Fluorescent Chemosensors Based on Polyamine Ligands: A Review

Abstract

Polyamine ligands are water-soluble receptors that are able to coordinate, depending on their protonation degree, either metal ions, anionic, or neutral species. Furthermore, the presence of fluorescent signaling units allows an immediate visual response/signal. For these reasons, they can find applications in a wide variety of fields, mainly those where aqueous media is necessary, such as biological studies, wastewater analysis, soil contamination, etc. This review provides an overview of the recent developments in the research of chemosensors based on polyamine ligands functionalized with fluorescent signaling units. The discussion focuses on the design, synthesis, and physicochemical properties of this type of fluorescent chemosensors in order to analyze the applications associated to the sensing of metal ions, anions, and neutral molecules of environmental and/or biological interest. To facilitate a quick access and overview of all the chemosensors covered in this review, a summary table of the chemosensor structures and analytes, with all the corresponding references, is also presented.

1. Introduction

Since the first fluorescent chemosensor was reported in 1867, by Goppelsröder, a great number of these systems has been developed, many of which have been applied in fields such as analytical chemistry, biology, physiology, pharmacology, and environmental sciences. Particularly, the development of fluorescent chemosensors for analytes that are present in aqueous solution has aroused great interest due to their potential applications in important areas, such as biology, environmental, or medicinal chemistry [1,2,3].

Polyamine chains are characterized by their solubility in water and their ability to coordinate either metal ions or neutral/anionic species as a function of their protonation degree [4,5,6,7,8,9,10,11]. The functionalization of polyamines with fluorescent groups has allowed obtaining different chemosensors for metal ions and/or anions [12]. The deprotonation of polyammonium groups is accompanied by a characteristic quenching of the fluorescence emission, which is associated with a photoinduced electron transfer (PET) from the nitrogen lone pair to the excited fluorophore. Protonation engages the lone pair in the amine, causing thereby the recovery of the fluorescence emission (Figure 1).

The subject of fluorescent chemosensors based on polyamine receptors was the subject of a review published two decades ago [12]. The present work is intended to be an update on this topic, covering some recently reported polyamine receptors functionalized with fluorescent signaling units acting as chemosensors. The selected ligands are summarized in three categories, attending to the polyamine topology: open chain, branched, and macrocyclic. As a result of the great relevance of nanoparticulate systems, we also introduce a section discussing devices in which the polyamines have been grafted to different surfaces. We have also given a comprehensive analysis about the selectivity and the signaling capacities of these polyamine ligands with a wide range of metal ions and/or anions, based on fluorescence changes.

2. Open Chain Polyamine Derivatives

2.1. Linear Polyamines

Open-chain polyamines can be easily functionalized with fluorescent moieties, developing chemosensors capable of signaling substrate coordination by changing the physical properties of these functional groups. Thus, this type of chemosensor can be considered as one of the simplest examples in terms of structural design.

One of the first examples of simple open-chain linear polyamine chemosensors was related to the receptors developed by Pina et al., in which different open-chain polyamines were functionalized with naphthalene moieties at the terminal amino groups (Scheme 1, 1–4) [13,14,15].

Fluorescence emission studies showed the formation of an excimer species whose intensity depended on the length and the protonation degree of the polyamine chains. The authors associated this excimer to the existence of a bending movement that allowed one naphthalene moiety in the excited state and another one in the ground state to approach and interact (see Figure 2). These compounds can be considered as elementary molecular machines, whose movements were driven by light and switched on/off by pH.

Using the concept of metal-induced intramolecular excimer formation, Van Arman et al. prepared the first example of a water-soluble ratiometric fluorescent probe for Zn(II), consisting of a linear polyamine that functionalized two anthryl moieties (Scheme 2, 5). When titrating this ligand with Zn(II), a 4-fold increase in the excimer band at 495 nm is observed, together with a smaller increase of the band at 415 nm, which is attributed to the expected chelation enhanced fluorescence (CHEF) effect [16].

An analogous example was described by Shiraishi et al., who reported a chemosensor based on a diethylenetriamine moiety bearing one pyrene fragment at each end (Scheme 3, 6). In this case, a triple-mode fluorescence was observed in water consisting of a monomer emission (acidic-neutral pH), and of short- and long-lived (basic pH) excimer emissions, which were associated to a pH-controlled bending movement of the polyamine chain and the formation of an intramolecular ground-state dimer of the pyrene fragments [17,18]. Substitution of the terminal fluorophores of this polyamine by two quinoline moieties (7) revealed an interesting behavior as a fluorescent Zn²⁺ water-soluble sensor. In the absence of metal cations, no fluorescence emission was observed at the pH range of study; however, Zn²⁺ addition promoted a fluorescence emission enhancement, with a linear and stoichiometric response to the Zn²⁺ concentration [19]. Furthermore, no remarkable emission enhancement was observed for other cations, such as Cd²⁺, with similar electronic and binding properties [20,21,22,23].

The non-symmetrical functionalization of the terminal positions has also been reported by Shiraishi et al. [24]. Molecules 8–10 (Scheme 4) bear anthracene and benzophenone moieties at each end of the polyamine chain. As a result of this configuration, there is a sequential electron transfer and, for this reason, the changes in the emission induced by the pH follow a “gentle slope”, making these molecules suitable pH chemosensors in a wide range of values (pH 2–10).

Another type of architecture, also using the same 1,4,7-triazaheptane scaffold, was reported by García-España et al., who decorated this polyamine with 2-picolyl units at the terminal amines and a naphthyl (11) or a dansyl (12, Scheme 5) fluorescent unit attached to the central amino group, and they studied the Zn(II) complexation and anion-sensing capacity of these metal complexes. Interestingly, each compound showed a different behavior. Titration of the Zn(11)²⁺ complex with several anions led to a decrease of the emission, while in the case of Zn(12)²⁺, the opposite effect was observed; i.e., the dansyl emission was restored by the addition of the anions [25].

Tripier et al. developed a linear bis-tetraamine based on two 1,4,8,11-tetraazaundecane units linked by a chromophoric 4-(9-anthracenyl)-2,6-dimethylpyridinyl group (Scheme 6, 13) [26]. This ligand presents, at acidic and neutral pH values, a high affinity for glyphosate associated to the electrostatic interactions generated by the high number of protonable amino groups and the phosphates. At basic pH values, the presence of π-stacking interactions between the anthracene groups of 13 allowed maintaining a strong complexation for glyphosate, which was considered “probably carcinogenic” by the International Agency for Research on Cancer (WHO, World Health Organization) since 2017 [27,28,29]. The widespread use of this herbicide implies a risk to health and biodiversity, making necessary the development of low-cost technologies for its detection in situ [30,31,32]. Although different analytical methods for the determination of glyphosate and other organophosphonates derivatives are known, fluorescence-based assays stand out due to their high sensitivity, simplicity, and speed of response, allowing real-time monitoring.

Fluorescent metal complexes have also been used as signaling units in the preparation of chemosensors. This approach was explored by Martínez-Máñez et al., who synthesized receptors 14 and 15 (Scheme 7), containing a [Ru(tpy)₂]²⁺ core as a chromophore attached to triethylenetetramine or tetraethylenepentaamine, respectively [33]. When the fluorescent behavior of these ligands was studied against a panel of metal cations, as a function of pH, it was observed that Cd(II) and Zn(II) cations produced an enhancement of the emission, whereas Cu(II) and Ni(II) produced a strong quenching relative to the emission of the free receptors. Hg(II) cation induced a quenching for 14 but not for 15. However, the presence of different anions did not modify the fluorescence emission of these sensors.

2.2. Branched Polyamines

Tripodal tetraamines, containing a single tertiary nitrogen atom and one amino group in each arm, are widely used in supramolecular and coordination chemistry for the development of metal ion and anion receptors [34]. The preorganized structure of tripodal polyamines promotes topological matching with anions of the same symmetry, such as oxoanions, which are a class of anions of great biological and environmental relevance.

An early example is the tripodal anthracene-based chemosensors 16 and 17 (Scheme 8), reported by Czarnik et al. [35], which showed an enhancement of the fluorescence upon the addition of phosphate at pH = 6. The authors ascribed this behavior to the encapsulation of phosphate within the tripodal cavity and the subsequent formation of hydrogen bonds between one OH group of the phosphate with the lone pair of the benzylic nitrogen. This interaction hindered the PET process from the benzylic nitrogen to the excited fluorophore and, hence, the fluorescence enhancement [36].

The polyamine tris(2-aminoethyl)amine (tren) has been widely used as a scaffold in the preparation of fluorescent sensors. In this line, a recent article by García-España et al. reported on the preparation of the two BODIPY-tren Cu(II) chemosensors, 18 and 19 (Scheme 9) [37]. BODIPY dyes are an important class of fluorophores with excellent photoluminescent characteristics but limited water solubility. By combining them with a polyamine, it was possible to obtain water-soluble conjugates with a high selectivity for Cu(II) ions.

Another example of fluorescent receptors based on the polyamine tren was reported by Kataev et al., who used the fluorescent naphthalimide as the chromophoric unit. By different synthetic strategies, they were able to introduce the polyamine in different positions of the naphthalimide ring and prepare chemosensors bearing one or two tren units (20 and 21, Scheme 10). When studied against a panel of different anions, it was found that the ligands bind selectively to pyrophosphate anion. As expected, the ligand with six amino groups (21) and higher overall basicity showed the highest affinity toward this anion [38].

Molecule 22 (Scheme 11) was built by functionalizing the polyamine tren with an anthracene and two N,N-dimethylaniline moieties. For the Zn(II) complex of this ligand, it was observed that an intramolecular photoinduced electron transfer takes place, from the N,N-dimethylaniline units to the excited anthracene fluorophore, which are close to each other in the complex, resulting in a low fluorescence emission of [Zn(22)]²⁺. However, the presence of a bulky anion, such as triphenylacetate, filled the cavity, preventing the occurrence of the intramolecular PET process and, hence, enhancing the fluorescence emission [39].

Quinn et al. synthesized a tripodal anthracene-based ligand (23, Scheme 12), with an interesting sensing behavior for oxoanions and halides [40]. The ability of the protonated amino groups to form hydrogen bonds coupled with the electron-withdrawing properties of the attached anthracene groups significantly increased the stability of its complexes with anionic species. The addition of anions caused an enhancement of the fluorescence intensity attributed to the formation of a ligand–anion complex that restricts the free rotation of the attached fluorophores.

Prodi et al. prepared the mono and tri-functionalized ligands 24 and 25 (Scheme 13) using tren and dansyl chloride. These dansylated tripodal polyamines were studied as fluorescent sensors for Cu(II). As expected, this metal cation induces a strong quenching of the fluorescence emission. The competition experiments showed that most of the metal cations tested did not significantly interfere with the Cu(II) sensing. However, some of the metals, particularly Zn(II) and Cd(II), did have a large effect on the photophysical properties of the ligands as well. Nevertheless, the authors point out that this interference is limited to a certain pH range so, for each of the ligands, there is another pH range at which the Cu(II) sensing is selective [41].

Katerinopoulos et al. prepared a Zn(II) fluorescent chemosensor by incorporating coumarin to the polyamine tren (26, Scheme 14). In this case, complexation of the metal led to a shift in the maxima of the excitation wavelength, from 359 to 337 nm, together with a 42% decrease in the intensity of the fluorescence emission. An ion competition experiment showed that this response to Zn(II) was not affected by the presence of other biological relevant cations with the exception of the paramagnetic Ni(II) and Cu(II) ions. This led the authors to highlight the potential use of 26 as a probe for ratiometric sensing of Zn(II) [42].

Pina et al. developed an extended tripodal polyaminic chemosensor with six amino groups and containing naphthalene fluorophores at the terminal positions (27, Scheme 15) with the purpose of achieving higher water solubility. This molecule exhibited an intense excimer emission compared with the bis-fluorophoric systems previously reported by the authors. The molecular organization of 27 enhances the possibility for the naphthalene rings to encounter each other, providing a large excimer to monomer emission ratio. One of the most interesting characteristics of this system is that the kinetics of excimer formation, studied by time-correlated single photon counting in water, are dependent on the temperature. This result opens the possibility to use 27 as a fluorescent temperature sensor [43].

In a different approach, Fusi et al. synthesized the ditopic ligand 28 (Scheme 16) using two 1,4,7-triazaheptane (dien) moieties and 4,4′-dihydroxybiphenyl as the aromatic spacer [44]. The emission of the ligand responded to pH changes, being highly fluorescent from pH 4 to 6, which is an interval that corresponds with the presence of the neutral form of the biphenyl moiety. An aqueous solution of 28, buffered at pH 9, showed a weak fluorescence. However, when it was titrated with Zn(II), a considerable increase of the emission intensity was registered due to a CHEF effect. Thus, this ligand behaves as a fluorescent chemosensor for Zn(II) in alkaline aqueous solutions.

Following this work, Conti et al. have recently reported the high affinity of two open-chain polyamino-phenolic ligands by glyphosate and its degradation product aminomethyl phosphonic acid (AMPA) in aqueous solution [45]. Both ligands, 29 and 30 (Scheme 17), preferentially bind glyphosate over AMPA in a wide pH range, as indicated by the potentiometric studies. However, the Zn(II)–dinuclear complexes of these ligands could be considered as effective tools for the selective recognition of glyphosate by 29 and AMPA by 30. Different fluorescence titrations were performed to assess whether the anion-recognition processes can be detected by fluorescence signaling.

3. Macrocyclic Polyamine Derivatives

Macrocyclic polyamines represent a step further in the design of more preorganized receptors. Their cyclic structure allows the formation of polyammonium receptors in aqueous solution with a high positive charge density that are flexible enough to be able to wrap around the anions, stabilizing them through electrostatic interactions and/or hydrogen bonding formation [46]. Functional groups have also been appended to these polyazamacrocyclic receptors in order to increase their ability to bind anionic species or to confer specific functions to the resulting receptors.

3.1. Aza-Crown Macrocycles

Probably the most studied group of polyazamacrocyclic ligands is the aza-crown family, consisting of rings with the formulae (CH₂CH₂NH)_n, where n = 3, 4, 5, and 6. Their wide commercial availability and the possibility of functionalizing the secondary amino groups with fluorophores has made them excellent candidates for the development of fluorescent probes.

An early example can be found in the work of Kimura et al., who prepared the dansylated derivative of 1,4,7,10-tetraazacyclododecane (cyclen) 31 (Scheme 18) [47]. This ligand showed a high affinity toward Zn(II), with a linear response of the fluorescence enhancement until 1:1 ligand to Zn(II) ratio. However, this enhancement of the fluorescence was drastically affected by the presence of Cu(II), which leads to an almost complete quenching of the emission. The presence of other alkaline and alkaline earth cations did not affect the fluorescence response of the Zn(II) complex.

A similar approach was investigated by Lippard and Burdette. Using a hybrid fluorescein/rhodamine fluorophore as the signaling unit and cyclen as the Zn(II) binding unit, they prepared ligand 32 (Scheme 19), which acts as a PET sensor for this metal cation with a 50% increase of the emission upon complexation of Zn(II). The competition experiments revealed little interference by other divalent transition metals, with the exception of Cd(II) and, particularly, Cu(II), which induced a strong quenching [48].

In a more recent example of sensors containing cyclen, Li et al. exploited the Zn(II) affinity of this macrocycle and the strong fluorescence of tetraphenylethene (TPE) to prepare fluorescent chemosensors for pyrophosphate (PPi) and adenosine triphosphate (ATP) sensing. Different ligands were prepared, bearing one (33), two (34), or four (35) [Zn(cyclen)]²⁺ complexes attached to the TPE scaffold (Scheme 20). These ligands showed a pronounced and selective “turn-on” fluorescence response toward PPi and ATP in aqueous media, with detection limits in the nanomolar range [49,50].

Another polyamine macrocyclic scaffold that has been used in the preparation of fluorescent chemosensors is the 14-membered tetramine cyclam. The high stability of the transition metal complexes formed with this macrocycle has led to the study of a series of fluorescent derivatives as light-emitting devices with different applications, which has already been the subject of a review article [51]. Of particular interest are the Ni(III)/Ni(II) complexes that act as redox fluorescent switches with an OFF/ON behavior, such as those prepared with ligands 36 [52], 37 [53], and 38 (Scheme 21) [54].

Another approach in the preparation of fluorescent chemosensors based on macrocyclic polyamines is to introduce the fluorescent moiety as part of the macrocycle. This approach can be found, for example, in the work of Pina et al., who reported the photophysical properties of ligands 39–41 (Scheme 22) [55]. These polyazamacrocycles contain a phenanthroline moiety acting as an aromatic spacer and polyaminic chains of increasing length and number of nitrogen atoms. The presence of the aromatic unit as an integral part of the macrocycle confers rigidity to the structure and hinders the benzylic nitrogen atoms from participating in the coordination of metal cations in 1:1 complexes. Among the interesting photophysical properties of these ligands, a chelation enhancement of quenching (CHEQ) effect is observed when forming Zn(II) complexes as opposed to the commonly observed CHEF effect. In a different publication, the ability of 39 and a related compound with an extended hexaaza polyamine chain to selectively sense nucleotides was reported [56].

Pina et al. have continued to study these types of macrocyclic ligands, diversifying their structures with different aromatic spacers and varying the length of the polyaminic chain. Among those prepared, it is worth mentioning ligands 42 and 43 (Scheme 23), bearing bipyridine and terpyridine as fluorescent units. These ligands, as well as their Zn(II) complexes, were screened for their capacity to bind ATP in water, which is an interaction that takes places through the electrostatic interactions established between the ammonium groups of the protonated ligands and the phosphate oxygens of the nucleotide, as well as by π-stacking interactions between both aromatic units. The metal complexes showed a better capacity to act as sensors, since the fluorescence is enhanced when interacting with ATP [57,58].

Moreover, the exotopic coordination site of 42 with the bipyridine nitrogens pointing outwards was exploited by the authors to prepare the Ru(II) complex 44 (Scheme 24) and then study its properties as a water-soluble long lifetime chemosensor for cations and anions. Particularly, the authors thoroughly studied the sensing of metallocyanide complex anions, which are known for quenching the fluorescence emission of [Ru(bipy)₃]²⁺ by electron transfer. Their results showed that the presence of the polyamine chain results in high association constants between the ligand and [Fe(CN)₆]⁴⁻ with a better overall performance as sensor than the parent [Ru(bipy)₃]²⁺ complex [59].

Another interesting example of a polyamine macrocycle was published by Chelli et al. The acridine-containing macrocycle 45 (Scheme 25), developed as a fluorescent chemosensor for anions, showed unusual pH-dependent photophysical properties: at low pH values, the emission band resembled that of the unprotonated acridine, while at alkaline pH values, it was similar to the acridinium cation. This unexpected behavior was rationalized as the result of an exited state proton transfer from the aliphatic ammonium groups to the acridine nitrogen [60].

In certain cases, the polyamine macrocycle is not fluorescent or has a very low emission and therefore requires the use of a fluorescent indicator molecule for the signaling event to take place. This indicator can be bound to the receptor through non-covalent interactions, which is a supramolecular recognition event that quenches the fluorescence of the indicator. If the macrocycle has a higher affinity for a certain analyte, when it is present in solution, it will displace the indicator which, once released to the solution, will recover its fluorescence. This approach is generally known as a fluorescent indicator displacement assay (Figure 3) [61].

An example of such approach can be found in the work of Fabbrizzi et al., where the dicopper complex 46 (Scheme 26) interacted with the fluorescent indicator eosin Y, forming what the authors termed a “chemosensing ensemble”. The fluorescence of eosin Y is completely quenched in this situation. However, when titrating this supramolecular adduct with the amino acid histidine, the emission recovered. This sensing event was selective for histidine and did not take place with the other aminoacids assayed (glycine, alanine, and phenylalanine) [62].

3.2. Aza-Scorpiand Ligands

The term “scorpiand” is related to a macrocyclic ligand modified with a pendant arm containing additional donor atoms that exercises an active role in the coordination of metal ions or other substrates inside the macrocyclic cavity [63,64]. The molecular movements generated by the pendant arm as consequence of electrostatic repulsions and binding events can be signalized by the introduction of fluorophores, whose fluorescence changes depend on whether the donor atom in the tail is coordinated or not [65].

Over the last few years, different chemosensors based on aza-scorpiand ligands have been reported. One of the first examples is the phenanthrolinophane (47, Scheme 27) containing an anthracene group in the pendant arm, as reported by Bencini et al. The coordination of Zn²⁺ in the macrocyclic core and the consequent attachment/detachment of the nitrogen atom present in the pendant arm give rise to on/off switching of the exciplex emission, defining an elementary molecular machine whose movements are driven by both pH and light [66,67]. The coordination of the nitrogen atom in the pending arm to the metal ion brings about the occurrence of π-stacking interactions between the phenanthroline and anthracene rings.

Inclán et al. developed anthracene analogous ligands containing a pyridine moiety as an aromatic spacer [68]. 48 and 49 (Scheme 28) exhibited binding selectivity for GTP vs. ATP due to the higher ability of guanine to form π-stacking complexes with the anthracene present in the pendant arm. In addition, 48 and 49 displayed a large fluorescence quenching in the presence of GTP over the whole pH range, while the addition of ATP produced a significant increase in the fluorescence emission. This fluorescence change makes 48 and 49 efficient sensors to effectively and selectively distinguish GTP from ATP in aqueous solution.

In addition, these authors reported the interactions between calf thymus DNA and scorpiand-like ligands 48, 49, and 50 (Scheme 28 and Scheme 29) [69]. The presence or absence of metal ions induced molecular reorganizations from an open to a closed conformation, modulating the affinity of these systems for DNA. This is reflected by the strong fluorescence quenching observed after the addition of ctDNA to a solution of 48 or [M(48)]²⁺ (M = Cu(II), Zn(II)).

More recently, Formica et al. reported an aza-scorpiand ligand having a pendant arm functionalized with a fluorescent pyridyl-oxadiazole-phenyl moiety (51) [70,71]. The Zn(II) complex of 51 interacts selectively with a chloride anion, which displaces the pyridine of the pyridyl-oxadiazole-phenyl moiety from the coordination sphere, generating a quenching of the fluorescence emission. The emission could be easily restored by the addition of Ag⁺, which removes the chloride anion from the coordination sphere of the metal ion (see Figure 4).

1,4,7-Triazacyclononane or [9]aneN₃ is a well-known coordinating unit for cation and anion species, and the functionalization through its secondary amino groups has allowed the preparation of a wide array of supramolecular systems with potential application as chemosensors [72,73]. A recent example is the scorpiand like-ligand reported by Savastano et al., based on a [9]aneN₃ (1,4,7-triazacyclononane) macrocyclic unit bearing a pendant arm functionalized with an anthracene fluorophore (52, Scheme 30). This molecule was able to act as a chemosensor for Zn(II) in the pH range 6–10 [74]. Due to the low number of donor atoms, the sensing of Zn(II) with 52 was also studied in the presence of different coordinating anions (phosphate, benzoate, cyanide, and sulfide), showing no interference.

A similar ligand, but using cyclen instead of [9]aneN₃, had been reported earlier by Kimura et al. as a Zn(II) chelation-enhanced fluorophore (53, Scheme 31). The ligand showed several advantages when compared to the non-scorpiand one (i.e., with the anthryl unit directly attached to the cyclen scaffold, 54): a higher affinity toward Zn(II), with the complex forming at lower pH values; a more linear response of the fluorescence and better sensing capacity at neutral pH. However, other divalent transition metal cations exerted a strong interference [75].

To extend the complexation capacity of scorpiand-type ligands to other “hard” metal cations, such as Al(III) and Cr(III), oxygen donor atoms have also been introduced in the structure. An example of these type of systems was presented by Bastida et al., who prepared ligands 55 and 56 (Scheme 32) by incorporating a fluorescent hydroxy-quinoline unit in the pendant arm and then studied their fluorescent sensing capability against a series of divalent and trivalent metal cations. The photophysical characterization of these ligands revealed two quenching mechanisms taking place, PET and a photoinduced proton transfer (PPT). Coordination with Al(III) prevents this quenching [76].

3.3. Aza Lariat Ethers

In an effort to mimic the excellent binding and selectivity properties of some natural molecules, such as valinomycin, researchers quickly realized that the three-dimensional folding of the receptor molecule was essential to isolate the guest molecule from the surrounding media and achieve a high degree of selectivity and binding. For this purpose, the lariat ethers were developed by adding flexible arms to macrocycles, such as crown-ethers and aza-crowns [77,78].

One of the first examples of the sensing ability of this type of compounds was reported by Pina et al. The macrocyclic ligand 57 (Scheme 33) was built with two phenantroline units as aromatic spacers and two naphthalene units at both ends of the pendant arms, yielding a multichromophoric structure. The photophysical properties of this ligand were studied against the pH and also in the presence of Cu(II) and Zn(II), the later giving rise to the expected CHEQ and CHEF phenomena, respectively. However, the excimer emission of the ligand, arising from the interaction of the two phenantroline units, was blue-shifted only in the case of Cu(II) complexation, pointing at the possible use of this ligand as a selective sensor for this metal cation [79].

Following this line, Clares et al. reported on an azamacrocylic ligand obtained by 2 + 2 condensation of two tris(2-aminoethyl)amine units (functionalized with methylnaphthyl groups) with 2,6-pyridinedicarbaldehyde as an aromatic spacer (58, Scheme 34). This ligand presents a specific fluorescent response for citrate in the 5–8 pH range, while no modifications in the emission spectrum of the compound were detected for other Krebs cycle components (i.e., α-ketoglutarate, succinate, fumarate, L-malate, and oxaloacetate) [80].

Delgado et al. developed an analogous ligand, a diethylenetriamine-derived hexaazamacrocycle with two quinoline units (59, Scheme 35), whose dinuclear Zn(II) complex exhibited an enhancement of fluorescence emission by the addition of pyrophosphate, acting as a selective fluorescent sensor in aqueous solution at physiological pH [81]. Competition titrations revealed an association constant value of 6.22 logarithmic units for the binding of pyrophosphate by [(Zn)₂59]⁴⁺ complex, which is higher than those obtained for the other phosphorylated substrates (5.5–4.0 logarithmic units).

Recently, Kataev et al., evolving from their previously synthesized tripodal ligands (see 20), prepared the macrocyclic 60 (Scheme 36). This compound, bearing two fluorescent naphthalimide dyes, was sequentially tested for its sensing capacity against mononucleotides, tetranucleotides, and finally, oligonucleotides forming G-quadruplex (G4) structures. Addition of the mononucleotides generally led to an enhancement of the fluorescence, with ATP showing the largest effect. This was ascribed to a hindering of the PET process by the proton exchange produced upon binding to the nucleotide. When interacting with G4 structures, the fluorescence of 60 increased four to nine-fold [82].

4. Grafted Polyamine Derivatives

In order to obtain more efficient, selective, and sensitive chemosensors, an increasing number of papers have recently appeared in which the chemosensor is anchored to different nanosized supports [83,84,85,86]. One of them, boehmite nanoparticles, which is an aluminum oxyhydroxide (γ-AlO(OH)), presents different advantages such as the possibility to make fluorescence emission studies in pure water with little scattering, and the recovering of the sensor system after their use by centrifugation because a change from a sol to a gel state occurs at basic pH. These nanoparticles contain terminal groups that render high reactivity to the surface and provide a hydrophilic environment, improving the homogeneity of the medium. For all these reasons, boehmite is a promising nanosized support.

Delgado-Pinar et al. developed boehmite-silica nanoparticles functionalized with linear polyamines containing terminal anthracene units (61 and 62, Scheme 37) [87]. These grafted polyamines offered the possibility to detect Hg(II) selectively (detection limit = 0.19 ppb) over other metal ions such as Cu(II), Zn(II), Cd(II), and Pb(II). This behavior was attributed to the ability of Hg(II) to form stable complexes with low coordination numbers [88].

Analogously, Carbonell et al. developed boehmite functionalized materials containing pyrene as a fluorophore and different linear or tripodal polyamines (63, 64, and 65, Scheme 38) as coordination sites. A detailed analysis of the interaction with some halides and oxoanions revealed a selective decrease in intensity of the pyrene fluorescence emission only for iodide in aqueous solution with an estimated detection limit of 36 ppb, 65 being the most efficient system [89].

On the other hand, Martínez-Mañez et al. reported a pioneering work related to the development of polyamine surface-functionalized mesoporous materials for anion recognition and signaling systems by dye delivery ([Ru(bipy)₃]²⁺) as a function of pH in aqueous solution. [90] Analogously, they reported the design of gated nanodevices based on mesoporous silica materials for the detection of genomic DNA from bacteria (Mycoplasma fermentans) [91,92]. The external surface of these porous systems, loaded with a fluorophore dye, was functionalized with polyamine molecules and oligonucleotides (electrostatically anchored to the protonated amino groups) acting as a cap. Thus, the system remains capped until the presence of the complementary oligonucleotide promoted the hybridization reaction and a displacement of the cap, resulting in pore opening and dye delivery (Figure 5). Based on these examples, different capped mesoporous silica materials for the selective detection of cations, anions, and biomolecules have been described by Martínez-Mañez in a recent review [93].

Recently, Oshchepkov et al. expanded the work of Kataev to prepare cryopolymers based on a naphthalimide fluorescent ligand that had shown selectivity toward phosphonate (66, Scheme 39). Cryopolymers are super-porous gel structures, prepared via the freeze–thaw method, which show interesting mechanical and chemical properties [94]. Ligand 66 is similar to those described previously in this review (see 20 and 21) and by the reaction shown below. This ligand is similar to those described previously in this review (see 20 and 21). By the reaction shown below, the authors included this fluorescent chemosensor into a cross-linked polymeric material. However, when comparing with the monomer, in the polymeric materials prepared, the selectivity was lost, and a decrease of the fluorescence quantum yield was observed [95].

5. Conclusions

In this review, different examples of fluorescent chemosensors based on polyamine ligands have been presented. These molecules show changes in their fluorescence emission as a response to the sensing of metal ions and anions with environmental and/or biological interest. Over the past few decades, a great number of these systems have been reported in the literature with ligands of different topologies (linear, branched, macrocyclic with or without pendant arms, grafted), exploiting a wide variety of fluorophores that cover a range of emission wavelengths and other photophysical properties. As shown in this review, the polyamine chemosensor “tool-box” has expanded greatly, and now is the time for concrete applications to crystallize.

Among the most common photophysical mechanisms of detection in these systems, we find the photoinduced electron transfer (PET), the chelation-enhanced fluorescence (CHEF), and the chelation-enhanced quenching (CHEQ). Other relevant mechanisms are the photoinduced proton transfer (PPT) and electron transfer (ET).

Fluorescent chemosensors anchored to nanoparticulate materials are very promising systems that can translate the knowledge developed on fluorescent sensors to the industrial applications. We consider that there is still room for improvements in this field, since the examples found in the literature, so far, have been prepared with the simplest open-chain polyamines. Therefore, the variety and structural complexity of polyamine-based chemosensors studied in solution has still not fully reached the solid phase.

For a summary of all the chemosensor structures, analytes, and corresponding references, please refer to

Table A1. Summary of the chemosensor structures, analytes, and corresponding references.

Compounds	Analytes Tested	Refs.
	H+, Co2+, Cu2+, Zn2+, Cd2+	[13,14,15]
	Zn2+	[16]
	H+, Zn2+, Co2+, Ni2+, Cu2+, Cd2+, Mn2+, Hg2+, Pb2+, Ag+, Li+, K+, Mg2+, Ca2+, Fe3+	[17,18,19]
	H+	[24]
	H+, Zn2+ In the case of [ZnL]2+: triphosphate, diphosphate, phosphate, iodide, fluoride, citrate, D,L-isocitrate, cyanurate	[25]
	H+, ATP, PMG	[26]
	Ni2+, Cu2+, Cd2+, Hg2+, Pb2+, bromide, sulfate, phosphate, ATP	[33]
	Phosphate, citrate, sulfate, acetate, dimethyl phosphate	[35]
	H+, Zn2+, Co2+, Ni2+, Cu2+, Cd2+, Mn2+, Hg2+, Pb2+, Fe3+, Na+	[37]
	Sulfate, phosphate, pyrophosphate, nitrate, perchlorate.	[38]
	H+, Zn2+ In the case of [ZnL]2+: triphenylacetate, 1-adamantanecarboxylate, cyclohexylcarboxylate, benzoate, acetate.	[39]
	Fluoride, chloride, bromide, sulfate and nitrate.	[40]
	H+, Cu2+, Co2+, Ni2+, Zn2+, Cd2+, Hg2+	[41]
	Zn2+, Ca2+, Mg2+, Mn2+, Fe2+, Ni2+, Cu2+	[42]
	H+	[43]
	H+, Cu2+, Zn2+	[44]
	PMG, AMPA	[45]
	H+, Cu2+, Zn2+, Cd2+, Fe2+, Fe3+, Ca2+, Mn2+, Mg2+, Hg2+, Pb2+	[47]
	H+, Zn2+, Co2+, Ni2+,Cu2+, Cd2+, Fe2+, Ca2+, Mn2+, Mg2+	[48]
	Pi, ATP, ADP, AMP, PO43−, HPO42−, H2PO4−, Asp, Glu, malonic acid, oxalic acid, HCO3−, SO42−, Br−, N3−, F−, AcO−, I−, Cl−, SCN−, NO3−, S2−, SO32−, CO32−	[49,50]
	Ni2+, Ni3+	[52,53,54]
	H+, Zn2+, ATP, CTP, TTP, GTP	[55,56]
	H+, Zn2+, ATP	[57,58]
	H+, Cu2+, Zn2+, [Fe(CN)6]4−	[59]
	H+	[60]
	Coumarine, fluorescein, eosine Y, Hys, Gly, Ala, Phe, Val, Leu, Pro	[62]
	H+, Cd2+, Zn2+	[66,67]
	H+, Cu2+, Zn2+, ATP, GTP, UTP	[68]
	H+, Cu2+, Zn2+	[69]
	H+, Cu2+, Zn2+, Cd2+, Co2+, Hg2+, Mn2+, Ni2+, Pb2+ In the case of [ZnL]2+: F−, Cl−, Br−, I−, OAc−, HSO4−, H2PO4−, NO3−	[70,71]
	H+, Cu2+, Zn2+, phosphate, benzoate, CN−, S2−	[74]
	H+, Cu2+, Zn2+, Cd2+, Fe3+, Ca2+, Mn2+, Mg2+, Hg2+, Pb2+, Ag+, Ni2+, Co2+	[75]
	H+, Cu2+, Zn2+, Cd2+, Cr2+	[76]
	H+, Cu2+, Zn2+	[79]
	Citrate	[80]
	In the case of [Zn2L]4+: H2PO4−, PhP2−, HPPi, HAMP−, HADP2−, HATP3−	[81]
	ATP, GTP, CTP, UTP, G-quadruplex	[82]
	Cu2+, Zn2+, Cd2+, Pb2+, Hg2+	[87]
	H+, I−	[89]
	Phosphate, pyrophosphoric acid, 1-hydroxyethane 1,1-diphosphonic acid, aminotris(methylene- phosphonicacid)	[95]

(Appendix A).