A Coumarin-Hemicyanine Deep Red Dye with a Large Stokes Shift for the Fluorescence Detection and Naked-Eye Recognition of Cyanide.

In this study, we synthesized a coumarin-hemicyanine-based deep red fluorescent dye that exhibits an intramolecular charge transfer (ICT). The probe had a large Stokes shift of 287 nm and a large molar absorption coefficient (ε = 7.5 × 105 L·mol-1·cm-1) and is best described as a deep red luminescent fluorescent probe with λem = 667 nm. The color of probe W changed significantly when it encountered cyanide ions (CN-). The absorption peak (585 nm) decreased gradually, and the absorption peak (428 nm) increased gradually, so that cyanide (CN-) could be identified by the naked eye. Moreover, an obvious fluorescence change was evident before and after the reaction under irradiation using 365 nm UV light. The maximum emission peak (667 nm) decreased gradually, whilst the emission peak (495 nm) increased gradually, which allowed for the proportional fluorescence detection of cyanide (CN-). Using fluorescence spectrometry, the fluorescent probe W could linearly detect CN- over the concentration range of 1-9 µM (R2 = 9913, RSD = 0.534) with a detection limit of 0.24 µM. Using UV-Vis spectrophotometry, the linear detection range for CN- was found to be 1-27 µM (R2 = 0.99583, RSD = 0.675) with a detection limit of 0.13 µM. The sensing mechanism was confirmed by 1H NMR spectroscopic titrations, 13C NMR spectroscopy, X-ray crystallographic analysis and HRMS. The recognition and detection of CN- by probe W was characterized by a rapid response, high selectivity, and high sensitivity. Therefore, this probe provides a convenient, effective and economical method for synthesizing and detecting cyanide efficiently and sensitively.

A Potential Antidote for Both Azide and Cyanide Poisonings.

There do not appear to be any established therapeutics for treating azide poisoning at this time, and presently available antidotes to cyanide poisoning are far from ideal, being particularly impractical for use if multiple victims present. The cobalt (II/III) complex of the Schiff-base ligand trans-[14]-diene (5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (CoN4[14]) is shown to act as an effective antidote to both azide and cyanide toxicity in mice. Groups of animals challenged with an LD40 dose of NaCN (100 µmol/kg i.p.) exhibited significantly faster recovery from knockdown and fewer (zero) deaths if given CoN4[14] (50 µmol/kg i.p.) 2 minutes after the toxicant. Groups of animals challenged with an essentially lethal dose of NaCN (1.5 x LD50 = 150 µmol/kg i.p.) all survived if given the CoN4[14] (75 µmol/kg i.p.) 5 minutes before the toxicant dose. These data represent improved antidotal capability over the Food and Drug Administration-approved cobalt-based cyanide antidote hydroxocobalamin. Recovery of animals challenged sublethally with NaN3 (415 µmol/kg i.p.) was assessed employing a modified pole-climbing test. Mice given the CoN4[14] antidote (70 µg/kg i.p.) 5 minutes after the toxicant dose recovered twice as fast as the controls given no antidote. The interactions of cyanide and azide with CoN4[14] in vitro (buffered aqueous solutions) have been further investigated by a combination of spectroscopic approaches. The Co(II) form of the complex is able to bind two CN- anions while only binding a single N3 -, providing a reasonable explanation for the difference between their therapeutic abilities. SIGNIFICANCE STATEMENT: The Schiff-base complex CoN4[14] is shown to be an effective antidote to cyanide in mice, with improved therapeutic capabilities compared to the Food and Drug Administration-approved cobalt-containing hydroxocobalamin. CoN4[14] is also antidotal in mice toward azide poisoning, for which there is seemingly no approved therapy currently available. The activity toward cyanide involves a "redox-switching" mechanism that could be a common, but largely unrecognized, feature of all cobalt-based cyanide antidotes in use and under development.

Fluorescence-based ratiometric sensors as emerging tools for CN- detection: Chemical structures, sensing mechanisms and applications.

Hazardous cyanide anions (CN-) are increasingly threatening the environment and human health due to their widespread use in industry and many other fields. Over the past three decades, a large number of probes have been reported to sensitively and selectively detect this toxic anion, while a rather limited number of ratiometric fluorescent probes have been developed. The ratiometric probes have significant potential in bio-imaging and biomedical applications because of the ability to detect CN- in a quick, convenient and affordable way. In this review, we introduce 42 ratiometric fluorescent probes reported in the past 6 years (2018-2023) for CN- detection. Our description includes the chemical structures, photo-physical properties, CN- sensing mechanisms, solution color changes, limits of detection (LODs) and/or various applications of these chemical probes. This review provides guidelines for design and development of a new ratiometric probe for effective CN- detection.

Protein-Templated Ugi Reactions versus In-Situ Ligation Screening: Two Roads to the Identification of SARS-CoV-2 Main Protease Inhibitors.

Protein-templated fragment ligation was established as a method for the rapid identification of high affinity ligands, and multicomponent reactions (MCR) such as the Ugi four-component reaction (Ugi 4CR) have been efficient in the synthesis of drug candidates. Thus, the combination of both strategies should provide a powerful approach to drug discovery. Here, we investigate protein-templated Ugi 4CR quantitatively using a fluorescence-based enzyme assay, HPLC-QTOF mass spectrometry (MS), and native protein MS with SARS-CoV-2 main protease as template. Ugi reactions were analyzed in aqueous buffer at varying pH and fragment concentration. Potent inhibitors of the protease were formed in presence of the protein via Ugi 4CR together with Ugi three-component reaction (Ugi 3CR) products. Binding of inhibitors to the protease was confirmed by native MS and resulted in the dimerization of the protein target. Formation of Ugi products was, however, more efficient in the non-templated reaction, apparently due to interactions of the protein with the isocyanide and imine fragments. Consequently, in-situ ligation screening of Ugi 4CR products was identified as a superior approach to the discovery of SARS-CoV-2 protease inhibitors.

Isocyanide-based multicomponent reactions for the synthesis of benzopyran derivatives with biological scaffolds.

Benzopyrans (BZPs) are among the most privileged and influential small O-heterocycles that form the core of many natural compounds, commercial drugs, biological compositions, agrochemicals, and functional materials. BZPs are divided into six general categories including coumarins, chromans, 2H-chromenes, 4H-chromenes, chromones, and 4-chromanones, each of which is abundant in many plants and foods. These oxygenated heterocyclic compounds are fascinating motifs and have extensive applications in biology and materials science. Hence, numerous efforts have been made to develop innovative approaches for their extraction and synthesis. However, most of them are step-by-step or multi-step strategies that suffer from waste material generation and a tedious extraction process. Isocyanide-based multicomponent reactions (I-MCRs) offer a highly efficient method for overcoming these problems. The I-MCR is a simple and environmentally friendly one-pot domino procedure that does not require intermediate isolation or workup and is generally more efficient in material usage. This review covers all research articles related to I-MCRs for synthesizing BZP derivatives from the beginning to the middle of the year 2023. This strategy will be useful for organic and pharmaceutical chemists to design new drugs and optimize the synthesis steps of biological compounds and commercial drugs with benzopyran cores.

Isocyanide-based synthesis of spirorhodanine-cyclopentadiene and spirorhodanine-iminobutenolide conjugates from Winterfeldt's zwitterions and 5-ylidene rhodanines.

An ultrasonic-assisted isocyanide-based protocol to access a series of functionalized spirorhodanine-cyclopentadiene and spirorhodanine-iminobutenolide conjugates from alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 5-ylidene rhodanines in MeCN, is described. The reaction proceeds via interception of the reactive Winterfeldt's zwitterions by 5-ylidene rhodanine derivatives. The structures of the target compounds were confirmed by X-ray diffraction studies.

Fluorescent Nanoassembly of Tetrazole-Based Dyes with Amphoteric Surfactants: Investigation of Cyanide Sensing and Antitubercular Activity.

Tetrazole-based easily synthesizable fluorogenic probes have been developed that can form self-assembled nanostructures in the aqueous medium. Though the compounds could achieve detection of cyanide ions in apolar solvents, such as, THF, significant interference was observed from other basic anions, such as F-, AcO-, H2PO4-, etc. On the other hand, a highly specific response was observed for CN- ions in the aqueous medium. However, the sensitivity was so poor that it could hardly be useful for real-life sample analysis. Interestingly, the co-assembly of such probe molecules with hydroxyethyl-anchored amphoteric surfactants could drastically improve the sensitivity toward CN- ions in water without dampening their excellent selectivity. Also, it was observed that the degree of fluorescence response for CN- ions depends on the nature of the polyaromatic scaffolds (naphthyl vs anthracenyl), the nature of the surfactant assembly (micelle vs vesicle), etc. The mechanistic investigation indicates the hydrogen bonding interaction between the tetrazole -NH group and cyanide ions in the aqueous medium, which can effectively change the electronics of the tetrazole unit, resulting in alteration in the extent of charge transfer interaction. Then, the biocompatible composite materials (dye-surfactant assemblies at different ratios) were tested for antituberculosis activity. Fortunately, in a few cases, the compositions were found to be as effective as the commercially available antituberculosis drug, ethambutol.

New dual-responsive fluorescent sensor for hypochlorite and cyanide sensing and its imaging application in live cells and zebrafish.

Excessive levels of cyanide (CN-) and hypochlorite (ClO-) anions are the significant threats to the human health and the environment. Thus, great efforts have been to design and synthesize molecular sensors for the simple, instantaneous and efficient detecting environmentally and biologically important anions. Currently, developing a single molecular sensor for multi-analyte sensing is still a challenging task. In our present work, we developed a new molecular sensor (3TM) based on oligothiophene and Meldrum's acid units for detecting cyanide and hypochlorite anions in biological, environmental and food samples. The detecting ability of 3TM has been examined to various testing substances containing amino acids, reactive oxygen species, cations and anions, showing its high selectivity, excellent sensitivity, short response time (ClO-: 30 s, CN-: 100 s), and broad pH working range (4-10). The detection limits were calculated as 4.2 nM for ClO- in DMSO/H2O (1/8, v/v) solution and 6.5 nM for CN- in DMSO/H2O (1/99, v/v) solution. Sensor 3TM displayed sharp turn-on fluorescence increasement (555 nm, 435 nm) and sensitive fluorescence color changes caused by CN-/ClO-, which is ascribed to the nucleophilic addition and oxidation of ethylenic linkage by cyanide and hypochlorite, respectively. Moreover, sensor 3TM was applied for hypochlorite and cyanide detecting in real-world water, food samples and bio-imaging in live cells and zebrafish. To our knowledge, the developed 3TM sensor is the seventh single-molecular sensor for simultaneous and discriminative detecting hypochlorite and cyanide in food, biological and aqueous environments using two distinct sensing modes.

Controlled Synthesis, Chiral Assembly, and Circularly Polarized Luminescence of Poly(Phenyl Isocyanide)-Block-Polyfluorene Copolymers.

In this work, π-conjugated block copolymers consisting of poly(phenyl isocyanide) (PPI) and polyfluorene (PF) segments are facilely prepared by one-pot sequential polymerization of phenyl isocyanide (monomer 1) and 7-bromo-9,9-dioctylfluorene-2-boronic acid pinacol ester (monomer 2). The Pd(II)-terminated PPI is first prepared via polymerizing monomer 1 catalyzed with phenyl alkyne-Pd(II) complex and then utilized to initiate the controlled Suzuki cross-coupling polymerization of monomer 2, yielding various PPI-b-PF copolymers possessing controlled molar mass and narrow dispersity. Owing to the helical conformation of PPI segment and π-conjugated structure of PF segment, PPI-b-PF copolymers present distinctive optical property and fascinating chiral self-assembly behavior. During the self-assembly process, chirality transfer from helical PPI block to the supramolecular aggregates of helical nanofibers occurs to afford optically active helical nanofibers with high optical activity. Furthermore, the self-assembled helical nanofibers exhibit excellent circularly polarized luminescence performance.

A highly selective probe for fluorometric sensing of cyanide in an aqueous solution and its application in quantitative determination and living cell imaging.

A simple fluorescent probe (KS4) containing multiple reaction sites (phenolic -OH, imine and C = C bonds) is successfully synthesized and characterized using 1H NMR, 13C NMR, mass and single crystal XRD techniques. KS4 exhibits high selectivity towards CN- over a wide range of common anions in H2O:DMSO (1:1 v/v) leading to an amazing turn-on fluorescence at 505 nm via deprotonation of the phenolic -OH group. The limit of detection (1.3 µM) for CN- was much below the standard (1.9 µM) set by the World Health Organization (WHO). Stoichiometry of the interaction between KS4 and CN- was ascertained as 1:1 by the Job's plot method and the binding constant was determined to be 1.5x104 M-1. Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT) based theoretical insight has been appealed to understand the optical properties of KS4 before and after the addition of CN- ion. The probe shows respectable real-time applicability for qualitative detection of CN- in almond and cassava powder as well as quantification in real water samples with excellent recoveries (98.8 - 99.8%). In addition, KS4 is found to safe towards living HeLa cells and successfully applied to the detection of endogenous cyanide ions in HeLa cells.

Enhanced removal of metal-cyanide complexes from wastewater by Fe-impregnated biochar: Adsorption performance and removal mechanism.

Metal-cyanide complexes are common contaminants in industrial wastewater. Removal of these refractory contaminants is essential before their discharge into the environment. This study investigated a biochar (BC)-based sorbent material that could be applied for the efficient removal of metal-cyanide complexes from wastewater. In consideration of the strong electrostatic repulsion of the pristine BC toward anions, iron-modified BC (Fe-BC) composites were fabricated by a one-step co-pyrolysis of corn straw and FeCl3 at 600-800 °C. The adsorption performance and corresponding sorption mechanisms of representative metal-cyanide complexes (ferricyanide [Fe(CN)6]3- and tetracyanonickelate [Ni(CN)4]2-) onto the Fe-BC composites were investigated. The results indicated that the Fe-BC composites had significantly high affinity toward the metal-cyanide complexes, reaching a maximum sorption capacity of 580.96 mg/g for [Fe(CN)6]3- and 588.86 mg/g for [Ni (CN)4]2-. A mechanistic study revealed that Fe-impregnation during BC fabrication could effectively alter the negatively charged BC surface, forming more functional groups that could interact with the metal-cyanide complexes. Moreover, the transformation of carbon structure promoted the carbothermal reduction process, leading to the formation of various reductive-Fe minerals in the resulting Fe-BC composites. These modification-induced alterations to the surface and structural characteristics of BC were expected to facilitate the adsorption/precipitation of target contaminants. Different sorption mechanisms were proposed for the two metal-cyanide complexes that were the focus of this study. For [Fe(CN)6]3-, precipitation by Fe-bearing species in the Fe-BC composites was the major factor controlling [Fe(CN)6]3- removal, while for [Ni(CN)4]2- hydrogen bonding interactions between surface functional groups (especially hydroxyl (-OH) and carboxyl (-COOH)) and [Ni(CN)4]2- were the main factors controlling removal.

Study on Removal Mechanism for Copper Cyanide Complex Ions in Water: Ion Species Differences and Evolution Process.

A large amount of cyanide-containing wastewater is discharged during electrode material synthesis. Among them, cyanides will form metal-cyanide complex ions which possess high stability, making it challenging to separate them from these wastewaters. Therefore, it is imperative to understand the complexation mechanism of cyanide ions and heavy metal ions from wastewater in order to obtain a deep insight into the process of cyanide removal. This study employs Density Functional Theory (DFT) calculations to reveal the complexation mechanism of metal-cyanide complex ions formed by the interaction of Cu+ and CN- in copper cyanide systems and its transformation patterns. Quantum chemical calculations show that the precipitation properties of Cu(CN)43- can assist in the removal of CN-. Therefore, transferring other metal-cyanide complex ions to Cu(CN)43- can achieve deep removal. OLI studio 11.0 analyzed the optimal process parameters of Cu(CN)43- under different conditions and determined the optimal process parameters of the removal depth of CN-. This work has the potential to contribute to the future preparation of related materials such as CN- removal adsorbents and catalysts and provide theoretical foundations for the development of more efficient, stable, and environmentally friendly next-generation energy storage electrode materials.

Synthesis and characterization of phenothiazine sensor for spectrophotometric and fluorescence detection of cyanide.

A sensitive and selective phenothiazine-based sensor (PTZ) has been successfully synthesized. The sensor PTZ displayed specific identification of CN- 'turn-off' fluorescence responses with a quick reaction and strong reversibility in an acetonitrile:water (90:10, V/V) solution. The sensor PTZ for detecting CN- exhibits the marked advantages of quenching the fluorescence intensity, fast response time (60 s), and low value of the detection limit. The concentration that is authorized for drinking water by the WHO (1.9 µM) is far higher than the detection limit, which was found to be 9.11 × 10-9 . The sensor displays distinct colorimetric and spectrofluorometric detection for CN- anion due to the addition of CN- anion to the electron-deficient vinyl group of PTZ, which reduces intramolecular charge transfer efficiencies. The 1:2 binding mechanism of PTZ with CN- was validated by fluorescence titration, Job's plot, HRMS, 1 H NMR, FTIR analysis, and density functional theory (DFT) investigations, among other methods. Additionally, the PTZ sensor was successfully used to precisely and accurately detect cyanide anions in actual water samples.

Ugi Four-Component Reactions Using Alternative Reactants.

The Ugi four-component reaction (Ugi-4CR) undoubtedly is the most prominent multicomponent reaction (MCRs) that has sparked organic chemists' interest in the field. It has been widely used in the synthesis of diverse heterocycle molecules such as potential drugs, natural product analogs, pseudo peptides, macrocycles, and functional materials. The Ugi-4CRs involve the use of an amine, an aldehyde or ketone, an isocyanide, and a carboxylic acid to produce an α-acetamido carboxamide derivative, which has significantly advanced the field of isocyanide-based MCRs. The so-called intermediate nitrilium ion could be trapped by a nucleophile such as azide, N-hydroxyphthalimide, thiol, saccharin, phenol, water, and hydrogen sulfide instead of the original carboxylic acid to allow for a wide variety of Ugi-type reactions to occur.ß In addition to isocyanide, there are alternative reagents for the other three components: amine, isocyanide, and aldehyde or ketone. All these alternative components render the Ugi reaction an aptly diversity-oriented synthesis of a myriad of biologically active molecules and complex scaffolds. Consequently, this review will delve deeper into alternative components used in the Ugi MCRs, particularly over the past ten years.

Substituent-Dependent Azide Addition to Isocyanides Generates Strongly Luminescent Iridium Complexes.

Ligand-centered functionalization reactions offer diverse strategies to prepare luminescent organometallic compounds. These compounds can have unique structures that are not accessible via traditional coordination chemistry and can possess enhanced or unusual photophysical properties. Here we show that bis-cyclometalated iridium bis-isocyanide complexes (1) react with azide (N3-) to form novel luminescent structures. The fate of the reaction with azide is determined primarily by the substituent on the aryl isocyanide. Those with electron-withdrawing substituents (CF3 or NO2) react with 1 equiv of azide followed by N2 extrusion, forming aryl cyanamido products (2). With electron-donating groups on the aryl isocyanide the reactivity is more diverse, and three outcomes are possible. In two cases, the isocyanide and azide undergo a [3 + 2] cycloaddition to form a C-bound tetrazolato structure (3). In three other cases, 2 equiv of azide are involved in the formation of a previously unobserved structure, where a tetrazolato and aryl cyanamido couple and rearrange to form a chelating ligand comprised of an N-bound tetrazolato and an acyclic diaminocarbene (4). Finally, a bimetallic aryl cyanamido complex (5) is isolated in one case. All compounds are luminescent, some with exceptional photoluminescence quantum yields as high as 0.81 in solution for sky-blue emission, and 0.87 for yellow emission and 0.65 for orange-red emission in polymer films.

Domino synthesis of 5-aminoimidazoles from Strecker multicomponent adducts via ytterbium-promoted isocyanide insertion/5-exo-dig cyclization.

A new Lewis acid promoted domino isocyanide insertion/5-exo-dig cyclization of readily available Strecker 3-component adducts to 4-substituted 5-aminoimidazole derivatives is herein reported. Despite their potential as relevant heterocyclic scaffolds in medicinal chemistry programs, this class of compounds is still underrepresented, with current synthetic strategies poorly efficient in terms of timing and yields. To this end, we show how the exploitation of unconventional reactivities of isocyanides, promoted by ytterbium-triflate, could represent a key resource to enable a fast and easy access to such an unexplored area of the chemical space.

First-row transition metal for isocyanide-involving multicomponent reactions (IMCR).

First-row transition metal catalyzed transformations that are able to construct complex molecules from simple, readily obtainable feedstocks have become a keystone of modern synthetic organic chemistry. Particularly, the multicomponent reaction (MCR) involving carbon-carbon (C-C) as well as carbon-heteroatom (C-X) bond formation plays an essential role in many chemical conversions, and insurgencies in these reactions powerfully improve the overall synthetic efficiency. Recently, MCRs emerges rapidly because of its greener sides like eco-friendly nature, swift and straightforward execution, high atom/step economy, and construction of aimed product with lowest or no by-product, usually in quantitative yield. Curiously, the exceptional divalent carbon atoms of isocyanides make them predominantly useful components in multicomponent reactions. As a result of widespread research over the past few decades, numerous well-designed and effective procedures for the first-row TM-catalyzed MCR to afford the various entities have been reported. These aspects are summarized in this review article. A particular focus on comparative discussion of various first-row transition-metal catalyzed isocyanide-based multicomponent reactions through mechanistic details included in the review article.

Cyanide within gold mine waste of the free state goldfields: A geochemical modelling approach.

Cyanide, which remains the preferred chemical used in the gold extraction process, has the potential to be disposed of on goldmine tailings. South Africa has nine goldfields, producing approximately a third of the world's gold to date. The cyanide interacts with metals in the tailings environment, where Prussian blue [Formula: see text] and Turnbull's blue [Formula: see text] are among these. In previous studies, Prussian blue or Turnbull's blue have been found as a blue substance in tailings material. PHREEQC modelling software was used adding the mineralogical data from 16 tailings samples from the Free State goldfield. The results revealed that Prussian blue prefers to precipitate in an oxic environment and Turnbull's blue prefers an anoxic environment. It was also determined that their precipitation is affected by the availability of iron in solution. As soon as all of the iron is consumed in solution, all excess cyanide produces HCN, which is a free cyanide which volatilizes. Contrarily, Prussian and Turnbull's blue are CNSAD compounds, only dissociating in extremely low pH condition in the absence of photolysis. Ultimately, these iron-cyanide compounds are able to immobilize cyanide, preventing seepage into environments such as the ground water. This along with an anoxic environment such as mine void, keeping the pH high, may be a possible solution for cyanide remediation.

Urea Synthesis from Isocyanides and O-Benzoyl Hydroxylamines Catalyzed by a Copper Salt.

In the presence of CuOAc, a series of unsymmetric ureas can be generated in moderate to good yields under mild reaction conditions (10 mol% of CuOAc, 2 equiv t-BuONa or PhONa, 30 °C), using aryl isocyanides and O-benzoyl hydroxylamines as the readily accessible starting materials. The reactions might undergo a cascade process involving isocyanide insertion into the N-O bond and Mumm-type rearrangement. This work represents a rare example of isocyanide insertion into N-O bonds, which would extend isocyanide insertion chemistry.

Construction of 5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles via the One-Pot Reaction of Alkyl Isocyanides with Aryl/Alkyl Carbonyl Chlorides and Diaminomaleonitrile: Fluorescence and Antimicrobial Activity Evaluation.

5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles were successfully synthesized in good to moderate yields by reacting alkyl isocyanides with aryl/alkyl carbonyl chlorides, followed by the addition of diaminomaleonitrile. The synthesized pyrazines were fully characterized in this investigation, and X-ray crystal structure analysis was performed on some derivatives. The antibacterial and antifungal activities of the newly synthesized pyrazine-2,3-dicarbonitriles were assessed in addition to their UV and fluorescence results. All the compounds showed similar UV-Vis spectral features with absorption peaks (λmax) around 267, 303, and 373 nm.