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REVIEW ARTICLE

A Review on the Recent Trends in Synthetic Strategies and Applications of Xanthene Dyes Ghulam Shabir, Aamer Saeed* and Pervaiz Ali Channar Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan

ARTICLE HISTORY Received: October 24, 2016 Revised: March 21, 2017 Accepted: March 22, 2017 DOI: 10.2174/1570193X14666170518130008

Abstract: A survey of literature covering the synthesis of xanthene dyes and their applications during the period 2000-2016 is carried out. A comparison of various synthetic strategies in terms of major starting materials and catalysts used has also been presented. Furthermore, a discussion of pH and metal cations detection has been provided for some well known xanthene chromophores and their derivatives. This review aims to examine all the aspects of xanthene scaffold, including some future prospects and further developments in this area.

Keywords: Xanthene Dye, Coumarin, Metal Ion Detector, pH Sensors, NIR absorbing xanthene chromophores, xanthene scaffold. 1. INTRODUCTION Xanthenes (dibenzo[a,e]pyrans) are tricyclic molecules containing pyran heterocycle as central a ring fused to benzene rings on both sides and belong to class of fluorescent dyes. Structurally related to xanthones, they are found in a wide variety of natural products having diverse pharmacological activities. The presence and position of substituents on ring have a large impact on the biological applications and fluorescent colors. Examples include the cationic red fluorescent dye rhodamine B, fluorescein (green fluorescent dye) and the anionic red fluorescent dye eosin. Advantages of xanthene dyes include large absorption and luminescence, exceptional light resistance, little toxicity in vivo, and moderately high water solubility. Applications of xanthene dyes involve optical materials and organic dyes for medical diagnosis research. Coumarin structural motif is a part of rhodol fluorophore the hybrid structure of fluorescein and rhodamine. The structural relationship between the xanthene dyes and coumarins and xanthone is illustrated in Fig. 1. Xanthenes are rare natural products and have been isolated from only two plant families, Compositae and Fabaceae [1-3]. Compounds 1, 2 and 3 are examples of natural xanthenes (Fig. 2). Blumeaxanthene I and blumeaxanthene II have been isolated from Blumeariparia DC (Compositae), a Chinese medicinal herb traditionally used to treat gynecological disorders [3] and the 3-isopropyl-9a-methyl-1,2,4a,9atetrahydroxanthene (3) has been isolated from Indigofera longeracemosa (Fabaceae) used in traditional Indian medicine as an antidote to all snake venoms.

*Address correspondence to this author at the Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan; Tel: +92-51-90642128; Fax: +92-51-9064-2241; E-mail: [email protected] 1570-193X/17 $58.00+.00

Qualitative and quantitative biological and chemical analysis has also been achieved with fluorescent dyes [4]. A variety of these dyes are widely used as the physicochemical properties of the dyes vary widely and different combination of properties is possible. These include absorption and emission maximum of chromophoric system, polarity and micro environmental dependence of the fluorescence for diverse applications [5, 6]. The high stability, both chemical and physical photostability is also a prominent and desirable feature of these dyes [7]. Fig. 3 shows a general structure of rhodamine derivatives where difference in photophysical properties arises due to the presence of substituents R1, R2, R3, R4, G and X-. 2. SYNTHETIC METHODOLOGIES XANTHENE DYES

TOWARDS

Different types of reagents have been tested from time to time in the synthesis of xanthene moieties which involves the condensation of aldehydes, carboxylic anhydrides and phenol derivatives in the presence and absence of solvents using Lewis acid catalysts. Biologically active benzoxanthene derivatives are synthesized by mixing β-naphthol, an aromatic or aliphatic aldehyde and a 1, 3-dicarbonyl substrate (Scheme 1) with various Lewis acids. Similarly, aryldibenzo (Scheme 2), dioxooctahydroxanthene, dioxo-hexahydroxanthene and dioxotetrahydrobenzoxanthene have been synthesized using various acid combinations: These include a) H2SO4, Sulfamic acid or pTSA, dodecylbenzenesulfonic acid, diammonium hydrogen phosphate, silica gel supported ferric chloride, Dowex-50W, polyethylene glycol, indium (III) chloride; b) tetrabutyl ammonium fluoride in water (c) para-toluene sulfonic acid; d) solventfree with iodine and e) sodium hydrogen sulfate on silica gel in dichloromethane [8-18]. However, the use of substituted salicylaldehydes instead of common aldehydes in these reactions, led © 2017 Bentham Science Publishers

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to the synthesis of 1-oxo-1,2,3,4,9,10-hexahydroxanthene derivatives upto 94 % yield (Scheme 3) [19]. Singh et al., investigated the preparation of 12-aryl8,9,10,12-tetrahydrobenzo[a]xanthene-11-from multicomponent condensation of aromatic aldehydes, 2,7dihydroxynaphthalene/2-naphthols/2,6-dihydroxy naphthlene and cyclic 1,3-dicarbonyl compounds in an acidic ionic liquid [NMP]H2PO4 at 80oC (Scheme 4) [20]. Venkatesan, et al., conducted the synthesis of 1,8dioxooctahydroxanthene (xanthene) derivatives in excellent yields by the condensation reaction between an aldehyde and diketone catalyzed by the ionic liquid, [Hbim]BF4 (IL). The advantages of this method include the use of a recyclable, non-volatile ionic liquid, which promotes this protocol under ambient temperature without the requirement of any added catalyst (Scheme 5) [21].

Scheme 2. Dibenzoxanthenes derivatives synthesis.

The synthesis of 9-aryl-6-hydroxy-3H-xanthen-3-one fluorophores was reported by Bacci using aryl aldehydes and fluororesorcinol which proceed through a triarylmethane intermediate followed by oxidative cyclization with DDQ (Scheme 6) [22]. Brase et al. reported synthesis of tetrahydroxanthenones using Ball milling as a mechanochemical technique from salicyclaldehyde and cyclohexenone through a domino oxaMichael aldol reaction (Scheme 7) [23]. A three-component one-pot synthesis of new 2,4diamino-5H-chromeno[2,3-b]pyridine-3-carbonitriles de-

Fig. (1). Structural relationship among xanthone, xanthene and coumarin chromophores.

Fig. (2). Naturally occurring xanthene in plants.

Fig. (3). General structure of xanthene derivatives with different photophysical properties.

Scheme 1. Benzoxanthene derivatives active heterocycles synthesis.

A Review on the Recent Trends in Synthetic Strategies and Applications

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Scheme 3. Dioxo-xanthenes derivatives synthesis.

Scheme 4. Synthesis of 12-Phenyl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one derivatives in ionic liquid [NMP]H2PO4.

Scheme 5. Synthesis of 1,8-dioxo-octahydro-xanthenederivatives.

Scheme 6. Synthesis of 9-aryl-6-hydroxy-3H-xanthen-3-one fluorophores.

Scheme 7. Synthesis of tetrahydroxanthenones.

Scheme 8. Synthesis of new 2,4-diamino-5H-chromeno[2,3-b] pyridine-3-carbonitriles.

rived from 2-amino-1,1,3-tricyanopropene, salicylaldehyde and secondary cyclic amine was reported by Shaabani et al (Scheme 8). The reaction was conducted in the ethanol medium at ambient temperature and afforded the products in good to excellent yields [24]. The chemical synthesis of xanthone C-glycosides has never been reported. Yu et al. reported a synthetic approach

to mangiferin, isomangiferin, and homomangiferin (Fig. 4), employing the C-glycosylation of a xanthene derivative with perbenzylglucopyranosyl trifluoroacetimidate as the key step (Scheme 9) [25]. An efficient iron-catalyzed, microwave-promoted cascade benzylation-cyclization of phenols was reported by Li et al. utilizing benzyl acetates, benzyl bromides and benzyl


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Fig. (4). Structures of mangiferin, isomangiferin and homomangiferin.

Scheme 9. C-glycosylation of a xanthene derivative with perbenzylglucopyranosyl trifluoroacetimidate.

Scheme 10. Synthesis of 9-aryl and 9-alkyl xanthene.

Scheme 11. Ferrocenyl-2 thioxodihydropyrimidines-based xanthenes.

Scheme 12. Synthesis of unsymmetrical 9-aryl/heteroaryl xanthenes.

carbonates as benzylating reagents. The reactions afforded both 9-aryl and 9-alkyl xanthene derivatives in good to high yields (75%) (Scheme 10) [26]. Sohár and co-workers carried out the Biginelli reaction of formyl ferrocene, thiourea and a variety of 1,3-dioxo components to obtain novel ferrocenyl-2 thioxodihydropyrimidines and condensed heterocycles catalyzed by boric acid and ytterbium triflate, respectively (4-7, Scheme 11) [27].

A general and efficient one-pot cascade/tandem approach to synthesize unsymmetrical 9-aryl/heteroaryl xanthenes has been reported by Singh et al. using 10 mol % of Sc(OTf)3 as a catalyst [Scheme 12]. The strategy was extended to synthesize 9(thioaryl)xanthenes through tandem carbon–sulfur (C–S) and carbon–carbon (C–C) bond formation [28]. 2,6,7Trihydroxyxanthen-3-ones have been prepared by a one-pot


protocol using alkali peroxosulfates in the key step (Scheme 13) [29]. Benzyne prepared from o-trimethylsilyphenyl triflate and CsF reacts with salicylaldehyde to yield xanthenes and xanthones. When the reaction was carried out under basic conditions, 9-hydroxyxanthenes (xanthols) were obtained in good yields (Scheme 14) [30]. The condensation of 2-hydroxynaphthalene-1,4-dione with isatin or aldehyde yielded spiro[dibenzo[b,i]xanthene13,3′-indoline]-pentaones and 5H-dibenzo[b,i] xanthenetetraones in up to 79% yeild (Scheme 15) [31].


Wiemer et al. synthesized a single diastereomeric cisfused hexahydroxanthene through a cascade cyclization initiated by Lewis acid (Scheme 16) [32-33]. One pot synthesis of hexahydroxanthene-9-N-arylamine derivatives has been developed from cyclohexanone and morpholine with salicylaldehyde in the presence of 20 mol % InCl3 catalyst under reflux conditions in acetonitrile (Scheme 17) [34]. Fluorinated benzo[c]xanthene dyes (15) were synthesized from 6-hydoxy-1-naphthoic acid in alkaline THF under reflux, and have been found suitable for determination of intracellular pH, confocal laser scanning microscopy and flow cytometry (Scheme 18) [35].

Scheme 13. Synthesis of 2,6,7-Trihydroxyxanthen-3-ones.

Scheme 14. Benzyne andsalicylaldehyde based xanthenes and xanthones.

Scheme 15. Synthesis of spiro[dibenzo[b,i]xanthene-13,3‘-indoline]-pentaones and 5H-dibenzo[b,i] xanthene-tetraones.

Scheme 16. Synthesis of hexahydroxanthene system.


The (3-hydroxy-2-naphthalenyl) methyl (NQMP) group acts as an efficient photocage for fluorescein based dyes and irradiation of the 6-NQMP ether of 2′-hydroxymethylfluorescein with low-intensity UV light resulted in a 4-fold increase in emission intensity. Photoactivation of nonfluorescent NQMP-caged 3allyloxyfluorescein produces a highly emissive fluorescein monoether (Scheme 19) [36]. For the synthesis of 1,8-dioxooctahydroxanthene derivatives indium (III) chloride InCl3 and metaphosphoric acid have been found efficient catalysts and several substituted

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xanthene nuclei have been synthesized in high yields (98%) and purity by these catalysts (Scheme 20) [37]. For example Methyl 2-[3-oxo-6-(2, 2‘, 5‘, 2‘‘-terthien-3‘ylmethoxy)-3H-xanthen-9-yl] benzoate (TTFlo) and its conducting polymers have been synthesized on ITO electrode surfaces with valuable yields (82%) ((Fig. 5) [38]. Thielbeer et al., investigated the synthesis and application of aminomethyl-functionalized fluorescent particles via polymerizable monomers and showed high fluorescence on ingestion by cells during applications (Scheme 21) [39].

Scheme 17. Synthesis of hexahydroxanthene- 9-N-arylamine derivatives through a one-pot reaction of cyclohexanone and morpholine with salicylaldehyde.

Scheme 18. Synthesis of carboxy SNARF-4F dye.

Scheme 19. Activation of NQMP-Caged 6-Hydroxy-9-(2-(hydroxymethyl)phenyl)-3H-xanthen-3-with UV light.

Scheme 20. Synthesis of 1,8-dioxooctahydroxanthene derivatives.



Scheme 21. Synthesis of polymerizable fluorescein monomers.

Novel fluorescent compounds having hindered amines and s-triazine moieties connected with polymerizable allyl function were synthesized and they exhibited high fluorescence on polymerization with acetonitrile (Fig. 6) [40]. H N

O

N N

HO

O

NH

N N

N O

O

COOH

HO

N N O

O

Fig. (7). Polymerizable xanthene dyes having combination of Fluorescein or Eosin with 2,2,6,6-tetramethylpiperidine.

COOH

Fig. (6). Novel fluorescent compounds having hindered amines and s-triazine moieties connected with polymerizable allyl function.

Polymerizable xanthene dyes, having a combination of Fluorescein or Eosin with 2,2,6,6-tetramethylpiperidine, have been synthesized (98%), polymerized and characterized for their photochemical properties. It was further deduced that xanthene dyes containing hindered amine light stabilizer gain high photostability (Fig. 7) [41]. Employing modified Ullmann reaction hole transporting molecules based on spiro (fluorine-9,9-xanthene) were accomplished and were found suitable for the hole injection from ITO anode (Fig. 8) [42].

Fig. (8). Hole-transporting molecules based on spiro(fluorene-9,9xanthene).

A large number of fluorescein derivatives incorporating imidazole nuclei have been developed as diagnostic agents for positron emission tomography and optical imaging [4347]. Recent development in the synthesis of Nutlin–Glycine has received eminence due to its usefulness regarding the imaging of tumor cells (24, 85%) [48-50] (Scheme 22).


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Scheme 22. Synthetic scheme of Nutlin–Glycine–FAM conjugate.

Scheme 23. Synthesis of Tetrahydrobenzo[a]xanthenes-11-one mediated by the presence of BF3.SiO2.

Tetrahydrobenzo[a]xanthenes-11-one synthesis catalyzed by BF3.SiO2 has been envisioned which resulted in several advantages including high purity, excellent yields, ease of operation and workup, and green route process (Scheme 23) [51]. In recent years, xanthene dyes especially fluorescein derivatives have been found valuable due to their key role in drug discovery and gene delivery systems, cancer [52], neurodegenerative diseases [53], biosensors [54-60], bioimaging [61-63] and as protein-based indicators [64-66]. Currently, fluorescein based N-glycosylamines (30-33) are being explored for cell imaging studies (Scheme 24). Similarly rhodols and rhodamine derivatives (especially N-alkyl substitution) have been synthesized and their appli-

cations as lasing agents, tracer agents, and biological probes have been observed. The simplest member of this class of fluorescein dyes, rhodamine 110 (Rh110), exhibits fluorescein-like spectral properties with λmax = 496 nm, λem = 517 nm, ε = 7.4 × 104 M-1 cm-1, and Φ = 0.92 in aqueous solution [67]. In general, quantum yields of rhodols and rhodamines decrease with increasing carbon number and the bulk of the substituents [68, 69] except for that of sulforhodamine (Rh101) which shows high quantum yields and longer excitation and emission wavelengths. The above mentioned rhodamines are illustrated in Fig. 9. Rhodols, rhodamines and their derivatives are achieved through condensation of an aminophenol with a phthalic anhydride under acidic conditions (Scheme 25) [69].


Synthesis of Rhodamine and their derivatives has also been reported under ZnCl 2-catalyzed direct substitution of

Scheme 24. Synthesis of fluorescein-based N-glycosylamines.

Fig. (9). Structures of selected rhodamines.

Scheme 25. General synthesis of rhodols and rhodamines.


3‘,6‘-dichlorofluoresceins with amines (Scheme 26) [7072].


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Scheme 26. Synthesis of rhodamine derivatives from halogenated fluorescein.

Scheme 27. Palladium catalyzed synthesis of rhodol fluorophores.

Scheme 28. Palladium catalyzed synthesis of rhodamines.

Scheme 29. Synthesis of new fluorescent rhodamine bearing four carboxylic acid functionalities

Recently, a similar strategy for the synthesis of rhodols was reported by Peng et al. in 2010 employing the Buchwald-Hartwig amination reaction (Scheme 27) [73]. Following the same route as in Scheme 27, the preparation of rhodamines and N, N-diacetylated rhodamines was achieved Grimm et al. (Scheme 28) [74]. Synthesis of a new fluorescent rhodamine bearing free carboxylic group to promote water solubility has also been achieved (Scheme 29) [75]. 3. CAGED XANTHENE DYES Small organic molecules such as fluorescent dyes can be used for investigation of living cell dynamics. One approach

is the use of caged fluorescent dyes which contain photochemically labile protective groups, which mask the fluorescence. The photosensitive masking group or molecular cage is removed by irradiation with UV light and fluorescent dye molecule is obtained. Among many caged fluorophores, fluoresceins and rhodamines are the most popular dyes. Rhodamines and fluoresceins exist in equilibrium between their brightly fluorescent “open” quinoid structure and a colorless, closed lactone. Caged fluorescein is in the bis-caged lactone form, full activation requires deprotection of two photoremovable protecting groups (Scheme 30) [76]. Ito et al. investigated the synthesis of azido-masked fluoresceins for recognizing nucleic acids in living cells. Reduc-


ing agents like dithio-1,4-threitol or triphenylphosphine used to activate rhodamine-6’-azido incorporated into oligonucleotides. Further caged fluorescein derivatives bearing monoazidomethyl and bis-azidomethyl protective groups are uncaged upon UV irradiation which converts the azido group into nitrene, which form an amino-hemiacetal upon abstraction of a proton from water molecule. This hemiacetal intermediate is hydrolyzed in aqueous environment to produce an unmasked phenol group of fluorescein and the molecule emits fluorescence (Scheme 31) [77].


A novel class of caged compounds “Rhodamine spiroamides (RSAs)” has been introduced and applied in singlemolecule switching microscopy (SMS) in addition to dyes with standard cages at 3‘, 6‘ positions. The photochromic reaction of RSA was reported for the first time in the 1970s by Knauer and Gleiter. This light induced ring-opening reaction releases the rhodamine chromophore, which exhibit absorption in green region and emission in the red region of electromagnetic radiation spectrum. The closed spiro form is transparent in the whole visible region and is formed from open isomer thermally within milliseconds (Scheme 32).

Scheme 30. Uncaging scheme of caged fluorescein.

Scheme 31. Light induced uncaging of mono and bis-azidomethyl fluorescein labeled oligodeoxynucleotide ODN.

Scheme 32. Photochromic (caged) RSAs in the colorless and colored form.

Scheme 33. Uncaging of TMR-NN derivative.


Markers in the “open” form (OF) are bleached by a strong pulse of the same excitation laser after being imaged, to reduce imaging time [78]. Belov et al reported the incorporation of rhodamine NN dyes, having 2-azidoketone (COCNN) caging group into a spiro-9H-xanthene fragment and uncaging occurs under regular irradiation conditions (λ ≤ 420 nm) (Scheme 33) [79]. 4. LEUCO XANTHENE DYES Fluoresceins and rhodamines are converted into colorless, non-fluorescent leuco dyes on substation at hydroxy and amino groups of these dyes respectively. Acylation or alkylation of substituents lock the molecule into non fluorescent lactone form and thus they their role as array of fluorogenic substrates for esterases, phosphatases, glycosylases and other enzymes (Scheme 34) [80, 81]. For monitoring enzyme activity, leuco dyes contain two moieties, each of which act as a substrate for enzyme. These

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substrates are hydrolyzed by enzyme, first to the mono substituted analogue and then to free fluorescent dye (Scheme 35) [82]. Fluorescein di-β-galactopyranoside (FDG) has been found suitable to determine glycosidase enzyme activity in living cells (Scheme 36) [83]. Tokyo green dye coupled with β-galactoside was used as novel fluorescent probe to visualize the β–galactosidase activity in living cells. In comparison with di-O-β-galactoside fluorescent probe, this probe exhibited enhanced fluorescence and high sensitivity (Scheme 37) [84]. Detection of reactive oxygen species (ROS) has been made possible with commercially available leuco dyes which are reduced into dihydro derivatives because of their better stability toward auto oxidation (Schemes 38, 39) [85]. Srikum et al. also employed H2O2-mediated deprotection of boronate esters of boronate-caped Tokyo green dyes for site specific protein labeling with small molecules on the surface or interior of living cells (Scheme 40) [86].

Scheme 34. Synthesis of leuco xanthene derivatives under Solvent free conditions at 100 oC.

Scheme 35. Esterase hydrolysis of di-acetylated fluorescein.

Scheme 36. Reaction of fluorescein di-β-galactopyranoside (FDG), fluorescent probe for β-galactosidase.



Scheme 37. Reaction of Tokyo Green- β-Galactose with β-galactosidase.

Scheme 38. Oxidation of 2‘,7‘-dichlorodihydrofluorescein diacetate (H2DCFDA).

Scheme 39. Detection of reactive oxygen species with APF and HPF.

Scheme 40. Activation of coumarin donor and a boronate protected fluorescein acceptor reporter.

Following the above method, Maeda et al. developed H2O2-mediated deprotection of mono pentafluorobenzenesulfonyl fluoresceins by non-oxidative mechanism. It was demonstrated that the acetylated 35, upon permeation into the cells of green algae was converted into 34 again by cellular esterases and was further deprotected by cellular H2O2. The di-substituted fluorescein (36) was applied as a selective probe for detection of O2- via a nonredox mechanism (Scheme 41, 42) [87]. One pot two component synthesis of dibenzoxanthene leuco dyes from the reaction of aromatic aldehyde such as benzaldehyde, p-methylbenzaldehyde, p-nitrobenzaldehyde, p-bromobenz aldehyde with β-naphthol in acidic conditions is described in Fig. 10 [88].

5. CATALYSTS USED IN SYNTHESIS OF XANTHENE DYES Different kinds of salts including organic and inorganic salts have been intended to catalyze the synthesis of xanthene derivatives under solvent-free conditions. Xanthene derivatives have been synthesized under ultrasonic irradiation at room temperature in the presence of N-Sulfonic acid poly (4-vinylpyridinium) hydrogen sulfate (NSPVPHS) catalyst by Khaligh et al. The present methodology has provided several advantages such as accelerated reaction rate and excellent yields (78-97%), less energy consumption, no side reactions, ease of preparation and handling of the catalyst, cost efficiency, simple experimental procedure and mild conditions (Scheme 43) [89].


Spiro [dibenzo[b,c] xanthene-1,3,3‘-indole]-pentaones and 5H-dibenzo[b,i]xanthene-tetraones are prepared from the

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condensation of 2-hydroxynaphthalene-1,4-dione with isatins or aldehydes (Scheme 44) [90].

Scheme 41. Reaction of selective H2O2 probe.

Scheme 42. O2-• Mediated deprotection of fluorescent probe.

Fig. (10). Dibenzoxanthene leuco-dye from the reaction of aromatic aldehydes.

Scheme 43. NSPVPHS catalyzed synthesis of xanthenes under grinding and solvent-free conditions.



Scheme 44. p-TSA catalyzed synthesis of spiro[dibenzo[b,i]xanthene-13,3‘-indoline]pentaones and 5H-dibenzo[b,i]xanthenetetraones.

Scheme 45. Double condensation of resorcinol and aromatic aldehydes.

Scheme 46. Synthesis of xanthene derivatives in the presence of SuSA under solvent-free conditions.

Proficient condensation of resorcinol with various aromatic aldehydes in the presence of homogenous catalyst RuCl3.nH2O under reflux conditions has also been investigated and good to excellent yields of desired products are achieved. (Scheme 45) [91]. A mild, simple and convenient procedure for the synthesis of xanthene derivatives has been described via threecomponent condensation of aldehydes with β-naphthol, 1,3cyclohexanedione and/or a mixture of 2-naphthol and 1,3cyclohexanedioneusing succinimide-N-sulfonic acid as efficient catalyst under solvent free conditions by Shirini and Khlaigh (Scheme 46) [92]. Heterogeneous catalyst, AgI nanoparticles have been used by Safaei-Ghomi, Javad, and M. A. Ghasemzadeh for the one pot synthesis of 14-aryl-14H-dibenzo [a, j] xanthenes via multi component reaction of aldehydes with β-naphthol under solvent free conditions. The present investigation offers several advantages such as short reaction times, high yields, easy purification, the reusability and low catalyst loading (Scheme 47) [93]. Another heterogeneous catalyst based on silica supported ammonium dihydrogen phosphate (NH4H2PO4/SiO2) has

investigated for the rapid and efficient synthesis of 14-aryl14H-dibenzo [a, j] xanthenes (Scheme 48) [94].

Scheme 47. One-pot synthesis of xanthene derivatives in the presence of silver iodide nanoparticles under solvent-free conditions.

Scheme 48. Silica supported ammonium dihydrogen phosphate (NH4H2PO4/SiO2) catalyzed synthesis of aryl-14Hdibenzo[a,j]xanthenes.

14-aryl- or alkyl-14H-dibenzo[a,j]xanthene derivatives have also been synthesized using Fe(HSO4)3 as catalyst for the condensation of 2-naphtol and aldehydes. Different types of aromatic and aliphatic aldehydes were used in the reaction and in all cases the products were obtained in good to excellent yields (Scheme 49) [95].


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14-aryl-14H-dibenzo[a,i]xanthene-8,13-dione derivatives were accomplished by the one pot condensation of 2naphthol, aldehydes, and 2-hydroxy-1,4-naphthaquinone under solvent free conditions in the presence of SiCl2 heterogeneous catalyst (Scheme 50) [96].

The condensation of β-naphthol with various aromatic aldehydes in the presence of catalytic amount of Bronsted acidic ionic liquid [H-NMP][HSO4] under solvent free conditions at 110 oC has been described by Naeimi and Nazifi (Scheme 53) [99].

Madhav et al., described the condensation of β-naphthol with aromatic aldehydes in the presence of cellulose sulfuric acid under solvent-free conditions to achieve the corresponding aryl-14H-dibenzo [a.j] xanthenes (Scheme 51) [97].

Nano-ZnAl2O4 has been used to catalyze the synthesis of xanthene chromophores (Scheme 54) [100].

Highly efficient and recyclable heterogeneous organocatalysts containing acidic functional groups such as COOH and SO3H have been investigated for the synthesis of xanthene dyes (Scheme 52) [98].

A facile and efficient method has been developed for the synthesis of 1-oxo-hexahydroxanthenes in the presence of FeCl3.6H2O catalyst and was applied for the condensation of salicylaldehydes with cyclic diketones to afford desired products in good yields at room temperature (Scheme 55) [101].

Scheme 49. Fe(HSO4)3 catalyzed one-pot synthesis of 14-aryl- or alkyl-14H-dibenzo[ a,j]xanthene derivatives.

Scheme 50. Synthesis of 14-aryl-14H-dibenzo[a,i]xanthene-8,13-diones.

Scheme 51. Synthesis of aryl-14H-dibenzo[a.j]xanthenes with cellulose sulfuric acid.

Scheme 52. Recyclable heterogeneous organocatalysts catalyzed synthesis of alkyl-14H-dibenzo[a.j]xanthenes.

Scheme 53. Synthesis of 14-(4-chloro-3-nitrophenyl)-14H-dibenzo[a,j]xanthene.



Scheme 54. Synthesis of 1-Oxo-hexahydroxanthene.

Scheme 55. Synthesis of 1-Oxo-hexahydroxanthenes catalyzed by FeCl3.6H2O.

Scheme 56. Synthesis of 9,10,12-Tetrahydrobenzo[a] xanthen-11-one derivatives (ATXOs) in the presence of rice husk (RiH).

Employing rice husk synthesis of 12-aryl-8,9,10,12tetrahydrobenzo[a] xanthen-11-one derivatives (ATXOs) has been reported by Farhad et al., via three-component reaction of aldehydes, β-naphthol and dimedone under solvent-free conditions (Scheme 56) [102]. Using 1-methyl-3-propane sulfonic-imidazolium hydrosulfate ([MIMPS]HSO4) as catalyst, synthesis of 14-alkyor- aryl-14H-dibenzo[a,j]xanthenes via one-pot condensation of 2-naphthol with aliphatic or aromatic aldehydes was described by Gong et al. The advantage of this catalyst is that it can be recycled and reused five times without a noticeable decrease in its activity (Scheme 57) [103].

dibenzo[a,j]xanthenes with excellent yields using ultrasonic irradiation (Scheme 58) [104].

Scheme 58. Silica supported ammonium dihydrogen phosphate (NH4H2PO4/SiO2) catalyzed synthesis of various aryl-14Hdibenzo[a,j]xanthenes.

Polyvinyl polypyrrolidone-supported boron trifluoride has been used as catalyst for the synthesis of 14-aryl-14Hdibenzo[a,j]xanthenes and bis(naphthalen-2-yl-sulfane) via condensation of aldehydes with 2-naphthol or 2-thionaphthol (Scheme 59) [105].

Scheme 59. The reaction of 2-naphthol with aldehydes catalyzed by PVPP-BF3.

Scheme 57. Synthesis dibenzo[a,j]xanthenes.

of

14-alkyl-

or

aryl-14H-

Recyclable silica supported ammonium dihydrogen phosphate (NH4H2PO4/SiO2) heterogeneous catalyst afforded a rapid and efficient synthesis of various aryl-14H-

The p-dodecylbenzenesulfonic acid (DBSA) has been successfully used catalyst for the microwave-assisted synthesis of a series of 14-aryl- or alkyl-14H-dibenzo[a,j]xanthenes via a one-pot condensation-cyclization reaction of 2naphthol with various aliphatic or aromatic aldehydes under solvent-free conditions (Scheme 60) [106]. Mirjalili et al., investigated the use of silica-supported boron trifluoride (BF3-SiO2) catalyst for the synthesis of 14-


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aryl or alkyl-14H-dibenzo[a,j]xanthenes by condensation of β-naphthol and aldehydes (Scheme 61) [107].

dia using conventional heating and microwave irradiations (Scheme 64) [110].

Heterogeneous solid acid nanoporous diatomite sulfonic acid has been used successfully for the synthesis of 14-aryl14H-dibenzo[a,j]xanthenes under solvent free conditions (Scheme 62) [108].

A one-pot condensation of 2-naphthol with aldehydes in the presence of Amberlyst-15 to give 14-substituted-14Hdibenzo[a.j]xanthenes under solvent-free condition has also been reported (Scheme 65) [111].

1,3-disulfonic acid imidazolium hydrogen sulfate (DSIMHS) has been used to conduct synthesis of xanthenes under solvent free conditions (Scheme 63) [109]. Sulfamic acid has been used as catalyst for the synthesis of aryl-14H-dibenzo[a.j]xanthenes from one-pot condensation of β-naphthol with aryl aldehydes in a solvent free me-

An efficient synthesis of 1,8-dioxooctahydroxanthenes and 14-aryl-14H-dibenzo[a,j]xanthenes is described through one-pot multi-component reaction of dimedone and 2naphthol with various aryl aldehydes using ZnO nanoparticles under solvent-free conditions (Scheme 66) [112].

Scheme 60. p-dodecylbenzenesulfonic acid (DBSA) synthesis of 14-aryl- or alkyl-14H-dibenzo [a,j] xanthenes.

Scheme 61. Silica-supported boron trifluoride (BF3-SiO2) catalyzed synthesis of 14-aryl or alkyl-14H-dibenzo[a,j]xanthenes.

Scheme 62. 14H-dibenzo[a,j]xanthenes Sulfonic acid functionalized diatomite afforded diatomite-SO3H synthesis of 14-aryl-14Hdibenzo[a,j]xanthenes.

Scheme 63. Synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes in the presence of DSIMHS under solvent-free conditions.

Scheme 64. Synthesis of aryl-14H-dibenzo[a.j]xanthenes catalyzed by sulfamic acid.

Scheme 65. A one-pot condensation of 2-naphthol with aldehydes in the presence of Amberlyst-15.


With the help of organocatalyst pentafluorophenyl ammonium triflate (PFPAT) an efficient method for the synthesis of 14-aryl and alkyl-14H-dibenzo[a,j]xanthenes and 1,8dioxooctahydro-xanthene derivatives via condensation of 2naphthol or dimedone with aldehydes under mild conditions (Scheme 67) [113]. N-sulfonic acid poly(4-vinylpyridinium) chloride (NSPVPC) a heterogeneous and efficient catalyst has been reported for the synthesis of 14-aryl-14Hdibenzo[a,j]xanthenes, 1,8- dioxooctahydroxanthenes and tetrahydrobenzo[a]xanthene-11-ones under solvent free conditions (Scheme 68) [114].


In aqueous medium a facile and efficient method for the synthesis 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-oxoquinolin-3yl)-2H-xanthene-1,8-(5H,9H)-diones has been investigated by Krishnakumar et al. (Scheme 69) [115]. A three-component domino reaction of dimedone, aromatic aldehydes and 1,3-cyclohexanedione in the regioselective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene1,8-(5H, 9H)-diones is reported. The desired product is efficiently promoted by ascorbic acid as an organocatalyst (Scheme 70) [116]. Multicomponent condensation of substituted aldehydes with 2,7-dihydroxynaphthalene/2-naphthol/2,6-diydroxy

Scheme 66. A novel and efficient route for the synthesis of 1,8-dioxooctahydroxanthenes and 14-aryl-14H-dibenzo[a,j]xanthenes catalyzed by ZnO.

Scheme 67. Synthesis of xanthene derivatives.

Scheme 68. N-sulfonic acid poly (4-vinylpyridinium) chloride (NSPVP) catalyzed synthesis of 14-aryl-14H-dibenzo [a, j] xanthenes and 1, 8- dioxo-octahydroxanthene.

Scheme 69. Synthesis of 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-oxoquinolin-3-yl)-2H-xanthene-1,8 (5H,9H)-dione.

Scheme 70. Multicomponent domino reactions of dimedone, benzaldehyde, and cyclohexane 1,3-dione.


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Scheme 71. Synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one derivatives in ionic liquid [NMP]H2PO4.

Scheme 72. Synthesis of various xanthene derivatives in the presence of Fe3O4-SiO2-SO3H under solvent free condition.

naphthalene and cyclic-1,3-dicarbonyl compounds for the synthesis of 12-Aryl-8,9,10,12-tetrahydrobenzo[a]xanthene11-one derivatives in the presence of acidic ionic liquid [NMP]H2PO4 at 80oC has been achieved (Scheme 71) [117].

mental pH of 4-6 and the acidic environments in lysosomes (pH 4.5-5.5) are known as reason for degradation of proteins in cellular metabolism [125, 126]. Thus cellular dysfunction is often related with abnormal pH values in organelles.

Using nano-iron oxide encapsulated silica particles bearing sulfonic acid synthesis of 1,8-dioxo-octahydroxanthene, 14H-dibenzo[a,j]xanthene, 12-aryl-tetrahydrobenzo [a]xanthenes-11-one and 13-aryl-5H-dibenzo [b,i] xanthene5,7,12,14-(13H)-tetraone derivatives under solvent free conditions at 110-130oC has been reported (Scheme 72) [118].

Various fluorescein derivatives were examined as fluorescent pH sensors. Fluorescein derivatives bearing benzylic amine moieties displayed opposite fluorescent changes compared to those of simple fluorescein derivatives upon pH changes. Photo-induced electron transfer (PET) mechanism controls the fluorescent changes of these derivatives. Sensors based on the ion induced changes in fluorescence appear to be particularly attractive due to the simplicity and high detection limit of fluorescence [127]. In particular fluorescein derivatives have been extensively utilized as fluorescent pH sensors 37-44 (Fig. 11) [128].

6. APPLICATIONS OF XANTHENE DYES a) As pH Sensors The hydrogen ion activity (pH) is a very important parameter in environmental monitoring, biomedical research and other applications. Optical pH sensors have several advantages over traditional potentiometric pH measurement such as high sensitivity, no need of calibration, easy for miniaturization and possibility for remote sensing. Several pH indicators have been successfully immobilized in different solid porous materials to use as pH sensing probes [119121]. To observe pH changes inside living cells is important for studying cellular internalization pathways such as phagocytosis and endocytosis [122]. Abnormal pH values inside the cell are observed in some common disease types such as cancer [123] and Alzheimers [124]. Some organelles for example endosomes and plant vacuoles show intracompart-

The intermediate 2-(2‘,4-dihydoxyphenyl) benzoxazole was used for the synthesis of substituted fluorescein derivatives. Photophysical properties of fluorescein derivatives showed that these compounds were very sensitive to pH and in basic medium these compounds showed hyperchromic shift. These compounds are also sensitive to the viscosity of the medium (Scheme 73) [129]. A new class of rhodamines based indicator dyes as fluorescent pH sensors has been introduced and their sensitivity is derived from photo induced electron transfer between nonprotonated amino groups and the excited chromophore which result in effective fluorescence quenching at increasing pH.


These indicators carry a pentafluorophenyl group at 9position of the xanthene core which is connected via covalent coupling to sensor matrices by “click” reaction with

Fig. (11). Different probes used in determination of pH (37-44).

Scheme 73. Synthesis of fluorescein derivatives for pH determination.


mercapto groups and their photophysical properties are similar to “classical” rhodamines carrying 2‘-carboxyl groups (Fig. 12) [130].


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amounts in biological and environmental samples are of great interest in modern research. [132-137]. Xanthene derivatives for detection of toxic (Cd2+, Hg2+, Pb2+ ) as well as non for toxic metals (Cu2+, Fe3+, Zn2+) have developed which exhibit different colors with different metal ions (Figs. 13, 14).

Fig. (12). A new class of rhodamines for the application as indicator dyes influorescent pH sensors.

A multicolor pH-dependent fluorophore was synthesized via Pd-mediated cross-coupling reaction of fluorescein mono-triflate with p-hydroxyphenylboronic acid. Novel indicator named anthofluorescein, green to red fluorescence shift making it a valuable candidate for biological studies (Scheme 74) [131]. b) Metal Ion Detectors Design and development of highly sensitive and selective fluorescent probes for determination of metal ions in trace

Fig. (13). Xanthene derivative for detection of Fe+3.

Morpholine functioned Rhodamine derivatives, which offer distinct color changes and rapid switch on fluorescence in selective and specific interaction with Fe+3 over a broad pH range (Scheme 75) [138].

Scheme 74. Multicolor pH-dependent fluorophore was synthesized via Pd-mediated cross-coupling.

Fig. (14). Xanthene derivative for detection of Fe+3.

Scheme 75. Synthesis of morpholine functionalized rhodamine derivative RBM which specifically binds to Fe +3.



Fig. (15). Rhodenal, a turn-on fluorescent sensor for iron, derived from rhodamine-B.

Scheme 76. An “off-on” rhodamine-based fluorescence probe for the selective signaling of Fe (III).

Scheme 77. A new rhodamine-based Hg2+-selective fluorescent probe.

Fig. (16). Ratiometric fluorescent chemodosimeter, Hg2+ induced conversion of thiosemicarbazide into 1,3,4-oxadiazole.

Another turn on fluorescent sensor “Rhodenal” based on rhodamine has been synthesized and characterized which reacts promptly with Fe3+, with an equilibrium constant of 1.3 × 106 mol-1 L, having fluorescence emission at 582 nm (Fig. 15) [139].

excellent selective and sensitive responses to Hg2+ over other transition metal ions in neutral aqueous solutions. The fluorescence increases linearly with the Hg2+ concentration up to 0.8 μmol L−1 with the detection limit of 9.4 nmol L −1 (3σ) (Scheme 77) [141].

An “off-on” rhodamine based fluorescent probe for the selective signaling for Fe3+ has been designed which showed a sharp Fe3+ selective fluorescence enhancement responses in 100% aqueous solution under physiological pH value exhibiting high selectivity over relevant metal ions including Al (+3), Cd (+2), Fe (+2), Co (+2), Cu (+2), Ni (+2), Zn (+2), Mg (+2), Ba (+2), Pb (+2), Na (+1) and K (+1). Under optimum conditions, the fluorescence intensity enhancement of this system is linearly proportional to Fe (III) concentration from 6.0×10-8 to 7.2×10-6 mol L-1 with a detection limit of 1.4×10−8 mol L-1 (Scheme 76) [140].

In ratiometric fluorescent chemodosimeter, Hg2+ induced conversion of thiosemicarbazide to 1,3,4-oxadiazole triggered ring opening of the rhodamine B moiety and consequently activated intramolecular FRET phenomena from fluorescein to rhodamine moiety [142]. The solution showed absorption maxima at 490 nm and fluorescence emission at 520 nm corresponding to fluorescein with no intramolecular FRET. Upon addition of Hg2+, a new absorption peak appeared at 565 nm and fluorescence intensity at 520 nm decreased with the simultaneous appearance of the emission band at 591 nm (Fig. 16).

Another rhodamine based Hg2+ selective fluorescent probe has been designed and synthesized which displayed

The reagent bearing a monothiospirolactone group in rhodamine 6G architecture and mercapto group served for


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Fig. (17). Chemodosimeter bearing monothiospirolactone for detection of Hg2+.

Fig. (18). Hg2+ induced spiro ring opening of rhodamine followed by deselenation to rhodamine B.

Fig. (19). Rhodamine hydrazone derivatives bearing multiple ether units or phenol group as selective fluorescent and colorimetric chemodosimeters for Hg2+.

the direct attack of thiophilic Hg2+. The fluorescence enhancement is attributed to the spirolactone ring opening and the coordination of two sulphur atoms to Hg2+ giving a 2:1 stoichiometry complex (Fig. 17) [143].

eye” and spectroscopic methods in aqueous medium (Fig. 21) [147].

The aqueous solution of non-fluorescent compound underwent 30-fold fluorescence enhancement upon addition of 10 equivalents of Hg2+ with a color change from colorless to pink [144]. The detection mechanism involved the Hg2+ induced spiro ring opening of rhodamine followed by deselenation of rhodamine B responsible for the fluorescence enhancement (Fig. 18). Rhodamine hydrazone derivatives carrying multiple ether units or phenol groups as selective fluorescent and colorimetric chemodosimeters for Hg2+ and a selective chemosensor for Cu2+ have been developed (Fig. 19) [145].

Fig. (20). A series of Rhodamine B derivatives has been synthesized which exhibited highly selective and sensitive recognition toward Fe3+.

A series of rhodamine B derivatives has been synthesized which exhibited high selectivity and sensitivity toward Fe 3+ over other metal ions upon the formation of 1:2 complexes between Fe3+ and probes (Fig. 20) [146]. The modified rhodamine chitosan material (CS-RB) has been reported to recognize and adsorb Hg2+ ions by “naked-

Fig. (21). The modified-rhodamine chitosan material for detection of Hg2+.



Fig. (22). Rhodamine based probes for Hg(II) ion detection.

Fig. (23). Fluorescein based probes for Au(III) ion detection.

Fig. (24). Rhodamine based probes for Ag+ ion detection.

For Hg2+ ions composite sensing systems based on rhodamine containing up-conversion host have been established which exhibited high emission stability and selectivity over other ions (Fig. 22) [148]. Detection of gold (Au3+) ions has been made possible with the help of fluorescein based fluorescent probes. These probes were accomplished from 4’, 5’-fluoresceindicarboxaldehyde and they showed selective and sensitive response toward gold (III) ions in aqueous solution. The limit of detection (LOD) was evaluated to be 0.07 μM based on

S/N = 3. Furthermore, the imaging experiments demonstrated that, this probe is cell-permeable and can be used to detect Au3+ within a living cell (Fig. 23) [149]. The rhodamine derivatives, prepared from Rhodamine B through a two-step procedure have been synthesized which showed a colorless to pink color (λmax: 558 nm) upon addition of Ag+ ion to ethanolic solution of probes and a strong orange fluorescence (λmax: 584 nm), indicating that the Ag + promoted ring opening takes place readily (Fig. 24) [150].


A fluorescein based fluorescent probe displayed fluorescence enhancement for palladium species in the typical oxidation state of 0, +2 and +4, and is applied to monitor accumulated palladium in living organisms [151]. Similarly for Zn (+2) ions a hydrophilic fluorescent probe with extreme sensitivity (7ppb) and selectivity have been designed and synthesized by combining a sulfonated naphthol as a receptor. The role of this sensor molecule in living cells was further confirmed with the treatment of N,N,N‘,N‘-tetrakis (2-pyridylmethyl) ethylenediamine with the injected probe in cells (Fig. 26) [152]. A triazole-linked fluorescein units have been synthesized by click chemistry and its multi-controllable fluorescence characteristics have been systematically investigated by the

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stimulation of light, base/acid, and metal ions. The absorption and fluorescence behaviors of the diarylethene displayed sequence-dependent responses via efficient interactions of the fluorescein unit with triethylamine/trifluoroacetic acid and UV/Vis light (Fig. 27) [153]. Rhodamine-based fluorescent probe was designed and synthesized for the selective detection of Cu2+ over other metal ions. Under optimal conditions, the proposed probe worked in a wide linear range of 1.0 × 10−6-1.0 × 10−5 M with a detection limit of 3.3 × 10 -7 M Cu2+ in ethanol-water solution (9:1, v:v, 20 mM HEPES, pH 7.0) (Fig. 28) [154]. A new fluorescein derivative, (E)-2-(((1H-pyrrol-2-yl) methylene)amino)-3‘,6‘-dihydroxy [isoindoline-1,9‘xanthen]-3-one (FLPY) was synthesized and its interaction

Fig. (25). A fluorescein-based fluorescent probe for Pd2+ ion detection.

Fig. (26). A hydrophilic fluorescence probe with extreme sensitivity (7 ppb) and selectivity for Zn 2+.

Fig. (27). Triazole linked fluorescein for detection of Cu+2.

Fig. (28). Proposed binding mode of rhodamine probe for detection of Cu +2.


toward Cu2+ in mixture of many other metal cations in a DMSO/HEPES (3:1, v/v, 1mM, pH=7.2) solution was examined and high selectivity was observed having binding constant (Ka) 1.29-104 M-1 based on 1:1 stoichiometry. The detection limit of Cu2+ by FLPY was further determined to be 0.2961 M (Fig. 29). An inducible fluorescent ligand 2-(2‘-(2‘‘-aminoethylamino) ethyl)-3‘,6‘-bis(ethylamino)-2‘,7‘-dimethyl-1spiro[isoindoline-1,9’-xanthen]-3-one was synthesized and used as fluorescent probe to detect Er3+ which induced the structural transformation of the fluorescent ligand and caused s sharp emission in a buffered solution. The fluorescence intensity of the fluorescent ligand was enhanced quantitatively with an increase in the concentration of erbium ion. The detection limit of Er3+ was 3.0 x 10-10 mol L-1 (50 ng L-1) under optimized conditions. The method applied for the determination of Er3+ in four alloy samples had achieved satisfactory results (Fig. 30) [155].


Organic-inorganic fluorescent nano-composites have been synthesized from fluorescein isothiocyanate (FITC) and 3-aminopropyltriethoxysilane (APTEOS) by following and improving the Stober route. The nano-composite fluorescent materials considerably reduced dye leaching and showed strong fluorescence when washed by water for several times (Fig. 31) [156]. Hypochlorite anion in aqueous buffer solution has been detected by fluorescein based probes which have been found very sensitive and selective. The probe displayed high water solubility, pH-independent fluorescence and biocompatibility. Results evidenced that the probe had a detection limit 7.3 nM to -OCl anion (Fig. 32) [157]. Fluorescein derived fluorescent probe for H2S based on the thiolysis of dinitrophenyl ether have been synthesized which exhibited turn on fluorescence imaging of H2S in living cells and bulk solutions with excellent selectivity.

Fig. (29). Fluorescein derivative, (E)-2-(((1H-pyrrol-2-yl) methylene) amino)-3‘,6‘-dihydroxyspiro [isoindoline-1,9’-xanthen]-3-one (FLPY), for detection of Cu+2.

Fig. (30). A inducible fluorescent ligand 2-(2-(2-amino-ethylamino) ethyl)-3‘,6‘- bis (ethylamino)- 2‘,7‘-dimethy-lspiro[isoindoline-1,9‘xanthen]-3-one for the detection of Er3+.

Fig. (31). Organic-inorganic fluorescent nano-composites for metal ion detection.

Fig. (32). Hypochlorite anion in aqueous buffer solution has been detected by fluorescein based probes.


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Fig. (33). Fluorescein-derived fluorescent probe for H2S based on the thiolysis of dinitrophenyl ether.

Fluorescein-derived fluorescent probe for H2S, based on the thiolysis of dinitrophenyl ether have been synthesized which exhibited turn on fluorescence imaging of H2S in living cells and bulk solutions with excellent selectivity (Fig. 33) [158].

the continuing activity in this field, it is reasonable to expect further advances.

7. SUMMARY

CONFLICT OF INTEREST

It is clear from the contents of this review that the synthesis of xanthene dyes and their derivatives remained a very active field of research. This research continues to be driven by the attractive photophysical properties of these compounds, and their applications in cation and anion detection, and pH determination. In recent years, modification in the structures and catalysis of the reaction has shifted the xanthene chromophores synthesis from harsh to easiest accessible conditions of green chemistry at room temperature. The different catalysts used for synthesis are N-Sulfonic acid poly(4-vinylpyridinium) hydrogen sulfate, p-TSA, RuCl3.nH2O, succinimide-N-Sulfonic acid, AgI, NH4H2PO4/SiO2, Fe(HSO4)3, silica chloride, cellulose sulfuric acid, mesoporous silica materials, H-NMP/HSO4, NanoZnAl2O4, FeCl3.6H2O, rice husk, 1-methyl-3-propane sulfonic-imidazolium hydrosulfate, ammonium dihydrogen phosphate (NH4H2PO4/SiO2), polyvinyl polypyrrolidonesupported boron trifluoride, p-dodecylbenzene sulfonic acid (DBSA), silica-supported boron trifluoride (BF3-SiO2), diatomite-SO3H, 1,3-disulfonic acid imidazolium hydrogen sulfate, sulfamic acid, Amberlyst-15, ZnO, pentafluorophenyl ammonium triflate (PFPAT), using N-Sulfonic acid poly(4vinylpyridinium) chloride (NSPVPC), ascorbic acid, ionic liquid [NMP]H2PO4, nano-iron oxide encapsulated silica particles and most of them are recyclable having repeating operational capacity. Xanthene chemodosimeter probes show higher sensitivity and selectivity as compared to other probes used for Fe2+, Ba2+, Al3+, K+, Ca2+, Ni2+, Co2+, Cd2+, Cr3+, Hg2+, Mg2+, Mn2+, Na+, Cu2+, Zn2+, Au3+, Er3+, CN-, S2- and HClO- ions.

The author (editor) declares no conflict of interest, financial or otherwise.

THE FUTURE DEVELOPMENTS The future developments in this area must address improvements in the practical and general means of producing the NIR absorbing xanthene chromophores and their derivatives on a large scale in order to permit focused studies of their mode of action in DSSCs. Adjustments in the current synthetic protocols will be required in order to prepare the compounds of well recognized biological activities. Given

CONSENT FOR PUBLICATION Not applicable.

ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2]

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