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Herein we describe an efficient construction of HCF2Se and HCF2S groups by tandem substitutions between alkyl bromides and a reagent system consisting of MSeCN (or MSCN) and Ph3P+CF2H Br-. The tandem process occurs via the first nucleophilic substitution of alkyl bromides by -SeCN (or -SCN) and the subsequent nucleophilic difluoromethylation.

Background: The disorders of glucolipid metabolism are prevalent in patients with type-2 diabetes mellitus (T2DM). Palmitic-Acid-Hydroxy-Stearic Acid (PAHSA) had been reported to benefit glucolipid metabolism in diabetic mice. Given the importance of autophagy in T2DM, the aim of the present study was to investigate whether S-9-PAHSA has specific therapeutic effects on diabetics, particularly with regards to autophagy. Methods: 19-week-old male C57BL6 mice were fed with high-fat-diet for 4 months, and administered with 22.5 mg/kg/d or 5.5 mg/kg/d fatty acids or an equivalent volume of vehicle for 35 days. Glucose levels and weight were determined. Insulin, glycosylated serum protein (GSP), glucagon-like peptide-1(GLP-1) and oxidized modified low-density lipoprotein (ox-LDL) were assessed by ELISA kit. Autophagy-related proteins P62 and Beclin-1in cerebral cortex were detected by western blot. SH-SY 5Y cells were incubated under diabetic environment (glucose 100mmol/L, fatty acid 200μmol/L), and then treated with S-9-PAHSA, R-9-PAHSA and 9-PAHSA. Cell viability, cell proliferation, lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) production were detected by respective kits. Apoptosis was assessed by the TUNEL assay. The protein levels of apoptosis (Cleaved caspase-3, BAX/Bcl-2), autophagy (Beclin1, p62 and LC3II/I) and PI3K/AKT pathway were determined by western blot. Results: Although S-9-PAHSA did not alter glucose levels, weight, GLP-1 and GSP in mice, high-does S-9-PAHSA improved insulin resistance and lowered ox-LDL. Compared with control group, the up-regulated expression of P62 and down-regulated expression of Beclin1 in diabetic mice were found, and the S-9-PAHSA administration reduced P62. In vitro, S-9-PAHSA increased cell viability and proliferation while reduced LDH release and ROS production, which were better than R-9-PAHSA and 9-PAHSA. S-9-PAHSA could lower the levels of Cleaved caspase-3 and percentage of TUNEL-positive cells. S-9-PAHSA enhanced the expression of LC3II/I under high glucose and fatty acid stimulation. PI3K and p-AKT/AKT ratio under diabetic environment had a downward trend, and S-9-PAHSA might enhance their expression, but there was no statistical difference. Conclusions: S-9-PAHSA could regulate glycolipid metabolism in HFD-induced T2DM mice through autophagy-associated protein, and exerted protective effects on diabetes by the regulation of autophagy, reducing oxidative stress, partially activating PI3K/AKT signaling pathway.

Herein we describe an efficient construction of HCF

Fluorinated molecules have a wide range of applications and are used as medicines, agrochemicals and refrigerants and in smartphone liquid crystal displays, photovoltaic solar cells, Teflon tapes and the coatings of textiles and buildings. Fluorination and fluoroalkylation — incorporation of a trifluoromethyl, difluoromethyl or monofluoromethyl group — are the major strategies used for the construction of carbon–fluorine bonds and fluorinated carbon–carbon bonds, respectively. The past two decades have witnessed a rapid growth in fluorination and fluoroalkylation methods thanks to the development of new reagents and catalysts. This Primer aims to provide an overview of state-of-the-art strategies in fluorination, trifluoromethylation, difluoromethylation and monofluoromethylation, with an emphasis on using C–H functionalization, although other strategies for fluorination and fluoroalkylation are also discussed. Further landmark achievements are expected in the fields of fluorination and fluoroalkylation as organofluorine compounds are used increasingly in everyday applications. This Primer describes contemporary fluorination and fluoroalkylation reactions in chemical synthesis. The authors describe the main fluorination and fluoroalkylation reactions. The many applications of these reactions in pharmaceuticals, imaging agents and agriculture are discussed, along with the history and future of synthetic organofluorine chemistry.

Described here is the radical-mediated hydrodifluoromethylation of alkenes that occurs under transition-metal-free conditions by using the phosphonium salt [Ph3P+CF2H]Br− under the irradiation of 26 W household compact fluorescent light. The reaction lends itself to a convenient protocol for the installation of a C–CF2H bond while maintaining good functional group tolerance.

To provide feasible methods for the extraction of valuable metals from spent batteries or low-grade primary ores, the extraction behavior of some representative acidic phosphorus-containing compounds (APCCs) as extractants is evaluated from the perspective of experimental and theoretical investigations in this work. Aqueous solutions containing five metal ions, Ca(II), Co(II), Mg(II), Mn(II), and Ni(II), were made to simulate leaching liquids, and the extraction of these metals was investigated. A simplified calculated model was used to evaluate the interaction between each extractant and metal ions. The calculation results agree well with the experimental tests in trend. This work not only provides potential extractants for the extraction of valuable metals from spent batteries or low-grade primary ores but also demonstrates the practicability of the simplified calculation model.

Ag-mediated trifluoromethylthiolation of inert Csp3–H bond with CF3SOCl is described. Widely available reagents and operational simplicity make this protocol attractive.

Molecular acidity of trivalent rare-earth metal cations in aqueous solution is an important factor dedicated to the efficiency of their extraction and separation processes. In this work, the aqueous acidity of these metal ions has been quantitatively investigated using a few theoretical approaches. Our computational results expressed in terms of pKa values agree well with the tetrad effect of trivalent rare-earth ions extensively reported in the extraction and separation of these elements. Strong linear relationships have been observed between the acidity and quantum electronic descriptors such as the molecular electrostatic potential on the acidic nucleus and the sum of the valence natural atomic orbitals energies of the dissociating proton. Making use of the predicted pKa values, we have also predicted the major ionic forms of these species in the aqueous environment with different pH values, which can be employed to rationalize the behavior difference of different rare-earth metal cations during the ex...

The highly diastereoselective synthesis of CF3-containing vicinal diamines by a convenient two-step procedure without the need to isolate the intermediate products is described.

Trifluoromethylthiolation by sulfuration of difluorocarbene with elemental sulfur is described for the first time, which overrides long-standing trifluoromethyl anion-based theory. Mechanistic elucidation reveals an unprecedented chemical process for the formation of thiocarbonyl fluoride and also enables transition-metal-mediated trifluoromethylthiolation and [18 F]trifluoromethylthiolation of α-bromo carbonyl compounds with broad substrate scope and compatibility.

As a versatile intermediate, difluorocarbene is an electron-deficient transient species, meaning that its oxidation would be challenging. Herein we show that the oxidation of difluorocarbene could occur smoothly to generate carbonyl fluoride. The oxidation process is confirmed by successful trifluoromethoxylation, 18O-trifluoromethoxylation, the observation of AgOCF3 species, and DFT calculations., Difluorocarbene is a versatile and efficient intermediate for fluorine incorporation. Here, the authors show that difluorocarbene can be oxidized to carbonyl fluoride and this process is confirmed in 18O-trifluoromethoxylation reactions, by observation of AgOCF3 species and theory.

The differences of thermodynamics energies from the pure phase to a solution were used to predict the solubility properties of acidic phosphorus-containing rare-earth extractants. Four solvents, namely, tributylphosphate, n-dodecane, toluene, and n-octanol were used. The thermodynamic cycle of the implicit solvation model and the structure model with short carbon chains were used. The relationship obtained by simulation of the solubility properties and extractant structures agreed qualitatively with reported experimental results. These results provide guidance for the design of new efficient extractants.

The O-difluoromethylation of 1,3-diones with S-difluoromethyl sulfonium salt is described. The sulfonium salt was previously believed to be a direct difluoromethylation reagent, but our mechanistic investigation reveals that the O-difluoromethylation reaction proceeds not only via the direct transfer of the CF2H group, but also via a difluorocarbene process. This work represents the first protocol for mild O-difluoromethylation of acyclic 1,3-diones.

The hydroperfluoroalkylation of electron-deficient olefins with perfluoroalkyl iodides promoted by a zinc/viologen system is described. Interestingly, no iodoperfluoroalkylation product was observed without the presence of a radical H-donor.

In this work, the effect of the substituent at the α or β position in dialkylphosphinic acids on the extraction of trivalent lanthanide ions was investigated using experimental and theoretical methods. Five dialkylphosphinic acids were synthesized. Their extractions of seven trivalent lanthanide ions, La/Pr, Nd/Dy, and Ho/Yb/Lu, which represent light, middle, and heavy rare-earth metals, were explored. A simplified coordination model was built to explore the bonding between the extractants and lanthanide ions. The results obtained using this model generally explained the experimental results. The model could therefore be used to study the effects of the α and β substituents of extractants on their extraction properties. The theoretical and experimental results indicate that the significance of a β substituent in the dialkylphosphinic acid on extraction was greater than that of an α substituent.

Ag-mediated trifluoromethylthiolation of inert Csp

Molecular acidity of trivalent rare-earth metal cations in aqueous solution is an important factor dedicated to the efficiency of their extraction and separation processes. In this work, the aqueous acidity of these metal ions has been quantitatively investigated using a few theoretical approaches. Our computational results expressed in terms of pK

The first trifluoromethylthiolation and [(18)F]trifluoromethylthiolation of alkyl electrophiles with in situ generated difluorocarbene in the presence of elemental sulfur and external (radioactive) fluoride ion is described. This transition-metal-free approach is high yielding, compatible with a variety of functional groups, and operated under mild reaction conditions. The conceptual advantage of this exogenous-fluoride-mediated transformation enables unprecedented syntheses of [(18)F]CF3S-labeled molecules from most commonly used [(18)F]fluoride ions. The rapid radiochemical reaction time (≤1 min) and high functional-group tolerance allow access to a variety of aliphatic [(18)F]CF3S compounds in high yields.

Dialkylphosphinic acids were synthesised by a microwave-assisted method with high yields and wide substrate applicability. A structure–reactivity study indicates that an increase in steric hindrance in the β position led to a decrease of extraction ratio and heavy rare earth element separation activity. A computational study was also conducted to understand the steric effect.

Difluoromethylation of the activated X-H bond (X = N, O and S) and aliphatic thiols, and gem-difluorocyclopropenation of alkynes with difluorocarbene generated in situ from difluoromethylene phosphobetaine (Ph3P(+)CF2CO2(-)) by decarboxylation occurred smoothly without the presence of any base or other additives.

Dehydroxytrifluoromethylthiolation of alcohols with a Ph3P+CF2CO2–/S8/F– system is described. Difluorocarbene generated from Ph3P+CF2CO2– would readily combine with elemental sulfur to furnish S═CF2. S═CF2 can be considered as a bifunctional intermediate, activating alcohol and providing scaffold for CF3S– formation, thus allowing for the convenient dehydroxytrifluoromethylthiolation of alcohols.

The highly diastereoselective synthesis of CF

The fluorinated phosphonium salt (Ph3P+CF2CH3 BF4–) was shown to act as a nucleophilic 1,1-difluoroethylation agent to enable difluoroethylation of aldehydes and imines.

We discovered trifluoromethylthiolation occurred through sulfuration of difluorocarbene with elemental sulfur for the first time, which overrides our putative and long-standing trifluoromethyl anion-based theory. This mechanistic elucidation not only allows the discovery of an unprecedented chemical process for the formation of thiocarbonyl fluoride, but also enables transition metal-mediated trifluoromethylthiolation and [18F]trifluoromethylthiolation of α-bromo carbonyl compounds with broad substrate scope and compatibility.

An efficient method for the copper-catalyzed trifluoromethylation of terminal alkenes with an electrophilic trifluoromethylating reagent has been developed. The reactions proceeded smoothly to give trifluoromethylated alkenes in good to excellent yields. The results provided a versatile approach for the construction of Cvinyl–CF3 bonds without using prefunctionalized substrates.

Organic phosphonium salts have served as important intermediates in synthetic chemistry. But the use of a substituent on the positive phosphorus as a nucleophile to construct C–C bond remains a significant challenge. Here we report an efficient transition-metal-free protocol for the direct nucleophilic arylation of carbonyls and imines with tetraarylphosphonium salts in the presence of caesium carbonate. The aryl nucleophile generated from phosphonium salt shows low basicity and good nucleophilicity, as evidenced by the successful conversion of enolizable aldehydes and ketones. The reaction is not particularly sensitive to water, shows wide substrate scope, and is compatible with a variety of functional groups including cyano and ester groups. Compared with the arylmetallic reagents that are usually moisture sensitive, the phosphonium salts are shelf-stable and can be easily handled., Carbon based nucleophiles often are synthetically limited by the high basicity/reactivity of the starting materials. Here, the authors show that tetraarylphosphonium salts can be induced to act as C-aryl nucleophiles for the addition to carbonyls and imines.

Oxidative coupling of benzylamines to imines by molecular oxygen is efficiently realized in the presence of very low catalyst loadings of Co(II) β-tetrakis(trifluoromethyl)-meso-tetraphenylporphyrin. Due to the effect of four β-CF3 groups, the catalyst shows good selectivity and very high turnover number. The reaction is easily scaled up and may provide a convenient way to prepare many imines in large scale.

CF3-containing esters smoothly reacted with electron-deficient alkenes in the presence of a phosphine (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) organocatalyst at room temperature in an aerobic atmosphere. These Michael reactions efficiently provided products with a CF3 quaternary carbon center.

A new room-temperature ionic liquid has been synthesized from 2,2‘-bipyridine. This liquid improved the copper-catalyzed cross-coupling reactions between perfluoroalkyl or pentafluorophenyl halides and aryl iodides. Good recyclability using this solvent system was observed.

Neat reactions of 2,2'-biimidazole with an excess of alkyl or polyfluoroalkyl iodides at 140 degrees C, followed by anion exchange with LiN(SO(2)CF(3))(2) or KPF(6), gave the diquaternary salts 3a-k in80% yields. However, by controlling the reaction stoichiometry, 2,2'-biimidazole can also be monoquaternized with the same electrophiles at 100 degrees C under similar conditions. Subsequent metathesis reactions with LiN(SO(2)CF(3))(2) or KPF(6) resulted in the ionic liquids 4a-m in high yields. Thermal properties were determined with a differential scanning calorimeter (DSC) and a thermogravimetric analyzer (TGA). Most of the monoquaternary salts are room-temperature ionic liquids. 1,3,1'-Tributyl-2,2'-biimidazolium hexafluorophosphate was demonstrated to be an excellent solvent and ligand for palladium-catalyzed Suzuki cross-coupling reactions. The catalytic ionic liquid system may be recycled at least 14 times without a significant decrease in catalytic performance.