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Research has been conducted on tri- and difluoromethylsilanes. The authors describe the preparation of these compounds via the use of magnesium metal-mediated reductive tri- and difluoromethylation of chlorosilanes.

ConspectusAs fluorine has played an increasingly important role in modulating the physical, chemical, and biological properties of organic molecules, the selective introduction of fluorine atom(s) or fluorinated moieties into target molecules has become a powerful tool in the development of new pharmaceuticals, agrochemicals, and functional materials. In this context, the difluoromethylene (CF 2 ) and difluoromethyl (CF 2 H) groups are of special interest because of their ability to serve as bioisosteres of ethereal oxygen atoms and hydroxyl (OH) and thiol (SH) groups, respectively. Difluorocarbene is one of the most versatile reactive intermediates to incorporate CF 2 and CF 2 H groups; however, before 2006, most of the previously known difluorocarbene reagents suffered from several drawbacks such as using ozone-depleting substances (ODSs), difficult-to-handle reagents, or harsh reaction conditions or having narrow substrate scope and/or low yields. Moreover, the reactivity of difluorocarbene generated from different precursors (reagents) was often unpredictable, since the difluorocarbene generation conditions (activation modes) of various difluorocarbene precursors are different, and these conditions may mismatch those required for subsequent difluorocarbene-involved transformations. Therefore, the development of new environmentally friendly and versatile difluorocarbene reagents, as well as the investigation of the mechanistic insights into difluorocarbene-involved reactions, has been highly desirable.In this Account, we summarize our contributions to the development of new difluorocarbene reagents and their applications in organic synthesis since 2006. We have developed seven new difluorocarbene reagents, including 2-chloro-2,2-difluoroacetophenone ( 1 ), chlorodifluoromethyl phenyl sulfone ( 2 ), S -difluoromethyl- S -phenyl- N -tosylsulfoximine ( 3 ), difluoromethyltri( n -butyl)ammonium chloride ( 4 ), (chlorodifluoromethyl)trimethylsilane (TMSCF 2 Cl, 5 ), (bromodifluoromethyl)trimethylsilane (TMSCF 2 Br, 6 ), and (trifluoromethyl)trimethylsilane (TMSCF 3 , 7 ). In this journey, we realized the key factor for an ideal difluorocarbene reagent that can be used for a broad range of reactions, that is, the reagent should allow various activation modes for the generation of difluorocarbene species, such as under basic/acidic/neutral conditions, at wide range of temperatures, and in different solvents, which are compatible with a wide range of difluorocarbene-involved transformations. Among all known difluorocarbene reagents, silanes TMSCF 2 X (X = Br, F, Cl) have stood out as privileged ones, which paves a new avenue for further developing difluorocarbene chemistry. In particular, TMSCF 2 Br was recognized as an "all-rounder": TMSCF 2 Br can be applied in almost all common difluorocarbene-involved reactions, and more importantly, TMSCF 2 Br also enables many other novel transformations that other difluorocarbene reagents cannot achieve, thanks to its unique structure and rich activation modes of releasing difluorocarbene under different reaction conditions. It can be expected that with the commercial availability of TMSCF 2 X reagents (X = Br, F, Cl) now, the development of difluorocarbene chemistry will be accelerated in the years to come.

A new difluoroalkylation reagent Sulfox-CF 2 SO 2 Ph bearing both sulfoximine and sulfone moieties was prepared from commercially available SulfoxFluor and PhSO 2 CF 2 H. On one hand, the Sulfox-CF 2 SO 2 Ph reagent could act as a (phenylsulfonyl)difluoromethyl radical source under photoredox catalysis, in which the arylsulfoximidoyl group is selectively removed. On the other hand, under basic conditions, Sulfox-CF 2 SO 2 Ph could serve as a difluorocarbene precursor for S- and O-difluoromethylations with S- and O-nucleophiles, respectively, in which the phenylsulfonyl group in Sulfox-CF 2 SO 2 Ph is selectively removed (followed by α-elimination of the arylsulfoximidoyl group).

Controllable fluorocarbon chain elongation (CFCE) is a promising yet underdeveloped strategy for the well-defined synthesis of structurally novel polyfluorinated compounds. Herein, the direct and efficient trifluorovinylation and pentafluorocyclopropylation of aldehydes are described by using TMSCF 2 Br (TMS = trimethylsilyl) as the sole fluorocarbon source, accomplishing the goals of CFCE from C 1 to C 2 and from C 1 to C 3 , respectively. The key to the success of these CFCE processes lies in the unique and diversified chemical reactivity of TMSCF 2 Br, which can serve as two different precursors, namely, a TMSCF 2 radical precursor and a difluorocarbene precursor. Various functional groups are amenable to this new synthetic protocol, providing streamlined access to a broad range of alcohols containing trifluorovinyl or pentafluorocyclopropyl moieties from abundantly available aldehydes. The potential utility of these methods is further demonstrated by the gram-scale synthesis, derivatization, and measurement of log P values of the products.

Fluorinated carbon dots (FCDs) have garnered interest owing to their distinct physicochemical properties. Nevertheless, intricate synthesis procedures and quite low fluorine doping levels limit its development and application. Herein, we propose a facile approach based on the Claisen-Schmidt reaction to realize gram-scale synthesis of highly fluorinated carbon dots (up to 20.79 at. %) at room temperature and atmospheric pressure, and a comprehensive exploration of the specific reaction mechanism is conducted. Furthermore, in consideration of the high fluorine content, good dispersibility, and compatibility with polymer electrolyte, the synthesized FCDs are utilized as an additive for PEO-based solid electrolytes of a Li battery to improve its ionic conductivity, interface stability, and mechanical properties. The introduction of FCDs can not only reduce the crystallinity of PEO and enhance the interaction of polymer chains, but also facilitate the establishment of uninterrupted pathways and in situ fluorination at the interface, which is substantiated by both theoretical calculations and experimental findings. As a result, the lithium symmetrical battery can operate stably for 1000 h at a current density of 0.4 mA cm -2 . Simultaneously, the LiFePO 4 /Li battery utilizing the composite electrolyte exhibits a capacity of 130.3 mAh g -1 over 300 cycles while maintaining a capacity retention rate of 95.10%. This study develops a strategy for synthesizing highly fluorinated carbon dots, which demonstrate a useful influence on PEO electrolytes, thus boosting the advancement of FCDs and solid-state batteries.

The selective introduction of perfluoro- tert -butyl group (PFtB, the bulkier analogue of CF 3 group) into arenes has long been sought after but remains a formidable task. We herein report the first general synthetic protocol to realize aromatic perfluoro- tert -butylation. The key to the success is the identification of PFtB phenyl sulfone as a new source of PFtB anion, which reacts with arynes in a highly regioselective manner to afford perfluoro- tert -butylated arenes in high yields. The application of the method is demonstrated by the preparation of sensitive 19 F-labeled NMR probes with an extraordinary resolving ability.

The selective difluoromethylene insertion into a C-Cu bond is a challenging task and is currently limited to either a single CF 2 insertion into CuCF 3 or double CF 2 insertions into CuC 6 F 5 (or ( Z )-CF 3 CF = CFCu). Achieving both selective single and double CF 2 insertions into the same C-Cu bond is even more difficult. Herein, highly controllable single and double CF 2 insertions into CuCF 2 H species with a TMSCF 2 Br reagent have been described, affording two previously unknown fluoroalkylcopper species "Cu(CF 2 ) n CF 2 H" ( n = 1 and 2) independently under different reaction conditions. This work represents the first example of both single and double CF 2 insertions into the same C-Cu bond in a highly selective manner. The synthetic value of the obtained "Cu(CF 2 ) n CF 2 H" ( n = 1 and 2) species is demonstrated by their reactions with aryl iodides, halogenation agents, and cinnamyl chloride, which enables the direct transfer of HCF 2 CF 2 and HCF 2 CF 2 CF 2 moieties into organic molecules. The key to controllable fluorocarbon chain elongation from C 1 to C 2 and from C 1 to C 3 is presumably attributed to the different reactivities of "Cu(CF 2 ) n CF 2 H" species ( n = 0, 1, 2 and 3) and the loading of the TMSCF 2 Br reagent.

Aryl perfluorocyclopropyl ethers have been synthesized for the first time by [2 + 1] cyclopropanation between aryl trifluorovinyl ethers and a commercially available TMSCF 2 Br reagent. This cycloaddition reaction between two fluorine-containing reactants proceeds smoothly in toluene at 120 °C in the presence of a catalytic amount of n -Bu 4 NBr, and the reaction tolerates a variety of functional groups. A wide range of aryl trifluorovinyl ethers, easily accessible from phenols, were successfully transformed to aryl perfluorocyclopropyl ethers.

A copper-mediated cross-coupling reaction between a diazo compound and a sodium alkane(arene)sulfinate gives a sulfone as the product. This reaction proceeds under mild conditions and features excellent functional group compatibility. A wide range of sodium alkane(arene)sulfinates were successfully applied in this chemistry. Mechanistic studies revealed that the overall reaction efficiency of the sulfinates was in line with their nucleophilicity in this reaction.

3,3-Difluoro-1,2-diphenylcyclopropene (CpFluor), a bench-stable fluorination reagent, has been developed in the deoxyfluorination of carboxylic acids to afford various acyl fluorides. This all-carbon-based fluorination reagent enabled the efficient transformation of (hetero)aryl, alkyl, alkenyl, and alkynyl carboxylic acids to the corresponding acyl fluorides under the neutral conditions. This deoxyfluorination method was featured by the synthesis of acyl fluorides with in-situ formed CpFluor, as well as the one-pot amidation reaction of carboxylic acids via in-situ formed acyl fluorides.

An efficient method for nucleophilic (phenylsulfonyl/arylthio)difluoromethylation of aldehydes with TMSCF 2 Br was developed. The reaction proceeds through in situ generation of difluorocarbene, which is captured by PhSO 2 Na or ArSNa to form the corresponding PhSO 2 CF 2 - or PhSCF 2 - anions, followed by nucleophilic addition to aldehydes to give the desired difluoromethylated products.

A mild cross-coupling reaction of heteroaryl sulfinates with Grignard reagents has been developed under transition-metal-free conditions. This study provides an example of the SO 2 2- as a leaving group in an aromatic system and an effective methodology for the construction of C-C bond.

We report the first iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone via selective C-S bond cleavage. This method employs the readily available, bench-stable fluoroalkyl sulfone reagent and inexpensive iron catalyst, allowing facile access to structurally diverse difluoromethylated arenes at low temperatures. The experiment employing a radical clock indicates the involvement of radical species in this iron-catalyzed difluoromethylation process.

An atom-economical method for radical (phenylsulfonyl)difluoromethylation of isocyanides with PhSO 2 CF 2 H under transition-metal-free conditions has been developed. A PhSO 2 CF 2 radical is generated through the oxidation of PhSO 2 CF 2 - after the deprotonation of PhSO 2 CF 2 H in one pot. The reaction exhibits excellent functional-group tolerance and the resulting products can be further modified with the removal of a PhSO 2 group to give other CF 2 -containing compounds.

A new strategy for the synthesis of aryl trifluoromethyl ethers (ArOCF3) by combining O-carboxydifluoromethylation of phenols and subsequent decarboxylative fluorination is reported. This protocol allows easy construction of functionalized trifluoromethoxybenzenes and trifluoromethylthiolated arenes (ArSCF3) in moderate to good yields. Moreover, it utilizes accessible and inexpensive reagents sodium bromodifluoroacetate and SelectFluor II and, thus, is practical for O-trifluoromethylation of phenols. The potential application of this method is demonstrated with the preparation of a plant-growth regulator, Flurprimidol.

A new, efficient method for iododifluoromethylation of carbonyl compounds utilizing difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) is described. This transformation is achieved by a nucleophilic addition of 2-PySO2CF2H with carbonyl compounds and a subsequent iodination of sulfinate, which is generated in situ by a novel zinc-mediated depyridination reaction. The method employs mild reaction conditions, exhibits excellent functional-group tolerance, and can be used in the synthesis of various iododifluoromethylated carbinols.

A one-pot trifluoromethylthiolation-iodination of arynes with trifluoromethylthiosilver (AgSCF3) and 1-iodophenylacetylene is described. This protocol allows rapid construction of o-trifluoromethylthiolated arene building blocks in moderate yields. These products were found to be excellent precursors for Yagupolskii-Umemoto-type electrophilic trifluoromethylation reagents.

An efficient copper-catalyzed trifluoromethylation of polysubstituted alkenes assisted by decarboxylation of β,γ-unsaturated carboxylic acids has been achieved. The reaction provides a general method to construct allylic and vinylic CF3-substituted compounds under mild conditions.

A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.

The first palladium-catalyzed direct monofluoromethylation of arylboronic esters to produce monofluoromethyl arenes is reported. The reaction is typically carried out at room temperature within 4 h and has a good functional group tolerance. The monofluoromethylating agent, CH2FI, was readily prepared via a halogen-exchange process.

The monofluoroalkene motif is important in drug development as it serves as a peptide bond isostere and is found in a number of biologically active compounds with various pharmacological activities. Direct olefination of carbonyl compound is a straightforward way to prepare monofluoroalkenes; however, these methods often result in a mixture of Z- and E-isomers that cannot be easily separated. We discovered a unique spontaneous resolving reaction that simultaneously addresses the problems in the synthesis and separation of Z- and E-monofluoroalkenes. The reaction is accompanied by a highly efficient spontaneous kinetic resolution and phase labeling of monofluoroalkene precursors which allows the separation of Z- and E-monofluoroalkenes by liquid-liquid extraction. The application of the method is demonstrated by the synthesis and separation of potential anticancer agents, which are inseparable by HPLC.

Fluorinated sulfinate salts RfSO2Na (Rf = CF2H, CF2Ph, and CH2F) have been prepared via NaBH4-mediated reduction of the corresponding benzo[d]thiazol-2-yl sulfones, and their synthetic application as di- and monofluoroalkyl radical precursors is demonstrated in the silver-catalyzed cascade fluoroalkylation/aryl migration/SO2 extrusion of conjugated N-arylsulfonylated amides.

Reference electrodes are used in almost every electroanalytical measurement. Here, all-solid-state reference electrodes are described that employ colloid-imprinted mesoporous (CIM) carbon as solid contact and a poly(vinyl chloride) reference membrane to contact the sample. Such a reference membrane is doped with a moderately hydrophilic ionic liquid and a hydrophobic redox couple, leading to well-defined constant potentials at the interfaces of this membrane to the sample and to the solid contact, respectively. Due to the intrinsic properties of CIM carbon, reference electrodes with a CIM carbon solid contact exhibit excellent resistance to common interfering agents such as light and O2, with outstanding potential stability in continuous potentiometric measurements. The potential drift of CIM carbon-based reference electrodes without redox couple is as low as 1.7 μV/h over 110 h, making them the most stable all-solid-state reference electrodes reported so far. To demonstrate the compatibility of CIM carbon-based reference electrodes with miniaturized potentiometric systems, these reference electrodes were integrated into paper-based potentiometric sensing devices, successfully replacing the conventional reference electrode with its reference electrolyte solution. As a proof of concept, disposable paper-based Cl(-) sensing devices that contain stencil-printed Ag/AgCl-based Cl(-) selective electrodes and CIM carbon-based reference electrodes were constructed. These sensing devices are inexpensive, easy to use, and offer highly reproducible Cl(-) measurements with sample volumes as low as 10 μL.

A new method for the generation of trifluoromethylcopper ("CuCF3") species from readily available phenyl trifluoromethyl sulfoxide has been developed. The "CuCF3" reagent can be applied in efficient trifluoromethylations of aryl iodides and activated aryl bromides in the absence of additional ligands. Furthermore, the "CuCF3" species can also undergo oxidative cross-coupling with terminal alkynes and arylboronic acids.

This paper describes the design and fabrication of ion-sensing electrochemical paper-based analytical devices (EPADs) in which a miniaturized paper reference electrode is integrated with a small ion-selective paper electrode (ISPE) for potentiometric measurements. Ion-sensing EPADs use printed wax barriers to define electrochemical sample and reference zones. Single-layer EPADs for sensing of chloride ions include wax-defined sample and reference zones that each incorporate a Ag/AgCl electrode. In EPADs developed for other electrolytes (potassium, sodium, and calcium ions), a PVC-based ion-selective membrane is added to separate the sample zone from a paper indicator electrode. After the addition of a small volume (less than 10 μL) of sample and reference solutions to different zones, ion-sensing EPADs exhibit a linear response, over 3 orders of magnitude, in ranges of electrolyte concentrations that are relevant to a variety of applications, with a slope close to the theoretical value (59.2/z mV). Ion-selective EPADs provide a portable, inexpensive, and disposable way of measuring concentrations of electrolyte ions in aqueous solutions.