoms of triazole and O atoms of the ether groups take part in binding in 40-Zn2+ complexation with forming a 1:1 complex.

A naphthalene-diimide (NDI) containing bis-triazole macrocycle 41 (Fig. 16) was synthesized by Li and co-workers [70], and its fluorescent responses to metal ions was investigated in CH2Cl2 solution. Compound 41 exhibited a weak emission for the electron transfer from the triazole moieties to NDI planes. Upon binding Fe3+, Co2+, Ni2+ and Mn2+ ions, the monomer NDI emission of 41 at 400 nm give a large enhancement. However, the presence of `Mg2+, Ba2+, Hg2+, Ca2+, Zn2+ and Pb2+ not only enhanced the emission at 400 nm but also led to a new excimer band at 480 nm.

4. Recognition of ion-pair

The design of ditopic receptors capable of the simultaneous binding of both cation and anion, which called ion-pair receptors, is a topical field of supramolecular chemistry. Regarding the dual cation-anion binding role of the triazole group, some triazolebased receptors for recognition ion pair were reported.

Beer and colleagues reported a new heteroditopic calix[4] diquinone bis-triazole macrocycle 42 (Fig. 17) [71], in which the calix[4]diquinone oxygen and triazole nitrogen donors bind the cation, while the CH protons of triazole and the NH protons of isophthalamide was used as the anions binding sites. The heteroditopic macrocycle cooperatively binds halide-monovalent cation combinations in a polar H2O-CH3CN (2:98, v/v) solution, which can be confirmed from the 1H NMR and UV–vis experiments. Further, the X-ray crystallographic structural analysis of a variety of 42-KCl, 42-NaCl, 42-NH4Cl and 42-KBr adducts demonstrated the dual cation-anion binding role of the triazole group in the solid state.

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Fig. 17. Schematic representation of 42 and 43 binding with ion pair. Reproduced with permission [72]. Copyright 2015, American Chemical Society.

Flood and coworkers reported a glycol chain containing bistriazole macrocycle 43 (Fig. 17) [72], in which the rigid aryl-triazole crescent binds the anion, and the flexibility glycolic linker stabilizes cation. They used 1H NMR titration and DFT calculated binding energy to reflect how the electrostatic effect and the conformational allostery individually contribute to cooperativity in ion-pair binding. The trend of electrostatic synergy calculated using spherical ion pair (NaCl > NaBr > NaI) is related to the experimental observation results (NaI > NaClO4). It indicated that the charge separation distance in contact ion pairs and electrostatic cooperativity are determined by intrinsic ionic size.

More recently, Ulrich S. Schubert and co-workers reported a simple crown-ether embedded the iodo-triazole macrocycle 45 (Fig. 18) [73], in which the iodo-triazole moiety acts as the anions donor via the halogen bond interaction, and the Lewis-basic cavity consisting of a triethylene glycol chain and the nitrogen atoms of the triazole motif coordinates with cation. The single X-ray crystal analysis revealed that this heteroditopic macrocycle interacts with NaI in a 1:2 complex, with the iodo-triazole moiety coordinating simultaneously cationic and anionic guests. The cooperative effect boosting the anion affinity of 45 toward NaI was quantified by 1H/13C NMR titration experiments. In addition, the compared cycle 44 (Fig. 18) was also synthesized, which can only bind with Na+ ion.

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Fig. 18. Chemical structures of compounds 44-45 and schematic representation of 45 binding with ion pair.

5. Conclusion

The CuAAC 'click' reaction has evolved as a highly versatile and robust tool for design multiple functionalized macrocycles. In addition to anion and cation species, the click-derived macrocycles can also form inclusion complexes with neutral polycyclic aromatic hydrocarbons [74, 75], and can be used as building blocks for self-assembly functionalized nano materials [15, 76, 77]. In this review, we summarized the recent advances of click-derived macrocyclic receptors for ions recognition. The examples shown above give a glimpse that macrocycles can recognize various hosts including anions, cations and ion pair. In this review, many macrocyclic receptors are able to bind anions with high binding affinity through the multiple weak C-H hydrogen bonds, and some of them can be detected by CD, fluorescent or electrochemical methods. These click-derived macrocycles can coordinate metal ions such as Hg2+, Cu2+, Fe3+, Al3+, Zn2+. Some of them have been elegantly used in water samples and in living cells. Regarding the dual cation-anion binding role of the triazole group, some triazolebased receptors for recognition ion pair were reported.

Although numerous click-derived macrocyclic receptors have been reported in recent years, they restrict from some drawbacks, such as low selectivity or recognition of ions only in mixture of water and organic solution. It is still a major challenge to design new types of chemosensors especially for highly selective recognition of ions in water or in biological systems. Practical applications of these chemosensors should be explored in in vivo studies and sensing of biologically important analytes.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 21762028 and 21462027) and Jiangxi Province Natural Science Foundation (Nos. 20161BAB213065 and 20171BAB203009), which are greatly acknowledged by the authors.

References
[1]
[2]
J.M. Lehn, Science 260 (1993) 1762-173.
[3]
J.W. Lee, S. Samal, N. Selvapalam, H.J. Kim, K. Kim, Acc. Chem. Res. 36 (2003) 621-630. DOI:10.1021/ar020254k
[4]
G.W. Gokel, W.M. Leevy, M.E. Weber, Chem. Rev. 104 (2004) 2723-2750. DOI:10.1021/cr020080k
[5]
A.E. Hargrove, S. Nieto, T. Zhang, J.L. Sessler, E.V. Anslyn, Chem. Rev. 111 (2011) 6603-6782. DOI:10.1021/cr100242s
[6]
H. Li, Y.W. Yang, Chin. Chem. Lett. 24 (2013) 545-552. DOI:10.1016/j.cclet.2013.04.014
[7]
C.W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 67 (2002) 3057-3064. DOI:10.1021/jo011148j
[8]
V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem. Int. Ed. 41 (2002) 2596-2599.
[9]
M. Meldal, C.W. Tornøe, Chem. Rev. 108 (2008) 2952-3015. DOI:10.1021/cr0783479
[10]
V.K. Tiwari, B.B. Mishra, K.B. Mishra, et al., Chem. Rev. 116 (2016) 3086-3240. DOI:10.1021/acs.chemrev.5b00408
[11]
Y.H. Lau, P.J. Rutledge, M. Watkinson, M.H. Todd, Chem. Soc. Rev. 40 (2011) 2848-2866. DOI:10.1039/c0cs00143k
[12]
J.J. Cai, J.L. Sessler, Chem. Soc. Rev. 43 (2014) 6198-6213. DOI:10.1039/C4CS00115J
[13]
J.C. Jewett, C.R. Bertozzi, Chem. Soc. Rev. 39 (2010) 1272-1279. DOI:10.1039/b901970g
[14]
Y.Y. Zhu, G.T. Wang, Z.T. Li, Org. Biomol. Chem. 7 (2009) 3243-3250. DOI:10.1039/b907457k
[15]
K.D. Bodine, D.Y. Gin, M.S. Gin, J. Am. Chem. Soc. 126 (2004) 1638-1639. DOI:10.1021/ja039374t
[16]
K.D. Bodine, D.Y. Gin, M.S. Gin, Org. Lett. 7 (2005) 4479-4482. DOI:10.1021/ol051818y
[17]
R. Leyden, P.V. Murphy, Synlett 12 (2009) 1949-1950.
[18]
N.H. Evans, P.D. Beer, Angew. Chem. Int. Ed. 53 (2014) 11716-11754. DOI:10.1002/anie.201309937
[19]
P.A. Gale, N. Busschaert, C.J.E. Haynes, L.E. Karagiannidis, I.L. Kirby, Chem. Soc. Rev. 43 (2014) 205-241. DOI:10.1039/C3CS60316D
[20]
Santos-Figueroa L.E., M.E. Moragues, E. Climent, A. Agostini, Chem. Soc. Rev. 42 (2013) 3489-3613. DOI:10.1039/c3cs35429f
[21]
P.A. Gale, E.N.W. Howe, X. Wu, Chem 1 (2016) 351-422. DOI:10.1016/j.chempr.2016.08.004
[22]
X. Kan, H. Liu, Q. Pan, Z. Li, Y. Zhao, Chin. Chem. Lett. 29 (2018) 261-266. DOI:10.1016/j.cclet.2017.08.042
[23]
S. Kubik, Chem. Soc. Rev. 39 (2010) 3648-3663. DOI:10.1039/b926166b
[24]
J. Liu, Q. Lin, H. Yao, et al., Chin. Chem. Lett. 25 (2014) 35-38. DOI:10.1016/j.cclet.2013.10.026
[25]
[26]
Y. Li, A.H. Flood, J. Am. Chem. Soc. 130 (2008) 12111-12122. DOI:10.1021/ja803341y
[27]
Y. Hua, R.O. Ramabhadran, E.O. Uduehi, et al., Chem.-Eur. J. 17 (2011) 312-321. DOI:10.1002/chem.201002340
[28]
R.K. Chhatra, A. Kumar, P.S. Pandey, J. Org. Chem. 76 (2011) 9086-9089. DOI:10.1021/jo201161n
[29]
W. Li, Q. Xu, Y. Li, et al., Tetrahedron Lett. 54 (2013) 3868-3871. DOI:10.1016/j.tetlet.2013.05.031
[30]
D. Mungalpara, S. Stegmüller, S. Kubik, Chem. Commun. 53 (2017) 5095-5098. DOI:10.1039/C7CC02424J
[31]
Y. Zhao, Y. Li, Y. Li, et al., Org. Biomol. Chem. 8 (2010) 3923-3927. DOI:10.1039/c0ob00033g
[32]
L.C. Gilday, N.G. White, P.D. Beer, Dalton Trans. 41 (2012) 7092-7097. DOI:10.1039/c2dt30124e
[33]
M.G. Fisher, P.A. Gale, J.R. Hiscock, et al., Chem. Commun. (2009) 3017-3019.
[34]
T. Merckx, C.J.E. Haynes, L.E. Karagiannidis, et al., Org. Biomol. Chem. 13 (2015) 1654-1661. DOI:10.1039/C4OB02236J
[35]
M. Caricato, A. Olmo, C. Gargiulli, G. Gattuso, D. Pasini, Tetrahedron 68 (2012) 7861-7866. DOI:10.1016/j.tet.2012.07.038
[36]
K.M. Mullen, J. Mercurio, C.J. Serpell, P.D. Beer, Angew. Chem. Int. Ed. 48 (2009) 4781-4784. DOI:10.1002/anie.v48:26
[37]
G.T. Spence, M.B. Pitak, P.D. Beer, Chem.-Eur. J. 18 (2012) 7100-7108. DOI:10.1002/chem.201200317
[38]
S.W. Robinson, C.L. Mustoe, N.G. White, et al., J. Am. Chem. Soc. 137 (2015) 499-507. DOI:10.1021/ja511648d
[39]
J.M. Mercurio, A. Caballero, J. Cookson, P.D. Beer, RSC Adv. 5 (2015) 9298-9306. DOI:10.1039/C4RA15380D
[40]
J.Y.C. Lim, I. Marques, A.L. Thompson, et al., J. Am. Chem. Soc. 139 (2017) 3122-3133. DOI:10.1021/jacs.6b12745
[41]
T.A. Barendt, L. Ferreira, I. Marques, V. Félix, P.D. Beer, J. Am. Chem. Soc. 139 (2017) 9026-9037. DOI:10.1021/jacs.7b04295
[42]
J.L. Sessler, J. Cai, H.Y. Gong, et al., J. Am. Chem. Soc. 132 (2010) 14058-14060. DOI:10.1021/ja107098r
[43]
J. Cai, B.P. Hay, N.J. Young, X. Yang, J.L. Sessler, Chem. Sci. 4 (2013) 1560-1567. DOI:10.1039/c3sc22144j
[44]
Q. Duan, W. Xia, C. Lin, Y. Pan, L. Wang, Tetrahedron Lett. 56 (2015) 4002-4006. DOI:10.1016/j.tetlet.2015.05.013
[45]
Y.H. Zhang, H. Huang, S.S. Yang, Q.Y. Cao, J. Organomet. Chem. 871 (2018) 74-78. DOI:10.1016/j.jorganchem.2018.07.009
[46]
C.T. Li, Q.Y. Cao, J.J. Li, Z.W. Wang, B.N. Dai, Inorg. Chim. Acta 449 (2016) 31-37. DOI:10.1016/j.ica.2016.04.047
[47]
R. Jiang, Y. Li, Z. Qin, et al., RSC Adv. 4 (2014) 2023-2028. DOI:10.1039/C3RA46049E
[48]
N.G. White, S. Carvalho, V. Félix, P.D. Beer, Org. Biomol. Chem. 10 (2012) 6951-6959. DOI:10.1039/c2ob25934f
[49]
H.M. Kim, B.R. Cho, Acc. Chem. Res. 42 (2009) 863-872. DOI:10.1021/ar800185u
[50]
F.L. Que, C.J. Chang, Chem. Soc. Rev. 39 (2010) 51-60. DOI:10.1039/B914348N
[51]
C.J. Chang, Acc. Chem. Res. 50 (2017) 535-538. DOI:10.1021/acs.accounts.6b00531
[52]
B. Schulze, U.S. Schubert, Chem. Soc. Rev. 43 (2014) 2522-2571. DOI:10.1039/c3cs60386e
[53]
Y.W. Wang, Y.X. Hua, H.H. Wu, X. Sun, Y. Peng, Chin. Chem. Lett. 28 (2017) 1994-1996. DOI:10.1016/j.cclet.2017.07.019
[54]
M. Song, Z. Sun, C. Han, et al., Chem. Asian J. 9 (2004) 2344-2357.
[55]
J. Hu, J. Wu, J. Lu, Y. Ju, Tetrahedron Lett. 53 (2012) 6705-6709. DOI:10.1016/j.tetlet.2012.09.118
[56]
J. Wu, J. Lu, J. Liu, et al., Sens. Actuators B Chem. 241 (2017) 931-937. DOI:10.1016/j.snb.2016.10.117
[57]
M.K. Jaiswal, P.K. Muwal, S. Pandey, P.S. Pandey, Tetrahedron Lett. 58 (2017) 2153-2156. DOI:10.1016/j.tetlet.2017.04.067
[58]
B.N. Dai, Q.Y. Cao, L. Wang, Z.C. Wang, Z. Yang, Inorg. Chim. Acta 423 (2014) 163-167. DOI:10.1016/j.ica.2014.08.015
[59]
W. Zhu, X. Lü, J. Zhu, Q. Cao, Chin. J. Org. Chem. 37 (2017) 624-629. DOI:10.6023/cjoc201611004
[60]
S. Rahman, Y. Assiri, A.N. Alodhayb, et al., New J. Chem. 40 (2016) 434-440. DOI:10.1039/C5NJ01362C
[61]
M.D. Aljabri, S. Rahman, P.E. Georghiou, R. Shofiur, ChemistrySelect 2 (2017) 1214-1218. DOI:10.1002/slct.201601923
[62]
Z. Zhang, C. Deng, Y. Zou, L. Chen, J. Photochem. Photobiol. A:Chem. 356 (2018) 7-17. DOI:10.1016/j.jphotochem.2017.12.023
[63]
Y.C. Hsieh, J.L. Chir, H.H. Wu, C.Q. Guo, A.T. Wu, Tetrahedron Lett. 51 (2010) 109-111. DOI:10.1016/j.tetlet.2009.10.093
[64]
S.T. Yang, D.J. Liao, S.J. Chen, C.H. Hu, A.T. Wu, Analyst 137 (2012) 1553-1555. DOI:10.1039/c2an16315b
[65]
F. Miao, J. Zhou, D. Tian, H. Li, Org. Lett. 14 (2012) 3572-3575. DOI:10.1021/ol3007919
[66]
B. Khan, M.R. Shah, D. Ahmed, et al., J. Hazard. Mater. 309 (2016) 97-106. DOI:10.1016/j.jhazmat.2016.01.074
[67]
S.H. Kim, H.S. Choi, J. Kim, et al., Org. Lett. 12 (2010) 560-563. DOI:10.1021/ol902743s
[68]
J.T. Hou, Q.F. Zhang, B.Y. Xu, et al., Tetrahedron Lett. 52 (2011) 4927-4930. DOI:10.1016/j.tetlet.2011.07.050
[69]
Z. Wang, B. Dai, J. Qiu, Q. Cao, J. Ge, Chin. J. Org. Chem. 35 (2015) 2383-2388. DOI:10.6023/cjoc201506021
[70]
Y. Yu, Y. Li, S. Chen, et al., Eur. J. Org. Chem. (2012) 4287-4292.
[71]
S.C. Picot, B.R. Mullaney, P.D. Beer, Chem.-Eur. J. 18 (2012) 6230-6237. DOI:10.1002/chem.201200251
[72]
B. Qiao, A. Sengupta, Y. Liu, et al., J. Am. Chem. Soc. 137 (2015) 9746-9757. DOI:10.1021/jacs.5b05839
[73]
R. Tepper, B. Schulze, P. Bellstedt, et al., Chem. Commun. 53 (2017) 2260-2263. DOI:10.1039/C6CC09749A
[74]
J. Samanta, R. Natarajan, Org. Lett. 18 (2016) 3394-3397. DOI:10.1021/acs.orglett.6b01554
[75]
I.S. Tamgho, S. Chaudhuri, M. Verderame, D.J. DiScenza, M. Levine, RSC Adv. 7 (2017) 28489-28493. DOI:10.1039/C7RA05404A
[76]
A. Ghorai, E. Padmanaban, C. Mukhopadhyay, B. Achari, P. Chattopadhyay, Chem. Commun. 48 (2012) 11975-11977. DOI:10.1039/c2cc36566a
[77]
V. Haridas, A.R. Sapala, J.P. Jasinski, Chem. Commun. 51 (2015) 6905-6908. DOI:10.1039/C4CC09587A