C-CF3 Bond Research Articles

An Organocopper(III) Fluoride Triggering C-CF3 Bond Formation.

Copper(III) fluorides are catalytically competent, yet elusive, intermediates in cross-coupling. The synthesis of [PPh4 ][CuIII (CF3 )3 F] (2), the first stable (isolable) CuIII -F, was accomplished via chloride addition to [CuIII (CF3 )3 (py)] (1) yielding [PPh4 ][CuIII (CF3 )3 Cl(py)] (1⋅Cl), followed by treatment with AgF. The CuIII halides 1⋅Cl and 2 were fully characterized using nuclear magnetic resonance (NMR) spectroscopy, single crystal X-ray diffraction (Sc-XRD) and elemental analysis (EA). Complex 2 proved capable of forging C-CF3 bonds from silyl-capped alkynes. In-depth mechanistic studies combining probes, theoretical calculations, trapping of intermediate 4a ([PPh4 ][CuIII (CF3 )3 (C≡CPh)]) and radical tests unveil the key role of the CuIII acetylides that undergo facile 2e- reductive elimination furnishing the trifluoromethylated alkynes (RC≡CCF3 ), which are industrially relevant synthons in drug discovery, pharma and agrochemistry.

Mechanochemical Defluorinative Arylation of Trifluoroacetamides: An Entry to Aromatic Amides

The amide bond is prominent in natural and synthetic organic molecules endowed with activity in various fields. Among a wide array of amide synthetic methods, substitution on a pre-existing (O)C-N moiety is an underexplored strategy for the synthesis of amides. In this work, we disclose a new protocol for the defluorinative arylation of aliphatic and aromatic trifluoroacetamides yielding aromatic amides. The mechanochemically induced reaction of either arylboronic acids, trimethoxyphenylsilanes, diaryliodonium salts, or dimethyl(phenyl)sulfonium salts with trifluoroacetamides affords substituted aromatic amides in good to excellent yields. These nickel-catalyzed reactions are enabled by C-CF3 bond activation using Dy2O3 as an additive. The current protocol provides versatile and scalable routes for accessing a wide variety of substituted aromatic amides. Moreover, the protocol described in this work overcomes the drawbacks and limitations in the previously reported methods.

Pyrolysis and oxidative decomposition mechanism of trifluoromethylated fused triazinones

The pyrolysis and oxidative decomposition courses of a novel class of trifluoromethylated fused triazinones by using a Simultaneous thermal analysis (STA) coupled online with the Fourier transform infrared spectroscopy (FTIR) and the Quadrupole mass spectrometry (QMS) were determined. It was found that the pyrolysis and oxidation processes of these compounds run through simultaneous, radical processes in one, main stage in both: helium and air atmospheres. The FTIR and QMS analyses allowed confirming the simultaneous cleavage of CCF3, CN, NN, and CCl bonds, formation of radical intermediates, reactions of radical intermediates with each other in a gaseous phase leading to the formation of final volatile products such as RNCO, CF3CN, CF3H, HCOCOH, alkenes, aromatic amine derivatives, CO2 and H2O in inert conditions as well as RNCO, CF3CN, CF3H, HCOCOH, alkenes, aromatic amine derivatives, CO2, CO and H2O in oxidative conditions. Moreover, the favourable thermal properties and high purity were highlighted in evaluating the suitability of trifluoromethylated compounds as potential candidates for pharmaceutical applications.

Direct C(sp3 )-H Trifluoromethylation of Unactivated Alkanes Enabled by Multifunctional Trifluoromethyl Copper Complexes.

A mild and operationally simple C(sp3 )-H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench-stable CuIII complex, bpyCu(CF3 )3 , as the initiator of the visible-light photoinduced reaction, the source of a trifluoromethyl radical as a hydrogen atom transfer reagent, and the source of a trifluoromethyl anion for functionalization. The reaction was initiated by the generation of reactive electrophilic carbon-centered CF3 radical through photoinduced homolytic cleavage of bpyCu(CF3 )3 , followed by hydrogen abstraction from an unactivated C(sp3 )-H bond. Comprehensive mechanistic investigations based on a combination of experimental and computational methods suggested that C-CF3 bond formation was enabled by radical-polar crossover and ionic coupling between the resulting carbocation intermediate and the anionic CF3 source. The methylene-selective reaction can be applied to the direct, late-stage trifluoromethylation of natural products and bioactive molecules.

Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study.

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza‐Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C−F stereocentre in high enantioselectivity, and is also amenable to stereogenic C−CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate‐determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran‐type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.

ReaxFF reactive force field development and application for molecular dynamics simulations of heptafluoroisobutyronitrile thermal decomposition

Heptafluoroisobutyronitrile (i-C3F7CN, C4) has obtained widely attention accounts for its good dielectric property and low GWP as a potential alternative gas. To investigate the thermal decomposition characteristics of C4, new reactive force field (ReaxFF) parameters were developed by training against QM-derived calculations with Monte Carlo Annealing (MC) method. The reliability of new parameters was verified not only by the deviations between QM-based calculations and ReaxFF predictions but also by good agreement between molecular dynamics (MD) simulations and experimental results. Hence, various NVT-MD simulations were employed to determine the reaction mechanisms, rate constants and product distributions. Our simulation results showed that the C4 decay was fitted with first-order kinetic expression, and the apparent activation energy was predicted to be 33.9 ± 1.67 kcal/mol. The main products of C4 decomposition were CF4, C2F6, C3F6, FCN, CF3CN, C2F5CN, which were in accordance with experimental and theoretical results. As for the initial reactions, we noted that C-CF3 bond was revealed to be the weakest bond and followed by C-F and C-CN bonds in C4 as reported in previous work. Similar MD simulation was conducted with C4/CO2 mixture system, which suggested that CO2 could consume F and CF3 radicals, resulting in significant impacts for CF4 and FCN. Noteworthy, new products (CO, COF2) were also seen as observed experimentally. To investigate the C4/CO2 system under the moisture condition, C4/CO2 with 1% H2O content was performed and new toxic gas HF was observed as a characteristic product, indicating an unnegligible impact by water content.

Barbier Self-Condensing Ketyl Polymerization-Induced Emission: A Polarity Reversal Approach to Reversed Polymerizability.

SummaryCarbon-carbon bond formation through polarity reversal ketyl radical anion coupling of carbonyls has inspired new reaction modes to this cornerstone carbonyl group and played significant roles in organic chemistry. The introduction of this resplendent polarity reversal ketyl strategy into polymer chemistry will inspire new polymerization mode with unpredicted discoveries. Here we show the successful introduction of polarity reversal ketyl approach to polymer chemistry to realize self-condensing ketyl polymerization with polymerization-induced emission. In this polarity reversal approach, it exhibits intriguing reversed polymerizability, where traditional excellent leaving groups are not suitable for polymerization but challenging polymerizations involving the cleavage of challenging C-F and C-CF3 bonds are realized under mild Barbier conditions. This polarity reversal approach enables the polymer chemistry with polarity reversal ketyl mode, opens up a new avenue toward the polymerization of challenging C-X bonds under mild conditions, and sparks design inspiration of new reaction, polymerization, and functional polymer.

Experimental and theoretical analysis on decomposition and by-product formation process of (CF3)2CFCN mixture

Although sulfur hexafluoride (SF6) is widely used in gas-insulated electrical equipment due to the excellent electrical insulation and arc-interruption behaviors, its strong greenhouse effect with high glow warming potential (GWP) has been driving the research on environmentally friendly gases for SF6 alternatives. Recently, the heptafluoro-isobutyrontrile (CF3)2CFCN (3M NovecTM 4710) is reported to have the potential to replace SF6. The decomposition characteristic of gas insulating medium is one of the basic conditions to measure whether it has the feasibility of replacing SF6. However, the decomposition characteristic of (CF3)2CFCN and the formation mechanism of by-products are still unclear. In this paper, a series of AC corona discharge experiments were performed, and the gas by-products of (CF3)2CFCN mixed with CO2, N2 and air were qualitatively analyzed by gas chromatography mass spectrometry (GC/MS) method, respectively. Then, the decomposition mechanism of (CF3)2CFCN molecule and the formation mechanism of gas by-products were studied via density functional theory (DFT) method. The results show that the major gas by-products are CO, CO2, C2O3F6, CF4, C2F6, C3F6, C3F8, C2F4, (CF3)3CF, CF3CN, C2F5CN and CNCN, in addition to trace amounts of F3CC≡CCF3 and CF3CF=CFCF3. Among the three initial dissociation pathways of (CF3)2CFCN molecule, a C-CF3 bond fission pathway that produces CF3CFCN and CF3 radicals is identified as the thermodynamically favorable channel. The bond energy of C–CF3 bond calculated at M06-2X/def2-QZVP//M06-2X/6-311G(d,p) level is 94.7 kcal/mol.

Synthesis and Reactivity of Mn–CF3 Complexes

The synthesis, characterization and reactivity of several bi- and tridentate, N-ligated manganese carbonyl trifluoromethyl complexes are presented. These complexes exhibit elongated Mn–CCF3 bonds (versus Mn(CF3)(CO)5), suggesting a lability that could be utilized for the transfer or insertion of the CF3 functional group into organic substrates. Unlike their Mn–X congeners (X = Cl, Br), these Mn–CF3 complexes exhibit a preference for hard donor ancillary ligands, thus enabling the synthesis of 4 N-ligated Mn–CF3 complexes including a mixed-donor tridentate complex using an NNS Schiff base ([2-(methylthio)-N-(1-(pyridin-2-yl)ethylidene)aniline]). Although we have not yet identified efficient CF3 transfer reactions, fluoride abstraction from the Mn–CF3 complexes using trimethylsilyl triflate affords the first stable Mn fluorocarbenes as evidenced by 19F NMR spectroscopy.

Mechanistic and Kinetic Investigations on the Thermal Unimolecular Reaction of Heptafluoroisobutyronitrile.

Heptafluoroisobutyronitrile (C4) has been utilized as a dielectric compound to replace sulfur hexafluoride for the sake of environmental concern. Energetic profiles of the potential energy surface for the unimolecular reaction of C4 were calculated using density functional theory (M06-2X), quadratic complete basis set (CBS-QB3), Gaussian-4, multireference Rayleigh-Schrodinger perturbation theory (RS2, RS2C), and state-averaged multiconfiguration self-consistent-field (SA-MCSCF) ab initio methods. Among 38 production channels, the most energetically accessible reaction path is the three-centered rearrangement of cyanide to isocyanide. The C-CF3 bond appears to be the weakest bond in C4(X1A') and the symmetry-breaking C-CF3 bond cleavage undergoes to form the ground-state CF3(X2A1) and CF3CFCN (X2A″) radicals. All the possible isomerization pathways involving F- and CF3-migration together with the concerted elimination and stepwise decomposition routes were revealed for C4 and i-C4. Various isomers and potential toxic byproducts including FCN, CF3CN, C2F5CN, CF2═CFCF3, CF2═CFCN, CF4, C2F6, and alkyne compounds have been identified for the first time. Master equation analysis has been carried out to obtain the temperature- and pressure-dependent thermal rate constants. Theoretical kinetics for the loss of C4 due to pyrolysis is in good agreement with the temperature-ramped flow-tube experiment. The present theoretical work provides new insights on the thermal stability and chemical reactivity of C4. Moreover, i-C4 and C2F6 are proposed to be the potential characteristic gas molecules to monitor the insulation breakdown of C4 in the electric equipment.

Transition-Metal-Free Conversion of Trifluoropropanamides into Cyanoformamides through C-CF3 Bond Cleavage and Nitrogenation.

A new transition-metal-free transformation of trifluoropropanamides into cyanoformamides through a sequence of C-CF3 bond cleavage and nitrogenation using tert-butyl nitrite as the nitrogen source is described. The method features direct detrifluoromethylation, broad substrate scopes, and excellent selectivity control, representing a new shortcut for constructing the nitrile group involving C-CF3 σ-bond cleavage.

Enantioselective α-C-H functionalization of amides with indoles triggered by radical trifluoromethylation of alkenes: Highly selective formation of C[sbnd]CF3 and C[sbnd]C bonds

A dual copper/chiral phosphoric acid-catalyzed asymmetric tandem remote C(sp3)-H/unactivated alkene functionalization reaction triggered by radical trifluoromethylation of unactivated alkenes for the concomitant construction of CCF3 and CC bonds was described. This approach provided an efficient method for the synthesis of valuable chiral trifluoromethylated indole derivatives with excellent regio-, chemo-, and good enantioselectivity.

ChemInform Abstract: Visible‐Light‐Induced Trifluoromethylation of Isonitrile‐Substituted Methylenecyclopropanes: Facile Access to 6‐(Trifluoromethyl)‐7,8‐dihydrobenzo[k]phenanthridine Derivatives.

A novel visible-light-induced trifluoromethylation of isonitrile-substituted methylenecyclopropanes is developed. A range of substituted 6-(trifluoromethyl)-7,8-dihydrobenzo[k]phenanthridine derivatives are readily furnished by this newly developed tandem trifluoromethylation reaction with moderate to good yields. This reaction allows the direct formation of two six-membered rings and three new C-C bonds including the C-CF3 bond under the irradiation by visible light.

Visible-Light-Induced Trifluoromethylation of Isonitrile-Substituted Methylenecyclopropanes: Facile Access to 6-(Trifluoromethyl)-7,8-Dihydrobenzo[k]phenanthridine Derivatives.

A new visible-light-induced trifluoromethylation of isonitrile-substituted methylenecyclopropanes is developed. A range of substituted 6-(trifluoromethyl)-7,8-dihydrobenzo[k]phenanthridine derivatives are readily furnished by this newly developed tandem reaction with moderate to good yields. This reaction allows the direct formation of two six-membered rings and three new C-C bonds, including the C-CF3 bond, under visible light irradiation.

Trifluoromethylation of Arylsilanes with [(phen)CuCF3

A method for the trifluoromethylation of arylsilanes is reported. The reaction proceeds with [(phen)CuCF3 ] as the CF3 source under mild, oxidative conditions with high functional-group compatibility. This transformation complements prior trifluoromethylation of arenes in several ways. Most important, this method converts arylsilanes formed by the silylation of aryl C-H bonds to trifluoromethylarenes, thereby allowing the conversion of arenes to trifluoromethylarenes. The unique capabilities of the reported method are demonstrated by the conversion of a C-H bond into a C-CF3 bond in active pharmaceutical ingredients which do not undergo this overall transformation by alternative functionalization processes, including a combination of borylation and trifluoromethylation.

Insights into the Mechanism and Kinetics of Thermo-Oxidative Degradation of HFPE High Performance Polymer.

The growing requisite for materials having high thermo-oxidative stability makes the design and development of high performance materials an active area of research. Fluorination of the polymer backbone is a widely applied strategy to improve various properties of the polymer, most importantly the thermo-oxidative stability. Many of these fluorinated polymers are known to have thermo-oxidative stability up to 700 K. However, for space and aerospace applications, it is important to improve its thermo-oxidative stability beyond 700 K. Molecular-level details of the thermo-oxidative degradation of such polymers can provide vital information to improve the polymer. In this spirit, we have applied quantum mechanical and microkinetic analysis to scrutinize the mechanism and kinetics of the thermo-oxidative degradation of a fluorinated polymer with phenylethenyl end-cap, HFPE. This study gives an insight into the thermo-oxidative degradation of HFPE and explains most of the experimental observations on the thermo-oxidative degradation of this polymer. Thermolysis of C-CF3 bond in the dianhydride component (6FDA) of HFPE is found to be the rate-determining step of the degradation. Reaction pathways that are responsible for the experimentally observed weight loss of the polymer is also scrutinized. On the basis of these results, we propose a modification of HFPE polymer to improve its thermo-oxidative stability.

A detailed experimental and theoretical study of two novel substituted trifluoromethylchromones. The influence of the bulky bromine atom on the crystal packing

The new 3-methyl-2-trifluoromethylchromone (1) and 3-bromomethyl-2-trifluoromethylchromone (2) compounds were synthesized and characterized by vibrational (IR, Raman), UV–Vis and NMR (1H, 13C and 19F) spectroscopy and MS spectrometry. The crystal structures of 1 and 2 were determined by X-ray diffraction methods. Both compounds crystallize in the monoclinic P21/c space group with Z=4 molecules per unit cell. The structures were solved from 1423 (1) and 1856 (2) reflections with I>2σ (I) and refined by full-matrix least-squares to agreement R1-values of 0.0403 (1) and 0.0554 (2). Because of π-bonding delocalization, the organic molecular skeletons are planar and the molecular bonding structures can be described by formally single, double and resonant bonds. In 2, the CF3 group revealed a strong rotational disorder around the CCF3 bond, which could be explained in terms of four split positions with about uniform angular distribution. The vibrational, electronic and NMR, spectra were discussed and assigned with the assistance of DFT calculations.

PhI(OAc)2-Mediated Synthesis of 6-(Trifluoromethyl)phenanthridines by Oxidative Cyclization of 2-Isocyanobiphenyls with CF3SiMe3 under Metal-Free Conditions

A mild and efficient method for the synthesis of 6-(trifluoromethyl)phenanthridines through oxidative cyclization of 2-isocyanobiphenyls with CF3SiMe3 under metal-free conditions was developed. The reaction allows the direct formation of C-CF3 bonds and rapid access to phenanthridine ring systems in one catalytic cycle.

Copper‐Mediated Deoxygenative Trifluoromethylation of Benzylic Xanthates: Generation of a CCF3 Bond from an O‐Based Electrophile

The conversion of an alcohol-based functional group, into a trifluoromethyl analogue is a desirable transformation. However, few methods are capable of converting O-based electrophiles into trifluoromethanes. The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto's reagent as the source of CF3 to form C-CF3 bonds is described. The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the C-CF3 bond forms by reaction of the substrate with in situ generated CuCF3 and CuOTf. Further evidence suggests that the reaction could proceed via a radical cation intermediate.

Copper-catalyzed synthesis of trifluoromethyl-substituted isoxazolines

A mild and efficient copper-catalyzed trifluoromethylation reaction which involves the cyclization of oximes has been developed. This method provides a convenient access to a variety of useful CF3-containing 4,5-dihydroisoxazoles by constructing a C-CF3 bond and a C-O bond in one step.