Unusual rearrangement of imidazo[1,5-a]imidazoles and imidazo[1,2-b]pyrazoles into imidazo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines

A multicomponent reaction giving easy and cheap access to a variety of bicyclic 5,5-fused hetero-rings has been developed. Then, an usual rearrangement of imidazo[1,5-a]imidazoles or imidazo[1,2-b]pyrazoles leading to bi-heterocyclic imidazo- and pyrazolo[1,5-a]pyrimidines in the presence of a specific amount of I₂ in THF at room temperature has been achieved. This new method enables the hitherto unreported synthesis of functionalized imidazo- and pyrazolo[1,5-a]pyrimidines.

A multicomponent reaction giving easy and cheap access to a variety of bicyclic 5,5-fused hetero-rings has been developed.     

Mg3N2-assisted one-pot synthesis of 1,3-disubstituted imidazo[1,5-a]pyridine

A novel Mg₃N₂-assisted one-pot annulation strategy has been developed via cyclo-condensation reaction of 2-pyridyl ketones with alkyl glyoxylates or aldehydes, allowing the formation of imidazo[1,5-a]pyridines exclusively with an exellent yield.

A novel Mg₃N₂-assisted one-pot annulation strategy has been developed via cyclo-condensation reaction of 2-pyridyl ketones with alkyl glyoxylates or aldehydes, allowing the formation of imidazo[1,5-a]pyridines exclusively with an exellent yield.     

The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor

Because the majority of cancers exhibit direct or indirect deregulation of cyclin-dependent kinase (CDK) function, members of the CDK family are attractive targets for the development of anticancer agents. As part of an ongoing program, novel imidazopyridines were identified and developed as potent and selective CDK inhibitors. Here, we describe data on the in vitro biological activities of one of these compounds, AZ703. The selectivity profile of AZ703 was investigated in kinase assays against a range of CDK enzymes as well as a panel of protein kinases in vitro. IC50s were assessed against different tumor cell lines in vitro. The mechanism of action of AZ703 was determined by observing changes in phosphorylation of CDK substrates and cell cycle effects on tumor and normal cells. In vitro studies revealed that AZ703 is a selective inhibitor of CDK1 and CDK2 and displays a mode of action consistent with the induction of G1-, S-, and G2-M-phase arrest. AZ703 also showed potent antiproliferative activity across a wide range of tumor cell lines in vitro. Moreover, AZ703 induced reversible blockade of normal cells while causing tumor cells to undergo apoptosis. We have identified AZ703 as a novel selective imidazo[1,2-a]pyridine CDK inhibitor that shows promising antitumor properties in vitro.     

Facile synthesis of 3-substituted imidazo[1,2-a]pyridines through formimidamide chemistry

A facile entry to 3-aryl/alkenyl/alkynyl substituted imidazo[1,2-a]pyridines (3a–p, 6a–d & 9a–9e) has been developed from readily available benzyl/allyl/propargyl halides and 2-amino pyridines as substrates via formimidamide chemistry that is devoid of caustic or expensive reagents, such as transition metal complexes. Quantum chemical calculations performed to understand the underlying mechanism of the transformation revealed a preference for intramolecular Mannich-type addition over pericyclic 1,5-electrocyclization for the systems reported herein that enable a Baldwin allowed 5-exo-trig cyclization instead of a formally anti-Baldwin 5-endo-trig process.

A facile entry to 3-substituted imidazo[1,2-a]pyridines from halides and 2-amino pyridines via formimidamide chemistry has been developed through a formal anti-Baldwin 5-endo-trig cyclization that becomes a thermally allowed 5-exo-trig cyclization.     

Synthesis of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands for use in palladium-catalyzed cross-coupling reactions

3-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequence, respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and Buchwald–Hartwig amination compounds are presented with these ligands.

3-Aryl-2-phosphoimidazo[1,2-a]pyridine ligands were prepared via two complimentary synthetic routes and were evaluated in the Suzuki–Miyaura and Buchwald–Hartwig amination cross-coupling reactions.

Palladium-catalyzed cross-coupling reactions have revolutionized the formation of C–C and C–X bond formation in the academic and industrial synthetic organic chemistry sectors.^1,2 Applications such as synthesis of natural products,³ active pharmaceutical ingredients (API),⁴ agrochemicals,⁵ and materials for electronic applications⁶ are showcased. Snieckus described in his 2010 Nobel Prize review that privileged ligand scaffolds represented the “third wave” in the cross-coupling reactions where the “first wave” was the investigation of the metal catalyst-the rise of palladium and the “second wave” was the exploration of the organometallic coupling partner.¹ In the last twenty years, it was recognized that the choice of ligand facilitated the oxidative addition and reductive-elimination steps of the catalytic cycle of transition metal-catalyzed cross-coupling reactions, increasing the overall rate of the reaction. For example, bulky trialkylphosphines facilitated the oxidative addition processes of electron-rich, unactivated substrates such as aryl chlorides.^7,8 Sterically demanding ligands also provided enhanced rates of reductive elimination from [(L)_nPd(aryl)(R), R = aryl, amido, phenoxo, etc.] species by alleviation of steric congestion.⁹ Privileged ligands such as Buchwald''s biarylphosphines,^10,11 Fu''s trialkylphosphines,^7,8,12 Nolan–Hermann''s N-heterocyclic carbenes (NHC),^13–15 Hartwig''s ferrocenes,^16,17 Beller''s bis(adamantyl)phosphines^18,19 and N-aryl(benz)imidazolyl or N-pyrrolylphosphines,^20,21 Zhang''s ClickPhos ligands,^22,23 and Stradiotto''s biaryl P–N phosphines,^24,25 to mention a few, have found wide-spread use in Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonogashira, C–X (X = S, O, P) cross-coupling and Buchwald–Hartwig amination reactions (Fig. 1). Preformed catalysts with these ligands attached to the palladium metal center are also recognized as well-defined entities in cross-coupling reactions.²⁶Open in a separate windowFig. 1Privileged ligands for palladium-catalyzed cross-coupling reactions.The term privileged structure was first coined by Evans et al. in 1988 and was defined as “a single molecular framework able to provide ligands for diverse receptors”.²⁷ In the last three decades, it is clear that privileged structures are exploited as opportunities in drug discovery programs.^28–31 For example, imidazo[1,2-a]pyridines are privileged structures in medicinal chemistry programs (Fig. 2).³² Imidazo[1,2-a]pyridines are a represented motif in several drugs on the market such as zolpidem, marketed as Ambien™ for the treatment of insomnia,³³ minodronic acid, marketed as Bonoteo™ for oral treatment of osteoporosis,³⁴ and olprinone, sold as Coretec™ as a cardiotonic agent.³⁵Open in a separate windowFig. 2Imidazo[1,2-a]pyridines as privileged structures in medicinal chemistry and in our cross-coupling reactions approach.Our group is interested in a long-term research program directed at the use of key privileged structures that are employed in drug discovery programs as potential phosphorus ligands for cross-coupling reactions. In our entry into the use of privileged structures from the medicinal chemistry literature for our investigation into new phosphorus ligands, we have developed two complementary synthetic routes for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands from 2-aminopyridine as our initial substrate.Our first synthetic route for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l required the copper(ii) acetate iodine-mediated double oxidative C–H amination of 2-aminopyridine (1) with arylacetylenes under an oxygen atmosphere to give 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d (Scheme 1).^36,37Open in a separate windowScheme 1Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l from 2-aminopyridine via copper-catalyzed arylacetylene cyclizations/palladium-catalyzed phosphination reactions sequences.Phenylacetylene and 2-/3-/4-methoxyphenylacetylenes were commercially available reagents. With intermediates 2a–d in hand, we explored several cross-coupling phosphination reactions and we found that palladium-catalyzed phosphination with DIPPF ligand in the presence of cesium carbonate as the base in 1,4-dioxane under reflux provided twelve new ligands 3a–3l as shown in 38 Moderate to good yields were obtained under these cross-coupling conditions. There are few commercially available dimethoxyphenylacetylenes, and most are prohibitively expensive, and so an alternative synthetic strategy was explored.Palladium-catalyzed phosphination of 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d^a

A novel hydrophilic fluorescent probe for Cu2+ detection and imaging in HeLa cells

Copper is an essential element in living systems and plays an important role in human physiology; therefore, methods to detect the concentration of copper ions in living organisms are important. Herein, we report a highly water-soluble naphthalimide-based fluorescent probe that can be used for the detection of Cu²⁺. The probe, BNQ, has high selectivity and sensitivity. The fluorescence intensity of the probe at 520 nm was visible to the naked eye under a UV lamp; upon the gradual addition of Cu²⁺, there was a colour change from green to nearly colourless. Furthermore, the detection limit of BNQ for Cu²⁺ was 45.5 nM. The detection mechanism was investigated using a Job''s plot and density functional theory (DFT) calculations. In addition, owing to great biocompatibility, we were able to successfully use BNQ to detect Cu²⁺ in living HeLa cells with low toxicity.

Probe BNQ was successfully used for detection of exogenous Cu²⁺ in cells using a rare ESDPT sensing mechanism.     

A reasonably constructed fluorescent chemosensor based on the dicyanoisophorone skeleton for the discriminative sensing of Fe3+ and Hg2+ as well as imaging in HeLa cells and zebrafish

In this study, a new fluorescent sensor dicyanoisophorone Rhodanine-3-acetic acid (DCI-RDA) (DCI-RDA) has been developed by employing a DCI-based push–pull dye as the fluorophore and RDA as the recognition moiety for the simultaneous sensing of Fe³⁺ and Hg²⁺ with a large Stokes Shift (162 nm), high selectivity and sensitivity, and low LOD (1.468 μM for Fe³⁺ and 0.305 μM for Hg²⁺). In particular, DCI-RDA has a short response time (30 s). The Job''s plot method in combination with ¹H NMR titration and theoretical calculations was used to determine the stoichiometry of both DCI-RDA-Fe³⁺/Hg²⁺ complexes to be 1 : 1. Moreover, DCI-RDA is applied as a fluorescent probe for imaging in HeLa cells and zebrafish, indicating that it can be potentially applied for Fe³⁺/Hg²⁺ sensing in the field of biology.

A new fluorescent sensor dicyanoisophorone rhodanine-3-acetic acid has been developed by employing a DCI-based push–pull dye as the fluorophore and RDA as the recognition moiety for the simultaneous sensing of Fe³⁺ and Hg²⁺.     

An efficient synthesis of new imidazo[1,2-a]pyridine-6-carbohydrazide and pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives via a five-component cascade reaction

A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including N′-(1-(4-nitrophenyl)ethylidene)imidazo[1,2-a]pyridine-6-carbohydrazide and N′-(1-(4-nitrophenyl)ethylidene)pyrido[1,2-a]pyrimidine-7-carbohydrazide derivatives is successfully achieved via a five-component cascade reaction utilizing cyanoacetohydrazide, 4-nitroacetophenone, 1,1-bis(methylthio)-2-nitroethylene and various diamines in a mixture of water and ethanol. The new efficient domino protocol involving a sequence of N,N-acetal formation, Knoevenagel condensation, Michael reaction, imine–enamine tautomerization and N-cyclization as key steps. The merit of this catalyst free approach is highlighted by its easily available starting materials, operational simplicity, clean reaction profile, the use of environmentally benign solvents and tolerance of a wide variety of functional groups.

An easy synthesis of novel and highly substituted imidazo[1,2-a]pyridines and pyrido[1,2-a]pyrimidines using heterocyclic ketene aminals.     

Hydromagnesite sheets impregnated with cobalt–ferrite magnetic nanoparticles as heterogeneous catalytic system for the synthesis of imidazo[1,2-a]pyridine scaffolds

This paper manifests an A³-coupling strategy assisted by novel hydromagnesite sheets impregnated with cobalt ferrite (CoFe₂O₄-HMS) magnetic nanoparticles (MNPs) as an environmentally benign nanocomposite to synthesize imidazo[1,2-a]pyridine scaffolds under ultrasonication. The synthesis of these biologically active derivatives was achieved through A³-coupling employing 2-aminopyridines derivatives, pertinent aryl aldehydes, and phenylacetylene in the presence of polyethylene glycol 400 (PEG 400) as a green solvent under aerobic conditions. Based on its high product yield (up to 94%) in a short reaction time, with a modest catalyst loading, excellent catalyst, and solvent recyclability without substantial loss of operation (up to five synthetic cycles), as demonstrated by the high ecological compatibility and sustainability factors, this strategy follows the principles of green chemistry. The synthesized nanocomposite was characterized via several spectroanalytical techniques, including PXRD, FE-SEM, HR-TEM, EDAX, ICP-AES, FT-IR, Raman spectroscopy, CO₂-TPD, TGA-DTA-DTG analyses, magnetic studies, and nitrogen porosimetry. Furthermore, the structures of synthesized compounds were confirmed based on FT-IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis data.

Sustainable synthesis of imidazo[1,2-a]pyridine scaffolds assisted by hydromagnesite sheets impregnated with cobalt–ferrite (CoFe₂O₄-HMS) magnetic nanoparticles (MNPs).     

Remarkably selective biocompatible turn-on fluorescent probe for detection of Fe3+ in human blood samples and cells

The robust nature of a biocompatible fluorescent probe is demonstrated, by its detection of Fe³⁺ even after repeated rounds of quenching (reversibility) by acetate in real human blood samples and cells in vitro. Significantly trace levels of Fe³⁺ ions up to 8.2 nM could be detected, remaining unaffected by the existence of various other metal ions. The obtained results are validated by AAS and ICP-OES methods. A portable test strip is also fabricated for quick on field detection of Fe³⁺. As iron is a ubiquitous metal in cells and plays a prominent role in biological processes, the use of this probe to image Fe³⁺ in cells is a substantial development towards biosensing. Cytotoxicity studies also proved the nontoxic nature of this probe.

The robust nature of a biocompatible fluorescent probe is demonstrated, by its detection of Fe³⁺ even after repeated rounds of quenching (reversibility) by acetate in real human blood samples and cells in vitro.     

A curcumin-based AIEE-active fluorescent probe for Cu2+ detection in aqueous solution

Curcuminoids have been extensively investigated as metal ion probes, but the intrinsic aggregation-caused-quenching (ACQ) characteristic of curcumin would hinder their applications in aqueous solution. Fortunately, tetraphenylethylene (TPE) could endow the compounds with aggregation-induced emission (AIE)/aggregation-induced enhanced emission (AIEE) characteristics to eliminate the ACQ effect. According to this strategy, a series of TPE-modified curcumin derivatives L1–4 were prepared and studied for their AIEE properties. Among the four TPE-curcumin analogues, only L1 particles have been successfully used as an on-off fluorescence probe for detecting Cu²⁺ in aqueous solution. The fluorescence titration experiment determined its detection limit of 1.49 × 10⁻⁷ mol L⁻¹, and the binding ratio between L1 and Cu²⁺ was estimated as 2 : 1, which was in agreement with the results of high resolution mass spectrum and Job''s plot. In addition, the binding constant was evaluated as 6.77 × 10² M⁻¹ using a Benesi–Hildebrand plot. Finally, the obtained L1-based indicator paper showed significant fluorescence response to Cu²⁺ aqueous solution. This TPE-modified strategy improves the detection capability of curcumin probe in aqueous solution and provides a feasible way to obtain other probes with ACQ characteristics.

A curcumin-based AIEE-active L1 was synthesized and used to prepare an on-off fluorescent probe for Cu²⁺ detection in aqueous solution.     

1,3,4-Thiadiazol derivative functionalized-Fe3O4@SiO2 nanocomposites as a fluorescent probe for detection of Hg2+ in water samples

5-Amino-1,3,4-thiadiazole-2-thiol was used to synthesize a novel fluorescent functionalizing group on a Fe₃O₄@SiO₂ magnetic nanocomposite surface for detection of heavy metal ions in water samples. The prepared probe was characterized by using X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, and a vibrating sample magnetometer. Among various tested ions, the new nanocomposite responded to Hg²⁺ ions with an intense fluorescence “turn-off”. The limit of detection of the probe shows that it is sensitive to the minimum Hg²⁺ concentration of 48.7 nM. Theoretical calculations were done for estimating binding energies of the three possible bonding modes and the visualized molecular orbitals were presented.

VBYT-Fe₃O₄@SiO₂ fluorescent probe was designed for sensitive detection of mercury in water samples.     

Sulfhydryl functionalized carbon quantum dots as a turn-off fluorescent probe for sensitive detection of Hg2+

Mercury ion (Hg²⁺) is one of the most toxic heavy metal ions and lowering the detection limit of Hg²⁺ is always a challenge in analytical chemistry and environmental analysis. In this work, sulfhydryl functionalized carbon quantum dots (HS-CQDs) were synthesized through a one-pot hydrothermal method. The obtained HS-CQDs were able to detect mercury ions Hg²⁺ rapidly and sensitively through fluorescence quenching, which may be ascribed to the formation of nonfluorescent ground-state complexes and electron transfer reaction between HS-CQDs and Hg²⁺. A modification of the HS-CQD surface by –SH was confirmed using Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The HS-CQDs sensing system obtained a good linear relationship over a Hg²⁺ concentration ranging from 0.45 μM to 2.1 μM with a detection limit of 12 nM. Delightfully, the sensor has been successfully used to detect Hg²⁺ in real samples with satisfactory results. This means that the sensor has the potential to be used for testing actual samples.

Schematic presentation of the synthesis of HS-CQDs and the application as a “turn-off” fluorescent probe for Hg²⁺ detection.     

Rational design of fluorescent probe for Hg2+ by changing the chemical bond type

Two kinds of fluorescent probes DFBT and DFABT, and their corresponding water-soluble compounds WDFBT and WDFABT, based on the trimers containing a benzo[2,1,3]thiadiazole moiety and two fluorene moieties are synthesized. Their luminescent behavior towards Hg²⁺ ions and other various metal ions in organic and water solutions are studied in detail via absorption and emission spectroscopy. All these probes show a selective “on–off-type” fluorescent response to Hg²⁺ ions in solution over other metal ions with a maximum detection limit of 10⁻⁷ M. Importantly, the probe type can be changed from irreversible to reversible by altering the bridge mode between the functional units from C C triple bond to C–C single bond. Their detection mechanisms towards Hg²⁺ are studied in detail via mass spectrometry and Job plots, which are attributed to irreversible chemical reaction for DFABT and WDFABT and a reversible coordination reaction for DFBT and WDFBT respectively. Our research results about this kind of organic fluorescent probe provide valuable information to the future design of practical Hg²⁺ fluorescent probes.

Two kinds of fluorescent probes for Hg²⁺ with different detection mechanism have been realized by simply changing the chemical bond.     

Rutin-modified silver nanoparticles as a chromogenic probe for the selective detection of Fe3+ in aqueous medium

The development of nanoprobes for selective detection of metal ions in solution has attracted great attention due to their impact on living organisms. As a contribution to this field, this paper reports the synthesis of silver nanoparticles modified with rutin in the presence of ascorbic acid and their successful use as a chromogenic probe for the selective detection of Fe³⁺ in aqueous solution. Limits of detection and quantification were found to be 17 nmol L⁻¹ and 56 nmol L⁻¹, respectively. The sensing ability is proposed to proceed via an iron-induced nanoparticle growth/aggregation mechanism. A practical approach using image analysis for quantification of Fe³⁺ is also described.

The use of rutin-modified silver nanoparticles for selective detection and sensitive quantification of Fe³⁺ in aqueous solution is described.

Metal ions are key species in nature due to their essential functions in living organisms.^1,2 On the other hand, heavy metals as well as essential metals at abnormally high levels are toxic.² Iron, for instance, in addition to its popular use in industry and construction, is essential to the human body and active in biological processes. Although the trivalent form of iron is particularly important for oxygen transport in blood and the mitochondrial respiratory chain, high levels of this cation are associated with important pathologies.^3,4 The detection of metal ions in aqueous solution is traditionally performed by methods including atomic absorption spectrometry,⁵ electrochemical measurements,^6,7 and inductively coupled plasma techniques,⁸ among others. However, these techniques have important drawbacks, notably the need for sophisticated instrumentation, in addition to being time-consuming and requiring laborious procedures. To overcome these issues, the development of chromogenic and fluorogenic chemosensors for the selective detection of metal-targets has attracted great attention, especially due to the possibility of fast, sensitive and non-expensive analysis.^9,10 In the last decade, nanoscaled materials have been reported as selective probes for metal ions, including Fe³⁺.^11–24Silver nanoparticles (AgNPs) are of particular interest because of the affordable price of starting materials, ease of controlling size and morphology, possibility to functionalize their surface with organic molecules, and optical properties that enable detection of a variety of analytes via simple UV-vis spectroscopy and digital image analysis. Furthermore, applications of AgNPs are also biotechnologically relevant due to the possibility of green synthetic protocols, including the use of plant extracts,²⁵ natural sources,²⁶ glycerol,²⁷ among others.Flavonoids are secondary metabolites naturally found in fruits and other vegetables with relevant roles due to their nutritional, pharmaceutical and medicinal properties.²⁸ Because of their adequate structural features, flavonoids are candidates to be employed in the synthesis of AgNPs.²⁶ Rutin (RU), a sugar-based flavonoid, may be employed as reducing agent in the synthesis of AgNPs along with a stabilizer such as polyvinylpyrrolidone (PVP)²⁶ or used as crude plant extract component.^29,30This paper reports the use of RU-modified AgNPs (RU-AgNPs) as a chromogenic probe for Fe³⁺ in aqueous medium in the presence of ascorbic acid (AA). Sensing ability of RU-AgNPs for the selective detection of Fe³⁺ toward other metal cations was investigated with UV-vis spectroscopy analysis. These data and transmission electronic microscopy (TEM) results allowed a mechanistic proposal involved in the selective detection of Fe³⁺ by RU-AgNPs. Furthermore, a practical approach based on correlation of images of solutions obtained with a conventional smartphone and chemometrics was employed for a simpler quantification of Fe³⁺ in aqueous medium.Initially, the order of reagent combination was investigated in the synthesis of RU-AgNPs. Concentration of RU ranged from 0.10 to 0.50 mmol L⁻¹, while concentrations of other components were fixed at 0.20 mmol L⁻¹ AgNO₃, 0.10 mmol L⁻¹ AA and 0.10 M NaOH. Water was used as solvent in all cases. Narrower surface plasmon resonance (SPR) bands were obtained from adding a solution of AA and NaOH to a solution containing RU and AgNO₃ (Fig. 1a) against the addition of RU, AA, and NaOH to AgNO₃ solution (Fig. S1a – ESI^†), or the addition of RU and NaOH to a solution of AA and AgNO₃ (Fig. S1b^†). RU-AgNPs obtained from the condition presented in Fig. 1a are small (4.1 nm average diameter) and considerably polydisperse (standard deviation of 4.7 nm), however, presenting only one population (Fig. 1b and S2^†). A study of the influence of RU concentration (0.10 to 0.50 mmol L⁻¹) on the stability of RU-AgNPs over time indicated that 0.10 mmol L⁻¹ RU generates more stable RU-AgNPs (Fig. S3^†). Next, a study on the influence of pH indicated that RU-AgNPs are only stable under strong alkaline conditions (pH 12.5 or higher) (Fig. S4^†).Open in a separate windowFig. 1(a) UV-vis analysis of RU-AgNPs under strong alkaline condition (pH > 12.5) based on the order of adding reagents (RU, 0.10 to 0.50 mmol L⁻¹; AgNO₃, 0.20 mmol L⁻¹; AA, 0.10 mmol L⁻¹; NaOH, 0.10 mmol L⁻¹); (b) TEM image of RU-AgNPs under the selected condition.The ability of RU-AgNPs to sense metal cations was investigated by both naked-eye and UV-vis spectroscopy analysis (Fig. 2). The separate addition of 10 μmol L⁻¹ of several metal cations (Fe³⁺, Co²⁺, Zn²⁺, Sr²⁺, Cu²⁺. Al³⁺, Ba²⁺, Cd²⁺, Pb²⁺, Ni²⁺, Mg²⁺, Hg²⁺, Cu⁺ and Cr³⁺) to solutions of RU-AgNPs (prepared according to Fig. 1a) indicated that only Fe³⁺ induces a significant colorimetric change in the final aspect of solution after 50 minutes (Fig. 2a).Open in a separate windowFig. 2Naked-eye (a) and UV-vis (b) analysis of RU-AgNPs in absence (control, C) and presence of 10 μmol L⁻¹ of selected metal cations (Fe³⁺, Co²⁺, Zn²⁺, Sr²⁺, Cu²⁺. Al³⁺, Ba²⁺, Cd²⁺, Pb²⁺, Ni²⁺, Mg²⁺, Hg²⁺, Cu⁺ and Cr³⁺) after 50 min; (c) calibration curve obtained by the addition of different amounts (0 to 10 μmol L⁻¹) of Fe³⁺ to solutions of RU-AgNPs; (d) TEM image of RU-AgNPs after addition of Fe³⁺ (10 μmol L⁻¹). In all experiments, RU-AgNPs were prepared in the presence of ascorbic acid.The results presented in Fig. 2a are consistent with the UV-vis spectroscopy analysis (Fig. 2b). Co²⁺ ions also induce some change in the system, however at a considerably smaller extension than Fe³⁺. In this study, AA played a crucial role in the selective detection of Fe³⁺ by the referred nanoprobe. In the absence of AA, Co²⁺ (mainly) as well as other cations induce stronger colorimetric and spectral changes (Fig. S5a and b,^† respectively) in the analysis of solutions of RU-AgNPs when compared to the system containing AA. This selectivity may arise from two possible reasons: (i) preservation of RU by avoiding its oxidation in the reduction of Ag⁺ ions; (ii) coordination of ascorbate anion to cations other than Fe³⁺.Interaction of RU-AgNPs and Fe³⁺ (10 μmol L⁻¹) stabilizes after approximately 40 minutes (Fig. S6^†). Next, a calibration curve was built from the direct relationship between the absorbance at 396 nm and the concentration of Fe³⁺ (Fig. 2c), presenting a good correlation (R² = 0.9929). The limits of detection and quantification were found to be 17 nmol L⁻¹ and 56 nmol L⁻¹, respectively, which is very satisfactory.^13,14 The influence of other cations in the detection of Fe³⁺ was investigated by UV-vis spectroscopy. Fig. S7^† clearly demonstrates that there are only small changes when a second cation (30 μmol L⁻¹) is added together with Fe³⁺ to the RU-AgNPs solution.Mechanistically, the detection of Fe³⁺ by RU-AgNPs in aqueous medium proceeds via a growth/aggregation-combined process. This proposal is first evidenced by UV-vis analysis due the suppression of SPR band (Fig. 2b), a behavior consistent with the literature.^31,32 Interestingly, TEM analysis clearly shows a growth in AgNPs size after addition of Fe³⁺ to the solution (Fig. 2d), resulting in a final single AgNPs population with average diameter of 14.7 nm ± 8.9 nm. Due to the strong alkaline medium, the main specie responsible for the behavior of NPs is likely to be Fe(OH)₃. A schematic illustration of the mechanism involving aggregation of RU-AgNPs induced by the addition of Fe³⁺ is presented in Fig. 3. AgNPs are initially formed by adsorption of anionic RU to the silver surface via deprotonated 5-hydroxychromen-4-one moiety. This is supported by the literature³³ and confirmed by alteration in the 1800–1500 cm⁻¹ region of the RU infrared spectra before and after coordination with silver (Fig. S9^†). Afterwards, the addition of Fe³⁺ induces the formation of a coordination complex through an anionic catechol group, in which at least 2 : 1 ligand–Fe³⁺ stoichiometry is required for an aggregated effect.Open in a separate windowFig. 3Mechanistic proposal for growth/aggregation of RU-AgNPs in the presence of Fe³⁺. Insert: binding model for RU-AgNPs.Due to increasing interest in image processing as an analytical tool for many purposes,^34,35 Multiple Linear Regression was employed to verify the capacity of the RU-AgNPs to probe Fe³⁺ standards at distinct concentrations, as presented in Fig. 4. The curve was obtained by plotting the color absorbances RGB-based values versus the concentrations of Fe³⁺ standards after RU-AgNPs interaction. Predicted iron is a vector based on RGB values that were then extracted from the filtered images and inserted in the equation described by Beer–Lambert law in order to generate the absorbances for the construction of the analytical curve. A linear behavior between the predicted response and the measured concentrations was observed (R² = 0.9806).Open in a separate windowFig. 4Calibration curve for Fe³⁺ analysis showing the predicted iron (RGB) vs. iron(iii) concentration (1 to 8 μmol L⁻¹). Adjusted R² = 0.9806.Regression coefficients of the calibration model (using the R, G and B channels simultaneously) obtained by MLR method are shown in eqn (1):[Fe³⁺] = 44.5R − 4.9G − 16.4B + 5.11where Fe³⁺ concentration is the dependent variable (Predicted Iron), 5.1 is the intercept (β₀), 44.5, −4.9 and −16.4 are the regression coefficients of the independent variables (R, G and B channels, respectively).It is possible to observe an interesting performance of the method using the three RGB color channels allied with MLR to quantify the Fe³⁺ content, which presented reasonable deviations in its responses considering that it is simple and low-cost. The good linearity is similar to other colorimetric methods such as sodium determination in seawater and coconut water (R² > 0.91) by Moraes and coauthors,³⁶ or iron(ii) in simulated seawater (R² = 0.9993) by Gasparotto et al.³⁷Second order regression was applied to the dataset to obtain a better adjustment, resulting in an adjusted R-squared of 0.9955. RGB values were then inserted in eqn (2) in order to generate the construction of the correlation:[Fe³⁺] = 14.4R + 30.7G − 23.4B − 398RG − 348RB − 0.8BG − 978R² + 695G² + 26.9B² + 4.52This paper reports the use of AgNPs functionalized with RU as nanoprobes for selective detection and sensitive quantification of Fe³⁺ in aqueous solution. The synthesis of RU-AgNPs is reproducible, easily performed and requires no stabilizer agent other than RU. AA has a crucial role in the selectivity by either the avoidance of oxidation of RU by silver and/or coordination of ascorbate with other cations. The literature brings relevant examples of chromogenic and fluorogenic chemosensors for selective detection of Fe³⁺ in solution. Many of these artificial organic receptors present high selectivity and relevant limits of detection, requiring, however, very specific reagents and laborious synthetic procedures.^38–41 Metal-based nanoparticles have emerged as potential probes for detection of Fe³⁺.^11–16 Although effective in Fe³⁺ sensing, the synthesis of these nanoprobes require some toxic reagents, such as NaBH₄ or PVP, use plant extracts, which may lead to some drawbacks, such as the understanding of the sensing mechanism. In contrast, our method is based on commercially available, nontoxic, low-cost reagents. Fe³⁺ sensing performed satisfactorily in the 1–10 μmol L⁻¹ range, and the limit of detection obtained with this method (17 nmol L⁻¹) is comparable to the most sensitive methods reported in literature. A mechanism for the detection of Fe³⁺ by RU-AgNPs involves a combined growth/aggregation of the NPs. There is a still limited number of nanoscaled systems reported as being selective and sensitive in the detection of Fe³⁺, which reinforces the relevance of the method reported herein. The linearity range obtained by both UV-vis spectroscopy and image analysis comprises the maximum of residual Fe³⁺ in drinking water according to the European and US legislations.^15,42     

A highly selective colorimetric fluorescent probe for detection of Hg2+ and its application on test strips

An efficient fluorescent probe Pyr-Rhy based on pyrazole was developed, which can detect Hg²⁺ in water. Its fluorescence properties were studied by UV-vis and fluorescence spectroscopy, and the study results indicated that this probe can selectively detect Hg²⁺via complexation reaction, and then cause a remarkable color change from colorless to pink and a strong fluorescence enhancement can be observed. Furthermore, this probe showed high sensitivity with the detection limit down to 2.07 × 10⁻⁸ M, and its stoichiometric ratio toward Hg²⁺ ions was 1 : 1. The sensing mechanism was investigated by Job''s plot ¹H NMR titrations, and FT-IR spectra analysis, which demonstrated a chelation-enhanced fluorescence (CHEF) mechanism. More importantly, obvious color changes of sensor Pyr-Rhy can be observed when it was impregnated on filter paper testing strips and immersed in Hg²⁺ solution (water as solution), indicating its potential application for trace Hg²⁺ detection in environmental samples.

An efficient fluorescent probe Pyr-Rhy based on pyrazole was developed, which can detect Hg²⁺ in water.     

A novel coumarin-based colorimetric and fluorescent probe for detecting increasing concentrations of Hg2+in vitro and in vivo

Mercury has complex biological toxicity and can cause a variety of physiological diseases and even death, so it is of great importance to develop novel strategies for detecting trace mercury in environmental and biological samples. In this work, we designed a new coumarin-based colorimetric and fluorescent probe CNS, which could be obtained from inexpensive starting materials with high overall yield in three steps. Probe CNS could selectively respond to Hg²⁺ with obvious color and fluorescence changes, and the presence of other metal ions had no effect on the fluorescence changes. Probe CNS also exhibited high sensitivity against Hg²⁺, with a detection limit as low as 2.78 × 10⁻⁸ M. More importantly, the behavioral tracks of zebrafish had no obvious changes upon treatment with 10 μM probe CNS, thus indicating its low toxicity. The probe showed potential application value and was successfully used for detecting Hg²⁺ in a test strip, HeLa cells and living zebrafish larvae.

Mercury has complex biological toxicity and can cause a variety of physiological diseases and even death, so it is of great importance to develop novel strategies for detecting trace mercury in environmental and biological samples.     

Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal-free and solvent-free conditions for minimizing waste generation

Brønsted acidic ionic liquid was found to be an efficient and recyclable catalyst for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones. The reactions proceeded smoothly with a broad scope of substrates providing the expected products in good to excellent yields under an atom-economical pathway. The low-cost recyclable catalyst, metal- and solvent-free conditions, and the ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination in synthesized pharmaceuticals.

A facile, efficient, and atom-economic method for preparing benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal- and solvent-free condition has been developed.     

A novel pyrazolo[1,5-a]pyridine fluorophore and its application to detect pH in cells

A new fluorescent probe based on pyrazolo[1,5-a]pyridine was synthesized and used to monitor the pH in cells. This probe exhibited a fast response to acidic pH (less than 10 s), a high quantum yield (φ = 0.64), and high selectivity and sensitivity. The response mechanism of the fluorescent probes relies on the ICT change.

A new fluorescent probe based on pyrazolo[1,5-a]pyridine was synthesized and used to monitor the pH in cells.