In 1989, Qing-Yun Chen's research group at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences reported the development of methyl fluorosulfonyldifluoroacetate (FSO2CF2CO2Me or MFSDA) as trifluoromethylation reagent. This reagent is now known as Chen's reagent, which is perhaps the first well-recognized and widely used trifluoromethylation reagent originate from China. Despite the widespread use of Chen's reagent in both academia and industry, the detailed mechanism underlying the conversion of Chen's reagent into a trifluoromethyl source has remained elusive. In this contribution, we conducted a thorough investigation into the reaction mechanism, employing density functional theory (DFT) calculations. Geometry optimizations and frequency analyses were performed using the omega BE0/def2-SVP level of theory. To ensure accurate electronic energy calculations, single-point energy calculations were conducted at the.B97X-D/def2-TZVPP level of theory. The solvent effects were considered using the solvation model density (SMD) model during both geometry optimizations and single-point energy calculations. Furthermore, Gibbs free energies were corrected with GoodVibes, employing Truhlar et al.'s quasi-harmonic treatment by setting all positive frequencies less than 100 to 100 cm(-1). Concentration corrections were applied from 1 atm to 1 mol/L. Our calculations reveal the detailed mechanism governing the generation of copper(I) trifluoromethyl from Chen's reagent in the presence of a CuI catalyst. An in-depth understanding of such mechanistic details would be helpful for future development of new reaction and application with Chen's reagent.

As 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 (CF2) and difluoromethyl (CF2H) 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 CF2 and CF2H 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 (TMSCF2Cl, 5), (bromodifluoromethyl)trimethylsilane (TMSCF2Br, 6), and (trifluoromethyl)trimethylsilane (TMSCF3, 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 TMSCF2X (X = Br, F, Cl) have stood out as privileged ones, which paves a new avenue for further developing difluorocarbene chemistry. In particular, TMSCF2Br was recognized as an all-rounder: TMSCF2Br can be applied in almost all common difluorocarbene-involved reactions, and more importantly, TMSCF2Br 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 TMSCF2X reagents (X = Br, F, Cl) now, the development of difluorocarbene chemistry will be accelerated in the years to come.

The physical and chemical properties of polymer strongly depend on the structures of the polymer chain. The structure studies range from the structure of repeat units and their mole fractions to more detailed microstructures, such as molecular weight and its distribution, the sequence of monomer units (block, gradient, alternating, graft, etc.), topology (stars, combs, networks, brushes, etc.), the end-functionalities and tacticity. Among them, the regulation of the polymer tacticity is greatly significant. For example, the stereospecific coordination polymerization of propylene has shown great commercial value. The control of macromolecular structure is difficult for free radical polymerization, although it is one of the most widely used polymerization techniques in the production of polymer materials. The development of reversible deactivated radical polymerization (RDRP) has significantly improved the control over the molecular weight of polymer. However, the regulation of stereoselectivity is extremely challenging for all forms of radical polymerization. One of the reasons is because a terminal carbon of propagating radical takes essentially a neutral sp(2) planar-like structure without counter species in contrast to an anionic sp(3) pyramidal or cationic sp(2) planar-like structure with counter ion or chiral catalyst site. This brings about a non-stereospecific radical propagation, and results in the energy difference between two enantiomers of an active radical species is small and the energy barrier between the enantiomers is low compared to the thermal energy at the polymerization temperature. In this review, the regulation of stereoselectivity in free radical polymerization are comprehensively summarized, evaluated, and prospected from the perspective of regulation strategies, including polymerization in restricted environment, using monomer containing chiral or bulky substituents, solvent (hydrogen bond) effect, the addition of Lewis acid and catalyst or ligand effect. Although these strategies have achieved some preliminary progress, there are still some problems in general, such as limited monomer scope, high solvent cost, complex reaction system, high Lewis acid loading, low catalytic efficiency and insignificant regulatory effect. The use of controlled radical polymerization catalysts to regulate stereoselectivity is of great potential. In the future, the studies on the radical asymmetric catalysis of small molecule can be used for reference to carefully design the structure of the catalyst and optimize the reaction conditions. In this way, the distance between the catalytic center and the terminal radical of the polymer chain is narrowed, and a confined space environment is created to enhance the stereochemical influence of the catalyst structure on the radical addition polymerization process.

In recent decades, the development of traditional energetic materials has encountered a bottleneck. How to continue to improve the energy level and break the bottleneck has become an urgent problem in the field of energetic materials. Fluorine is a stronger oxidizing agent than oxygen, and theoretically the introduction of fluorine can further increase energy density. Thirteen kinds of energetic molecules containing (difluoramino)dinitromethyl substituted heteroaromatic rings were designed. To ensure the possibility of synthesis, all the structural designs are based on existing intermediates and could be transformed into target molecules through mature synthesis methodologies. The molecular structure, initial thermal decomposition mechanism and energy characteristics were studied theoretically with density functional theory (DFT) methods (B3LYP/6-311+G(d,p) and M06-2X/6-311+G(d,p)) using Gaussian16 program. By calculating the mechanism of the initial decomposition reaction, the trigger bond was determined to be one of the C-NO2 bonds in the (difluoramino)dinitromethyl group. Dynamic stability is evaluated by the energy barrier of the trigger bond breaking. The results show that most of these molecules have sufficient dynamic stability, the initial decomposition reaction barriers are around 30 kcal/mol. The relationship between the molecule structure and the dynamic stability is revealed. The carbon radical center in the transition state is connected with the strong electron-withdrawing groups (-NO2 and -NF2) and the heterocyclic ring with a certain electron-donating ability. This is a typical push-pull electronic structure, which makes the free radical particularly stable. Therefore, the homo-cleavage energy barrier of the trigger bond is determined by the stabilizing effect of heterocyclic rings on the methyl free radicals. The energy properties of these molecules were theoretically evaluated with nitrate ester plasticized polyether (NEPE) solid propellant formulations using EXPLO5 program. The results show that the specific impulse of one dynamic stable molecule is up to 280.1 s, which is about 8.4 s higher than that of the traditional HMX (Octogen) formulations.

Transition-metal-catalyzed asymmetric alkylation of aldehydes represents a straightforward strategy for the synthesis of chiral secondary alcohols. However, efficient methods using organoborons as coupling reagents are rare. Herein, we report a highly enantioselective nickel-catalyzed alkylation reaction of aldehydes, using readily available alkylborons as nucleophiles. A wide variety of chiral secondary alcohols were prepared from commercially available aldehydes with high yields. The key to the excellent enantioselectivity and chemoselectivity was the employment of a bulky C-2-symmetric chiral NHC ligand. This protocol features excellent enantiocontrol, mild conditions, and good functional group compatibility.

Difluorocarbene has found widespread applications in the synthesis of fluorine-containing molecules. We have previously found that difluorocarbene can react with elemental sulfur to produce thiocarbonyl fluoride, which is of great value for the new discoveries of difluorocarbene chemistry and the investigations of synthetic utilities of thiocarbonyl fluoride. We have developed the transformation of difluorocarbene into thiocarbonyl fluoride as a synthetic tool to achieve trifluoromethylthiolation of terminal alkynes and alkyl halides. In continuation of our research interest in this chemistry, herein we further apply the difluorocarbene transformation to the trifluoromethylthiolation of aryl and alkenyl iodides. Trifluoromethylthiolation is an active research area in organofluorine chemistry, and the commonly used trifluoromethylthiolation methods usually require the use of expensive CF3S-containing reagents. In contrast, in our protocol the CF3S group is generated in situ from difluorocarbene, elemental sulfur and a fluoride anion, all of which are cheap and easily available reagents. The general experimental procedure is shown as follows. Into a 5 mL sealed tube were added 4-phenyl phenyl iodide (1a, 56.0 mg, 0.2 mmol), S (57.8 mg, 1.8 mmol), Ph3P(+)CF(2)CO(2)(-) (PDFA) (213.8 mg, 0.6 mmol), AgF (0.5 mmol, 63.4 mg), ligand L-1 (0.6 mmol, 158.9 mg), CuI (76.2 mg, 0.4 mmol), and dioxane (1.0 mL) under a N-2 atmosphere. The reaction mixture was stirred at 110 degrees degrees C for 8 h. After the reaction system was cooled to room temperature, Et3N (0.5 mL) was added to remove the excess elemental sulfur by a redox reaction (the final product would be contaminated by elemental sulfur if elemental sulfur was not removed). The mixture was diluted with 10 mL of saturated brine, and then the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to 1 mL. The residue was subjected to flash column chromatography to afford the pure product.

Due to the unique properties of fluorine atom(s), the introduction of fluorinated functional groups into molecules has become one of the powerful strategies in the discovery of new pharmaceuticals, agrochemicals, and advanced functional materials. Consequently, considerable efforts have been made to develop new and efficient methods for preparing organofluorine compounds. Among the fluorine functionalities, the gem-difluoroallyl group represents one of the attractive moieties due to the unique properties of the difluoromethylene group (CF2) and the synthetic versatility of the carbon-carbon double bond. Over the past decade, important progress has been made in the catalytic gem-difluoroallylation reactions. However, the efficient methods for the preparation of gem-difluoroallyl arenes remain limited despite their important applications in medicinal chemistry. Here, we report a palladium-catalyzed gem-difluoroallylation of heteroaryl bromides with gemdifluoroallylboronates. The reaction proceeds under mild conditions with high efficiency, high functional group tolerance, and excellent regioselectivity. A series of heteroaryl bromides are applicable to the reaction, providing facile access to gem-difluoroallyl heteroarenes of medicinal interest. A representative procedure for the palladium-catalyzed cross-coupling of heteroaryl bromides with gem-difluoroallylborons is as following: heteroaryl bromide (0.40 mmol, 1.0 equiv.) and (P(t-Bu)(2)Ph)(2)center dot PdCl2 (3.0 mol%) were added to a 25 mL of Schlenck tube. The tube was then evacuated and backfilled with Ar (3 times). CsF (2.0 equiv.), gem-difluoroallylboron (0.44 mmol, 1.1 equiv.), and 1,4-dioxane (2.0 mL) were added under Ar. The tube was screw capped and put into a preheated oil bath (100 degrees C). After stirring for 2 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (2.0 mL). The yield was determined by F-19 NMR using fluorobenzene (1.0 equiv.) as an internal standard before working up. If necessary, the reaction mixture was diluted with EtOAc and filtered with a pad of cellite. The filtrate was concentrated, and the residue was purified with silica gel chromatography to give product 11.