Pyrylium Research Articles

Organophotocatalytic Remote Thiocyanation Reaction via Ring-Opening Functionalization of Cycloalkanols.

The remote C(sp3)-SCN bond formation via ring-opening functionalization of cycloalkanols with N-thiocyanatosaccharin as the precursor of SCN radicals and pyrylium salt as the organic photocatalyst under visible light has been developed. Thus, various terminal keto thiocyanates were prepared without transition metals and oxidants in moderate to good yields. The simplicity, wide substrate scope and mild conditions feature its synthetic application capability.

Piezochromic Behavior of 2,4,6‐Triphenylpyrylium Tetrachloroferrate

In advanced photonics, there is a growing interest in piezochromic luminescent materials that exhibit multicolor switching, driven by their potential applications in optical recording, memory, and sensors. Here, the piezochromic behavior of 2,4,6‐triphenylpyrylium tetrachloroferrate (Py‐FeCl4) under high pressures from 0 to 9 GPa is reported. The observed multicolor changing properties of Py‐FeCl4 (yellow–orange–red–maroon–black) are found to be fully reversible upon decompression to ambient conditions. The mechanism of Py‐FeCl4 piezochromism is investigated via Raman, infrared, and UV–vis spectroscopy combined with powder X‐ray Diffraction. The absence of structural phase transitions as well as the abrupt shifts of bandgap values together with characteristic Raman and IR peaks within 0‐9 GPa suggests that the Py‐FeCl4 multicoloring switching behavior is driven by an electron transfer between the inorganic FeCl4− anion and the organic pyrylium cation. The obtained results demonstrate that Py‐FeCl4 dye is a good candidate for developing high‐pressure sensing technologies designed to function in extreme environments. Moreover, due to the inherent role of molecular‐structure relationships in the pyrylium salt's photophysical properties, findings suggest the potential discovery of piezochromic behavior in other pyrylium compounds.

A Near‐IR Fluorimetric Chemosensing System for the Turn‐On Detection of Hydrogen Sulfate Anion

AbstractWe report a near‐IR fluorescence turn‐on chemosensing system for the selective detection of HSO4− anion in aqueous media. This system utilizes the equilibrium between the fluorescent pyrylium salt and its non‐fluorescent diketone form. The pyrylium compound we synthesized (λflo=674 nm) rapidly converts to its diketone form in the aqueous medium (ethanol‐water 4 : 1). HSO4− anion provides proton to diketone form inducing its conversion to pyrylium. Therefore, the sensor system responds to the presence of HSO4− by an increase in fluorescence. The change in the fluorescence increase is linear within the 20–55 μM range with a limit of detection of 12.8 μM. The system demonstrates high selectivity for HSO4− over other anions, as validated through fluorimetric titration studies. Additionally, interference studies highlight the minimal impact of common anions on bisulfate detection. Reversibility tests reveal the pronounced reversibility of the sensor system, with over 90 % recovery of fluorescence intensity achieved in subsequent iterations.

Synthesis of Triarylpyrylium Salts Using a Mild, Eco-friendly Route

AbstractPyrylium salts based on a cationic oxygen heterocycle are a key class of chromophores. However, synthesis of these salts generally requires use of harsh acids, copious organic solvents, and in many cases, hazardous conditions. This work provides a two-pot synthesis for substituted triphenyl pyrylium salts wherein chalcone intermediates are first prepared and then mild methanesulfonic acid is used in combination with a dehydrating agent to drive pyrylium cyclization. Purification is achieved through a simple, aqueous workup involving counterion metathesis which avoids the need for environmentally unfriendly organic solvents. This mild, green approach has been applied to synthesize a collection of known pyryliums as well as a new family of red-shifted pyrylium chromophores bearing p-pyrrolidinylphenyl substituents. The synthesis of the latter group demonstrates that unlike other current methods, our approach offers enhanced functional group tolerance as well as finer control over substituent placement.

2,5-[C4+C2] Ringtransformation of Pyrylium Salts with α-Sulfinylacetaldehydes.

A rapid synthesis of chiral sulfoxide-functionalized meta-terphenyl derivatives by a 2,5-[C4+C2] ring transformation reaction of pyrylium salts with in situ generated enantiomerically pure α-sulfinylacetaldehydes is described in this paper. This synthetic method demonstrates, for the first time, the use of α-sulfinylacetaldehydes in a reaction sequence initiated by the nucleophilic attack of pyrylium salts by α-sulfinylcarbanions to generate chiral aromatic systems. The method presented shows a broad applicability starting with various methyl sulfoxides and a number of functionalized pyrylium salts, furnishing meta-terphenyls with complex substitution patterns from readily accessible starting compounds.

Chemodosimetric discriminative analysis of cyanide, ammonia, aliphatic amine, and hydrazine utilizing the diverse reaction types of the pyrylium salt

Pyrylium salts are well known to react with different nucleophiles to form many different types of products like pyridinium salt, pyridine, cyanodienone, thiopyrylium, isoxazoline, N-aminopyridinium salt or 1,2-diazepine, depending on the nucleophile used. This property of pyrylium salts could be used to develop a multi-analyte chemosensor for the species having nucleophilic character. On this idea, we synthesized a pyrylium compound (PyrSen) bearing auxochromes and studied its photophysical responses to different nucleophiles. Different absorption spectra were observed to emerge upon the separate addition of cyanide, propylamine, ammonia, and hydrazine to the aqueous solution of PyrSen (ethanol-water 5:1). In the solutions containing ammonia and hydrazine were also observed fluorescence at different wavelengths. The products responsible for these photophysical properties were isolated and characterized. The developed sensor was proved to be usable for the discrimination and quantification of these four species in aqueous solutions.

Solvent-free synthesis of aryl-substituted pyrylium salts and investigation of the auxochromes’ effects on their photophysical properties

Pyrylium compounds are structures based on an oxonium heterocycle that has been extensively studied thanks to their superior absorption and fluorescence properties. In this study, pyrylium salts were first shown to be obtained in the solvent-free medium. Six pyrylium compounds, three of which were novel, were synthesized using this method. These compounds have different auxochromes on the phenyl groups at the 2,4 and 6 positions. In the final step, the photophysical properties of these compounds were examined and the effects of basic auxochromes on pyrylium photophysics were revealed.

DMMIC derivatization-assisted liquid chromatography-mass spectrometry method for metabolite profiling of the glutathione anabolic pathway in esophageal cancer tissues and cells

In this work, a new pyrylium derivatization-assisted liquid chromatography-mass spectrometry (LC-MS) method was developed for metabolite profiling of the glutathione anabolic pathway (GAP) in cancer tissues and cells. The pyrylium salt of 6,7-dimethoxy-3-methyl isochromenylium tetrafluoroborate (DMMIC) was used to label the amino group of metabolites, and a reductant of dithiothreitol (DTT) was employed to stabilize the thiol group. By combining DMMIC derivatization with LC-MS, it was feasible to quantify the 13 main metabolites on the GAP in complex biological samples, which had good linearity (R2 = 0.9981−0.9999), precision (interday precision of 1.6%–19.0% and intraday precision of 1.4%–19.8%) and accuracy (83.4%–115.7%). Moreover, the recovery assessments in tissues (82.5%–107.3%) and in cells (98.1%–118.9%) with GSH-13C2, 15N, and Cys-15N demonstrated the reliability of the method in detecting tissues and cells. Following a methodological evaluation, the method was applied successfully to investigate difference in the GAP between the carcinoma and para-carcinoma tissues of esophageal squamous cell carcinoma (ESCC) and the effect of p-hydroxycinnamaldehyde (CMSP) on the GAP in KYSE-150 esophageal cancer cells. The results demonstrate that the developed method provides a promising new tool to elucidate the roles of GAP in physiological and pathological processes, which can contribute to research on drugs and diseases.

Polyphenylenepyridines Based on Acetylaromatic Compounds

Nitrogen-containing polyphenylene type polymers containing pyridine rings were synthesized. The polymer-forming reaction is based on the interaction of diacetylarylene and triethylorthoformate with the formation of a pyrylium salt and subsequent treatment of the intermediate product with ammonia. The optimal ratios of the reagents for the formation of the pyridine fragment were determined. The mechanism of the main reaction is discussed. The formation of the pyridine ring and phentriyl (1,3,5-triphenylsubstituted benzene) fragments was confirmed using 1H NMR data of the example of model reactions. After heating at a temperature of 450 °C, when a more complete polycondensation process occurs, the polymers reach high values of thermal characteristics—10% weight loss in an inert atmosphere corresponds to 600 °C. The structure of the synthesized polymers was confirmed using elemental analysis, IR, XPS, and EPR spectroscopy. The conjugation length in cross-linked polyphenylene pyridines can be controlled by varying the arylene bridge groups between the phentriyl fragments, which opens up opportunities for the development of new composite materials for electrical applications.

Two-step synthesis and oxidizing power assessment of novel pyrylium

Photoredox catalysis is a relatively new concept, and it involves the absorption of light for more productive use of lower energy radiation and to catalyze selective reactions. Traditionally, catalysts used for oxidation or reduction reactions were metal catalysts, such as iridium. However, these metal catalysts are not environmentally friendly and are expensive, prompting the use of organic catalysts. Pyrylium salt, an organic catalyst, can be used as a catalyst. However, the oxidizing ability of basic pyrylium is not that good and can still be improved. In this project, a pyrylium salt with substituents that include fluorine and chlorine (halogens) was synthesized to boost its oxidizing ability in an alcohol oxidation reaction due to its electron-withdrawing groups. Despite unsuccessful oxidation, there is still much research to prove that it can substitute for metal catalysts.

LC-MS detection of amino acids and neurotransmitters by using α-active 2,4,5-triphenylpyrylium salt as an efficient derivatizing material

Herein, a series of pyrylium salts such as 2,4,6-trimethylpyrylium (P1), 2,6-dimethyl,4-phenylpyrylium (P2), 2,4-diphenylpyrylium (P3), 2,6-diphenylpyrylium (P4), 2,4,5-triphenylpyrylium (P5), 2,4,6-triphenylpyrylium (P6), 2-phenyl, 4,5-diphenylmethylprrylium (P7), 2,3,4,5-tetraphenylpyrylium (P8), 2,3,4,5,6-pentaphenylpyrylium (P9) and 3,4-dimethoxybenzyl,6-phenylpyrylium (P10) were used as highly specific derivatizing agent for mass spectrometric detection of neurochemicals (neurotransmitters and amino acids). Neurotransmitters of dopamine (DA), norepinephrine (NE), histamine (His), γ-amino butyric acid (GABA) and 5-hydroxytyramine (5-HT), and the amino acids of alanine (Ala), serine (Ser), proline (Pro), tryptophan (Trp), threonine (Thr), 4-hydroxy proline (4-Hyp), isoleucine (Ile), leucine (Leu), aspargine (Asn), aspartic acid (Asp), glutamine (Gln), lysine (Lys), glutamic acid (Glu), histidine (H), phenylalanine (Phe), arginine (Arg), valine (Val), tyrosine (Tyr) and cysteine (Cys) were successfully derivatized with the pyrylium salts. The hydrophobic and hydrophilic nature of pyrylium salts were modified by changing the side chain groups. The influence of pyrylium concentration, catalyst concentration, temperature and reaction time were thoroughly optimized. The obtained result suggests that the small molecules like neurotransmitters, amino acids and small peptides have better sensitivity than the peptides and intact proteins. We believe that hydrophobic pyrylium salts will be a potential derivatizing agent for the future mass spectrometric analysis using clinical samples.

Combined Transcriptome and Metabolome Analysis Reveals That the Potent Antifungal Pyrylium Salt Inhibits Mitochondrial Complex I in Candida albicans.

Based on the structural modification of SM21, xy12, a new pyrylium salt derivative with enhanced antifungal activities, was synthesized. The MICs (MIC90) of xy12 against Candida albicans ranged from 0.125 to 0.25 μg/mL, about 2-fold lower than those of SM21. In addition, xy12 inhibited hypha and biofilm formation in C. albicans in a dose-dependent manner. A total of 3,454 differentially expressed genes and 260 differential metabolites were identified in the xy12-treated C. albicans by RNA-seq and non-targeted metabolomics. By integrating KEGG pathway enrichment analysis, we found that inhibition of oxidative phosphorylation was the important antifungal mechanism of action of xy12. Electron transport through mitochondrial respiratory complexes I to IV is the common process of oxidative phosphorylation. Compared with the sensitivity of the wild-type SC5314 to xy12, decreased sensitivities in mitochondrial complex I (CI)-deficient mutants and increased sensitivities in mitochondrial complex III- and IV-deficient mutants suggested that the antifungal effects of xy12 were dependent on CI. Consistently, xy12 exhibited antagonism with rotenone, an inhibitor of CI, and significantly inhibited the expression and activity of CI. Meanwhile, the phenotypes in the xy12-treated C. albicans were similar to those in the CI-deficient mutants, such as decreased ATP production, reduced mitochondrial membrane potential, loss of mitochondrial DNA, inability to utilize nonfermentative carbon sources, and decreased cell wall N-linked mannoproteins. Collectively, our results revealed that the pyrylium salt xy12 could constrain oxidative phosphorylation by inhibiting mitochondrial complex I in C. albicans, providing a novel lead compound for the development of mitochondria-targeted antifungal drugs. IMPORTANCE The development of new antifungal drugs is critical for solving the problem of antifungal resistance and expanding the limited variety of clinical antifungal drugs. Based on the modification of the pyrylium salt SM21, a new lead compound, xy12, was synthesized which was effective against Candida species both in vitro and in vivo. In this study, conjoined analysis of the transcriptome and metabolome elucidated the antifungal mechanism of action of xy12, which inhibited the activity of mitochondrial complex I in C. albicans. Targeting fungi-specific mitochondrial complex proteins has been reported as a promising antifungal strategy. Our study provided a new lead compound for targeting C. albicans mitochondrial complex I, which could be beneficial for discovering novel antifungal drugs.

Thermodynamics Theoretical Investigation for Synthesis of Pyridine from Pyrylium Salt using Density Functional Theory

Pyridine is a heterocyclic compound that is widely used as an ingredient in medicines, vitamins, food flavors, pesticides, dyes, adhesives, and others. Currently, pyridine synthesis is carried out with coal tar as a raw material, which is a non-renewable natural resource. In this research, a theoretical study was carried out to evaluate the synthesis process of pyridine using pyrylium salt as an alternative raw material to displace coal tar. This study also aims to simulate the pyridine synthesis and the energy required or released in the process. Density Functional Theory (DFT) method was employed to calculate some thermodynamic properties of the species involved in the reaction such as enthalpy, entropy, and Gibbs free energy in a vacuum and solvated model in order to study the progress of the reaction and mechanism. Based on the calculation results, the lowest value of enthalpy, entropy, and free energy Gibbs is obtained when the reaction takes place in a vacuum. The change of entropy and free Gibbs energy of the reaction was not predominantly affected by the degree of polarity of the solvent. Meanwhile, the enthalpy of reaction simulated in water solvent is higher than in the ethanol solvent. The synthesis reaction of pyridine from pyrylium salt is exothermic and exergonic because it has a negative value of enthalpy change and Gibbs free energy at 298.15 K, which is potential to be done at room temperature without extreme condition control.

An organo-photocatalyzed visible-light-driven multi-component approach for carbothioaryl/alkylation of activated alkenes via C(sp3)-H bond functionalization.

A visible-light-driven organophotocatalyzed multi-component approach for carbothiolation of activated alkenes is demonstrated under environmentally benign and redox-neutral conditions, involving direct C(sp3)-H functionalization followed by electrophilic alkyl/arylthiolation. The three-component difunctionalization reaction is a complete transition-metal and peroxide-free process conducted under milder conditions. In this composite reaction, by employing bench-stable reagents, the formation of two new C(sp3)-C(sp3) and C(sp3)-S bonds is achieved for a wide variety of substrates, showcasing the excellent functional group tolerance and chemoselectivity of the methodology. Furthermore, the scalability and utilization of natural sunlight instead of artificial blue LEDs, along with the use of an inexpensive and easy-to-prepare pyrylium salt as an organo-photocatalyst, make this protocol greener and more energy efficient.

Structurally and electrochemically tunable pyrylium platforms: A new class of redox anolyte for non-aqueous organic redox flow battery operating at a high-current density

Non-aqueous all-organic redox flow batteries (NORFB) are a proficient candidate for large-scale energy storage applications. The higher operating potential window of non-aqueous solvents, diversity of redox-active organic molecules (ROMs), and independent scaling of power and energy, etc., captivate NORFB to be a potential choice for grid energy storage applications. Besides, the invention of new redox-active motifs significantly expands the development of NORFBs; thus, it is highly demanded. But, the low operational current density and slower redox kinetics are the bottlenecks for the further development of NORFB. Herein, we introduced a new class of anolyte material based on pyrylium salt (2,4,6-triphenylpyrylium tetrafluoroborate (TPT)) and demonstrated for the first time its applicability as a potential anolyte in NORFB. The substitutions at the 2, 4, and 6th positions of pyrylium salt prominently tune the structural and electrochemical behavior, thus providing a versatile platform to explore them in flow battery chemistry. TPT exhibited a one-electron reduction process with a high electron transfer rate constant of 9.94 × 10−3 cm s−1 and diffusion coefficient of 5.83 × 10−6 cm2 s−1, which is higher for the non-aqueous medium. By coupling with N-decylphenothiazine (DPTZ) catholyte, a mixed electrolyte flow cell was demonstrated with a capacity of 1.08 Ah/L and coulombic efficiency of 97 % at a high current density of 40 mA cm−2.

Analysis of the Amine Submetabolome Using Novel Isotope-Coded Pyrylium Salt Derivatization and LC-MS: Herbs and Cancer Tissues as Cases.

The amine submetabolome, including amino acids (AAs) and biogenic amines (BAs), is a class of small molecular compounds exhibiting important physiological activities. Here, a new pyrylium salt named 6,7-dimethoxy-3-methyl isochromenylium tetrafluoroborate ([d0]-DMMIC) with stable isotope-labeled reagents ([d3]-/[d6]-DMMIC) was designed and synthesized for amino compounds. [d0]-/[d3]-/[d6]-DMMIC-derivatized had a charged tag and formed a set of molecular ions with an increase of 3.02 m/z and the characteristic fragment ions of m/z 204.1:207.1:210.1. When DMMIC coupled with liquid chromatography-mass spectrometry (LC-MS), a systematic methodology evaluation for quantitation proved to have good linearity (R2 between 0.9904 and 0.9998), precision (interday: 2.2-21.9%; intraday: 1.0-19.7%), and accuracy (recovery: 71.8-108.8%) through the test AAs. Finally, the methods based on DMMIC and LC-MS demonstrated the advantaged application by the nontargeted screening of BAs in a common medicinal herb Senecio scandens and an analysis of metabolic differences among the amine submetabolomes between the carcinoma and paracarcinoma tissues of esophageal squamous cell carcinoma (ESCC). A total of 20 BA candidates were discovered in S. scandens as well as the finding of 13 amine metabolites might be the highest-potential differential metabolites in ESCC. The results showed the ability of DMMIC coupled with LC-MS to analyze the amine submetabolome in herbs and clinical tissues.

Visible-Light-Mediated Organophotocatalyzed C(sp3)–H Activation and Intramolecular Cyclization

AbstractA metal-free approach for C(sp3)–H activation followed by an intramolecular Giese reaction to construct a wide range of cyclic ether scaffolds of various ring sizes under environmentally benign and straightforward conditions is reported. An easily prepared pyrylium salt is employed as an organophotocatalyst for this visible-light-driven, highly atom-economical (PMI = 64.34 g/g for a 0.2 mmol scale), cost-effective, and chemoselective transformation. The reported method has a broad functional-group tolerance, resulting in good-quality products. Furthermore, downstream functionalizations of a product and a gram-scale synthesis (PMI = 17.41 g/g for a 10 mmol scale) are demonstrated, highlighting our method’s advantages.

New Pyridinium Salt Derivatives of 2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5- sulfonamide as Selective Inhibitors of Tumour-Related Human Carbonic Anhydrase Isoforms IX and XII.

The positively charged membrane impermeant sulfonamides were evaluated as a remarkable class of carbonic anhydrase inhibitors (CAIs) previously. Without affecting the human carbonic anhydrase (hCA), cytosolic isoforms hCA I and II, inhibition of two membrane-associated isoforms hCA IX and XII especially overexpressed in hypoxic tumour cells, makes the pyridinium salt derivatives potent promising therapeutic agents. A novel series of tri, tetra, and cyclo-substituted pyridinium salt derivatives of the lead compound 2- (hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide has been prepared by using sixteen different pyrylium salts, for the search of selective inhibitors of transmembrane tumour-associated human carbonic anhydrase hCA IX and XII. Molecular modeling studies were carried out to understand and rationalize the in vitro enzyme inhibition data. Six of the new compounds showed good inhibitory profiles with low nanomolar range (< 100 nM) against hCA IX/XII, and compound 5 showed excellent potency with Ki values lower than 10 nM. In addition, molecular modelling studies have presented the possible binding modes of the ligands. Most of the compounds displayed potent inhibitory activity against the tumor-associated hCA IX and XII in the low nanomolar range and selectivity over the off-targeted isoforms hCA I and II. Due to their cationic structure and membrane-impermeant behavior, it is also expected to maximize the selectivity over cytosolic isoforms hCA I/II while inhibiting tumor overexpressed isoforms hCA XI/XII of new compounds in in vivo conditions.

Design, Synthesis and Antifungal Evaluation of Novel Pyrylium Salt In Vitro and In Vivo

Nowadays, discovering new skeleton antifungal drugs is the direct way to address clinical fungal infections. Pyrylium salt SM21 was screened from a library containing 50,240 small molecules. Several studies about the antifungal activity and mechanism of SM21 have been reported, but the structure–activity relationship of pyrylium salts was not clear. To explore the chemical space of antifungal pyrylium salt SM21, a series of pyrylium salt derivatives were designed and synthesized. Their antifungal activity and structure-activity relationships (SAR) were investigated. Compared with SM21, most of the synthesized compounds exhibited equivalent or improved antifungal activities against Candida albicans in vitro. The synthesized compounds, such as XY10, XY13, XY14, XY16 and XY17 exhibited comparable antifungal activities against C. albicans with MIC values ranging from 0.47 to 1.0 μM. Fortunately, a compound numbered XY12 showed stronger antifungal activities and lower cytotoxicity was obtained. The MIC of compound XY12 against C. albicans was 0.24 μM, and the cytotoxicity decreased 20-fold as compared to SM21. In addition, XY12 was effective against fluconazole-resistant C. albicans and other pathogenic Candida species. More importantly, XY12 could significantly increase the survival rate of mice with a systemic C. albicans infection, which suggested the good antifungal activities of XY12 in vitro and in vivo. Our results indicated that structural modification of pyrylium salts could lead to the discovery of new antifungal drugs.

Pyrylium-based porous organic polymers via Knoevenagel condensation for efficient visible-light-driven heterogeneous photodegradation

Pyrylium salts are a type of representative and convincing example of versatility and variety not only as a nodal point in organic transformations but also as an attractive building block in functional organic materials. Herein, we report an effective synthetic protocol to fabricate a new pyrylium-containing porous organic polymers (POPs), named TMP-P, via Knoevenagel condensation with 2,4,6-trimethylpyrylium salt (TMP) as the key building block and 1,4-phthalaldehyde as the linker. The resulting ionic polymer TMP-P exhibited efficient visible-light-driven heterogeneous photodegradation of Rhodamine B, owing to the presence of wide visible light absorption and a narrow optical band gap triggered pyrylium core in the framework. : A new ionic porous organic polymer (iPOP) was readily fabricated via Knoevenagel condensation with pyrylium salts as the key building block, which exhibited efficient visible-light-driven heterogeneous photodegradation of Rhodamine B.