Generation of trifluoromethyl thiolsulphonate through one-pot reaction of sulfonyl chloride and trifluoromethanesulfanylamides

A novel and efficient tandem reaction of sulfonyl chloride and trifluoromethylsulfanylamide is described here for the synthesis of various trifluoromethyl thiolsulphonates with a broad functional group tolerance. In the process, it is believed that sulfinate generated from sulfonyl chloride is a critical intermediate and the additive 4-methylbenzenesulfonic acid (p-TsOH) facilitates the formation of “CF₃S⁺”. Electrophilic trifluoromethylthiolation of in situ generated sulfinate and “CF₃S⁺” provides the final products.     

Reactivity of fluorinated sulfur-containing heterocycles towards nucleophilic and oxidizing reagents

The reaction of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene, 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene and 2,2-bis(trifluoromethyl)-3,6-dihydro-4,5-dimethyl-2H-thiopyran with i-C₃H₇MgCl leads to the formation of ring opening products as the result of nucleophilic attack of the Grignard reagent on the sulfur atom. According to DFT calculations the reactivity of the sulphur-containing substrate correlates with the strain energy of the heterocycle. The oxidation of 3-thia-4,4-bis(trifluoromethyl)tricyclo[5.2.1.0^2,5]non-7-ene by hydrogen peroxide in hexafluoro-iso-propanol solvent resulted in formation of the corresponding sulfoxide however, the reaction with m-chloroperoxybenzoic acid produced the product of exhaustive oxidation of sulfur and the double bond. In sharp contrast, the oxidation of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene and 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene by MCPBA (2d, 25 °C) proceeds with the preservation of the double bond, leading to the selective formation of the corresponding sulfones.     

Novel 1:1 adducts from the reaction of hexafluoroacetone azine with various olefins and 1,3-dienes; Diels-Alder adducts as intermediates in the formation of criss-cross 2:1 adducts

Hexafluoroacetone azine¹ (I) has been reported^2,3 to react thermally (160–180°) with electron-rich olefins of type H₂CCHR (R  H, Me, or Et) to give “criss-cross” (1,3-:4,2-) adducts (II). In contrast, cis- or trans-but-2-ene and cyclohexene react under comparable conditions to give nitrogen and products derived formally from addition and insertion reactions of bis(trifluoromethyl)-carbene, although it is doubtful if the free carbene is involved^2,4. The reaction of azine (I) with alkanes is reported⁵ to involve a radical mechanism in which the diazo compound (CF₃)₂CN₂, and thence the carbene (CF₃)₂C:, is formed by a secondary process.     

Pulse radiolysis studies of intermediates derived from p-terphenyl in the oxygenated methyltributylammonium bis[(trifluoromethyl)sulfonyl]imide ionic liquid

Radiation-induced processes in oxygenated ionic liquid (IL) methyltributylammonium bis[(trifluoromethyl)sulfonyl]imide ([MeBu₃N][NTf₂]) solutions containing p-terphenyl (TP) were investigated by the nanosecond pulse radiolysis with UV-vis detection. The transient absorption spectra generated in these solutions were assigned to radical anions (TP^•−), radical cations (TP^•+), and triplet excited states (³TP*). Saturation of [MeBu₃N][NTf₂] solutions with oxygen (O₂) efficiently eliminates solvated electrons (e_solv⁻); however, it does not decrease significantly the radiation chemical yield of TP^•−, which are mainly formed in a reaction of TP with presolvated electrons (e_presolv⁻). On the other hand, the lifetime of TP^•− decreases significantly due to their reaction with O₂. The TP^•+ is formed in a reaction of electron-deficient centers of the IL (IL^⊕) with TP. Their radiation chemical yield and lifetime are not affected by the presence of O₂; however, they are decreased by the presence of triethylamine (TEA). The ³TP* are formed in a reaction of excited states of ionic liquid (IL*) with TP. The presence of O₂ and TEA effectively eliminates ³TP* in the time domain >1 μs.     

Trifluoromethylation of heterocycles via visible light photoredox catalysis

A method has been developed for the visible light-induced trifluoromethylation of heterocyclic compounds. A variety of electron-rich heterocycles were transformed into trifluoromethylated products by using CF₃I as the trifluoromethyl radical source and Ru(bpy)₃Cl₂ as the photocatalyst under mild reaction conditions. This operationally simple and eco-friendly process can introduce trifluoromethyl groups without prefunctionalization.     

Kinetics of the reactions of OH radicals with 2‐methoxy‐6‐(trifluoromethyl)pyridine,diethylamine, and 1,1,3,3,3‐pentamethyldisiloxan‐1‐ol at 298 ± 2 K

Rate constants for the reactions of 2‐methoxy‐6‐(trifluoromethyl)pyridine, diethylamine, and 1,1,3,3,3‐pentamethyldisiloxan‐1‐ol with OH radicals have been measured at 298 ± 2 K using a relative rate method. The measured rate constants (cm³ molecule^?1 s^?1) are (1.54 ± 0.21) × 10^?12 for 2‐methoxy‐6‐(trifluoromethyl)pyridine, (1.19 ± 0.25) × 10^?10 for diethylamine, and (1.76 ± 0.38) × 10^?12 for 1,1,3,3,3‐pentamethyldisiloxan‐1‐ol, where the indicated errors are the estimated overall uncertainties including those in the rate constants for the reference compounds. No reaction of 2‐methoxy‐6‐(trifluoromethyl)pyridine with gaseous nitric acid was observed, and an upper limit to the rate constant for the reaction of 1,1,3,3,3‐pentamethyldisiloxan‐1‐ol with O₃ of <7 × 10^{? 20} cm³ molecule^?1 s^?1 was determined. Using a 12‐h average daytime OH radical concentration of 2 × 10⁶ molecule cm^?3, the lifetimes of the volatile organic compounds studied here with respect to reaction with OH radicals are 7.5 days for 2‐methoxy‐6‐(trifluoromethyl)pyridine, 1.2 h for diethylamine, and 6.6 days for 1,1,3,3,3‐pentamethyldisiloxan‐1‐ol. Likely reaction mechanisms are discussed. © 2011 Wiley Periodicals, Inc. Int J Chem Kinet 43: 631–638, 2011     

Lability of the trifluoromethyl group of trifluoromethoxybenzenes under HF/Lewis acid conditions

The trifluoromethyl functionality of trifluoromethoxybenzenes (trifluoromethyl phenyl ethers) becomes labile under HF/Lewis acid conditions. Substrates with an unsubstituted para-position shed their -CF₃ groups while performing a Friedel-Crafts reaction upon another substrate molecule's trifluoromethoxy group to generate p-rosolic acids. Substrates that had blocking groups at the para-positions reacted ortho. The electron donating substituents methoxy and phenoxy interfered with the formation of rosolic acids.     

May Trifluoromethylation and Polymerization of Styrene Occur from a Perfluorinated Persistent Radical (PPFR)?

The radical polymerization of styrene (St) initiated by a trifluoromethyl radical generated from a perfluorinated highly branched persistent radical (PPFR) is presented with an isolated yield above 70 %. The release of ^.CF₃ radical occurred from a temperature above 85 °C. Deeper ¹H and ¹⁹F NMR spectroscopies of the resulting fluorinated polystyrenes (CF₃-PSts) evidenced the presence of both CF₃ end-group of the PSt chain and the trifluoromethylation of the phenyl ring (in meta-position mainly). [PPFR]₀/[St]₀ initial molar ratios of 3:1, 3:10 and 3:100 led to various molar masses ranging from 1750 to 5400 g mol⁻¹ in 70–86 % yields. MALDI-TOF spectrometry of such CF₃-PSts highlighted polymeric distributions which evidenced differences between m/z fragments of 104 and 172 corresponding to styrene and trifluoromethyl styrene units, respectively. Such CF₃-PSt polymers were also compared to conventional PSts produced from the radical polymerization of St initiated by a peroxydicarbonate initiator. A mechanism of the polymerization is presented showing the formation of a trifluoromethyl styrene first, followed by its radical (co)polymerization with styrene. The thermal properties (thermal stability and glass transition temperature, T_g) of these polymers were also compared and revealed a much better thermal stability of the CF₃-PSt (10 % weight loss at 356–376 °C) and a T_g of around 70 °C.     

Kinetics of hydrogen abstraction reaction between trifluoromethyl formate and OH radical: A theoretical investigation

Kinetics and mechanism of the hydrogen abstraction reaction between trifluoromethyl formate, CF₃OCHO, and OH radical have been investigated by using ab initio molecular orbital theory up to G2(MP2) level. The hydrogen abstraction rate constant has been calculated for the first time over a temperature range of 250–450 K by using standard transition state theory including the tunneling correction. Arrhenius parameters of the reaction have been estimated from the temperature dependence of the calculated rate constant. The calculated value for the rate constant (2.0 × 10^?14 cm³ molecule^?1 s^?1) at 298 K is found to be in very good agreement with the recent experimental results. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 500–507, 2002     

Kinetics of the reactions of isopropoxy radicals with NO,NO2, and O2

A fluorescence excitation spectrum of (CH₃)₂CHO (isopropoxy radical) is reported following photolysis of isopropyl nitrite at 355 nm. Rate constants for the reaction of isopropoxy with NO, NO₂, and O₂ have been measured as a function of pressure (1–50 Torr) and temperature (25–110°C) by monitoring isopropoxy radical concentrations using laser-induced fluorescence. We have obtained the following Arrhenius expressions for the reaction of isopropoxy with NO and O₂ respectively: (1.22±0.28)×10^?11 exp[(+0.62±0.14 kcal)/RT]cm²/s and (1.51±0.70)×10^?14 exp[(?0.39±0.28)kcal/RT]cm³/s where the uncertainties represent 2σ. The results with NO₂ are more complex, but indicate that reaction with NO₂ proceeds more rapidly than with NO contrary to previous reports. The pressure dependence of the thermal decomposition of the isopropoxy radical was studied at 104 and 133°C over a 300 Torr range using nitrogen as a buffer gas. The reaction is in the fall-off region over the entire range. Upper limits for the reaction of isopropoxy with acetaldehyde, isobutane, ethylene, and trimethyl ethylene are reported.We have performed the first LIF study of the isopropoxy radical. Arrhenius parameters were measured for the reaction of i-PrO with O₂, NO, NO₂, using direct radical measurement techniques. All reactions are in their high-pressure limits at a few Torr of pressure. The rate constant for the reactions of i-PrO with NO and NO₂ reactions exhibit a small negative activation energy. Studies of the i-PrO + NO₂ reaction produce data which indicate that O(³P) reacts rapidly with i-PrO. Unimolecular decomposition studies of i-PrO indicate that the reaction is in the fall-off region between 1 and 300 Torr of N₂ and the high-pressure limit is above 1 atmosphere of N₂.     

Reductively induced homolytic carbon-carbon bond cleavage in Co(CO)3(PPh3)(COCF3)

The chemical or electrochemical reduction of the trifluoroacetyl complex Co(CO)₃(PPh₃)(COCF₃) involves a single electron transfer yielding trifluoromethyl radical and an anionic cobalt carbonyl complex. The mechanism is proposed to involve electron transfer followed by initial dissociation of either a carbonyl or phosphine ligand from the 19-electron [Co(CO)₃(PPh₃)(COCF₃)]⁻ anion. The resulting 17-electron intermediate undergoes subsequent one-electron reductive elimination of trifluoromethyl radical by homolytic cleavage of the carbon-carbon bond of the trifluoroacetyl group. The radical can be trapped by either benzophenone anion, forming the anion of α-(trifluoromethyl)benzhydrol, or Bu₃SnH, yielding CF₃H. The ultimate organometallic product is an 18-electron anion, either [Co(CO)₄]⁻ or [Co(CO)₃(PPh₃)]⁻, depending upon which ligand is initially lost. Fluorine-containing products were identified and quantitated by ¹⁹F NMR while cobalt-containing products were determined by IR.     

Line dependence of CIDEP polarizations for the p-benzosemiquinone,radical

Time-resolved steady state experiments were performed on six prominent hf-lines of the p-benzosemiquinone radical (PBQH) dissolved in ethylene glycol using an improved experimental technique. For the same six lines T₁ and _T2 were determined experimentally. Initial and radical pair polarizations as well as the second order chemical decay constant β were obtained by simulating each of the time-resolved curves using a new procedure. It was found that both the initial polarization P_a^∞(I) and β were the same within experimental accuracy for all six lines in four different experiments. The radical pair polarization P_a*, however, varied within the experimental accuracy in the manner predicted qualitatively from the theory for a second order termination reaction. Light attenuation experiments with both pulsed and continuous light confirmed these results. The magnitude of P_a^∞ (I) may be interpreted in terms of the microscopic theory for the photo-activated triplet mechanism, whereas the magnitude of P_a* appears to be too high by a factor of four to six as compared to the microscopic theory for the radical pair mechanism.     

Formation and Dissociation of Phosphorylated Peptide Radical Cations

In this study, we generated phosphoserine- and phosphothreonine-containing peptide radical cations through low-energy collision-induced dissociation (CID) of the ternary metal?Cligand phosphorylated peptide complexes [Cu^II(terpy) _p M]^·2+ and [Co^III(salen) _p M]^·+ [ _p M: phosphorylated angiotensin III derivative; terpy: 2,2':6',2''-terpyridine; salen: N,N '-ethylenebis(salicylideneiminato)]. Subsequent CID of the phosphorylated peptide radical cations ( _p M^·+) revealed fascinating gas-phase radical chemistry, yielding (1) charge-directed b- and y-type product ions, (2) radical-driven product ions through cleavages of peptide backbones and side chains, and (3) different degrees of formation of [M ?C H₃PO₄]^·+ species through phosphate ester bond cleavage. The CID spectra of the _p M^·+ species and their non-phosphorylated analogues featured fragment ions of similar sequence, suggesting that the phosphoryl group did not play a significant role in the fragmentation of the peptide backbone or side chain. The extent of neutral H₃PO₄ loss was influenced by the peptide sequence and the initial sites of the charge and radical. A preliminary density functional theory study, at the B3LYP 6-311++G(d,p) level of theory, of the neutral loss of H₃PO₄ from a prototypical model??N-acetylphosphorylserine methylamide??revealed several factors governing the elimination of neutral phosphoryl groups through charge- and radical-induced mechanisms.     

Novel efficient synthesis of β-fluoro-β-(trifluoromethyl)styrenes

CF₃CFBr₂ was employed in catalytic olefination reactions of aromatic aldehydes. In situ prepared hydrazones of aldehydes were transformed to β-fluoro-β-(trifluoromethyl)styrenes by reaction with CF₃CFBr₂ under CuCl catalysis. Based on this reaction, a novel stereoselective approach towards β-fluoro-β-(trifluoromethyl)styrenes was elaborated. Nucleophilic vinylic substitution of fluorine by secondary amines, thiolates and alkoxides in β-fluoro-β-(trifluoromethyl)styrenes was also tested.     

Microwave‐Assisted Synthesis of Novel 2,4‐Dihydro‐5‐[4‐(trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones and Potentiometric Determination of Their pKa in Nonaqueous Solvents

The novel 4‐amino‐ or 4‐aryl‐substituted 2,4‐dihydro‐5‐[(4‐trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones 3a – 3g were synthesized by reaction of N‐(ethoxycarbonyl)‐4‐(trifluoromethyl)benzenehydrazonic acid ethyl ester ( 2 ) and primary amines or hydrazine by microwave irradiation. Compounds 3a – 3g were potentiometrically titrated with tetrabutylammonium hydroxide (Bu₄NOH) in four nonaqueous solvents, i.e., ⁱPrOH, ^tBuOH, MeCN, and N,N‐dimethylformamide (DMF). Also half‐neutralization potential values and the corresponding pK_a values were determined in all cases.     

Mechanistic Investigation of Phosphate Ester Bond Cleavages of Glycylphosphoserinyltryptophan Radical Cations under Low-Energy Collision-Induced Dissociation

Under the conditions of low-energy collision-induced dissociation (CID), the canonical glycylphosphoserinyltryptophan radical cation having its radical located on the side chain of the tryptophan residue ([G _p SW]^?+) fragments differently from its tautomer with the radical initially generated on the α-carbon atom of the glycine residue ([G^? _p SW]⁺). The dissociation of [G^? _p SW]⁺ is dominated by the neutral loss of H₃PO₄ (98 Da), with backbone cleavage forming the [b₂ – H]^?+/y₁ ⁺ pair as the minor products. In contrast, for [G _p SW]^?+, competitive cleavages along the peptide backbone, such as the formation of [G _p SW – CO₂]^?+ and the [c₂?+?2H]⁺/[z₁ – H]^?+ pair, significantly suppress the loss of neutral H₃PO₄. In this study, we used density functional theory (DFT) to examine the mechanisms for the tautomerizations of [G^? _p SW]⁺ and [G _p SW]^?+ and their dissociation pathways. Our results suggest that the dissociation reactions of these two peptide radical cations are more efficient than their tautomerizations, as supported by Rice–Ramsperger–Kassel–Marcus (RRKM) modeling. We also propose that the loss of H₃PO₄ from both of these two radical cationic tautomers is preferentially charge-driven, similar to the analogous dissociations of even-electron protonated peptides. The distonic radical cationic character of [G^? _p SW]⁺ results in its charge being more mobile, thereby favoring charge-driven loss of H₃PO₄; in contrast, radical-driven pathways are more competitive during the CID of [G _p SW]^?+.

Reactivities of aromatic compounds towards the amino radical

The reaction between hydroxylamine and a reducing ion such as V(III) or Ti(III) was studied at the dropping mercury electrode in the pH range 0–7 in presence of a substrate as benzenesulfonic acid or phenol.A method has been developed to calculate, from measurements of catalytic currents, the competition between the reducing ion and the benzene derivative for the amino radical. The strong change in the reactivities observed around pH 3 was interpreted in terms of protonation of the amino radical.The relative reactivities of the phenol and benzenesulfonic acid towards the NH·₃⁺ and NH·₃⁺ radicals were measured; assuming for the pK_a of the NH·₃⁺ radical the literature value of 3.65 the relative rate of addition of the charged and uncharged amino radical to the same aromatic substrate was obtained. An interpretation of the experimental results in terms of inductive effect is given.     

Reactions of polyfluorinated thietanes: Selective synthesis of 4-R-2,2-bis(trifluoromethyl)thietane-1-S-oxides and 2-substituted 5-fluoro-4-(trifluoromethyl)-2,3-dihydrothiophenes

Oxidation of 4-substituted 2,2-bis(trifluoromethyl)thietanes by m-chloroperoxybenzoic acid results in selective formation of the corresponding S-oxides in 65-86% yield. Oxidation of 4-C₂H₅S-2,2-bis(trifluoromethyl)thietane under mild conditions led to selective formation of 4-C₂H₅SO₂-2,2-bis(trifluoromethyl)thietane, which under more rigorous conditions was selectively converted into trans-4-C₂H₅SO₂-2,2-bis(trifluoromethyl)thietane-1-S-oxide. Reaction of 4-substituted 2,2-bis(trifluoromethyl)thietanes with activated aluminum powder results in a highly selective ring expansion process, producing the corresponding 5-fluoro-4-(trifluoromethyl)-2,3-dihydro-2-alkoxythiophenes in 58-93% yield. These compounds were also prepared in 61-85% yield using a “one-pot” procedure, starting from sulfur, hexafluoropropene and the corresponding vinyl ether without isolation of any intermediates. Both 2-i-C₃H₇O- and 2-t-C₄H₉O- 5-fluoro-4-(trifluoromethyl)-2,3-dihydrothiophenes were converted into 2-fluoro-3-trifluormethylthiophene by reaction with P₂O₅.     

Study of the Gas-Phase Intramolecular Aryltrifluoromethylation of Phenyl(Trifluoromethyl)Iodonium by ESI-MS/MS

The gas-phase reactions of the reactive λ ³-phenyl(trifluoromethyl)iodonium (PhI⁺(III)CF₃, 1 at m/z 273) to the radical cation of iodobenzene (PhI^?+, 2 at m/z 204) via the loss of ·CF₃ and the radical cation of trifluoromethylbenzene (PhCF₃ ^?+, 3 at m/z 146) via the loss of ·I, were studied by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Interestingly, the gas-phase intramolecular coupling reaction of CF₃ with phenyl via the CF₃ migration process of 1 at m/z 273 from iodine to the phenyl to give 3 at m/z 146 could only occur according to an intramolecular aromatic substitution mechanism. Density functional theory (DFT) calculations showed that the gas-phase intramolecular aryltrifluoromethylation of 1 at m/z 273 to 3 at m/z 146 occurred via a Meisenheimer complex intermediate (MC), where the triplevalent I center of 1 was reduced to monovalent I. Most importantly, the structure of 3 at m/z 146 derived from 1 at m/z 273 in ESI-MS/MS process was confirmed by comparison of its MS/MS with that of an authentic PhCF₃ ^?+ at m/z 146 acquired from the electron ionization (EI)-MS/MS analysis of PhCF₃. Thus, our studies revealed the intrinsic reactivity tendencies of λ³-phenyl(trifluoromethyl)iodonium under solvent-free conditions.      

Tris(trimethylsilyl)silane promoted radical reaction and electron-transfer reaction in benzotrifluoride

Tris(trimethylsilyl)silane (TTMSS) promoted free radical reaction in benzotrifluoride (BTF) was investigated. Compared to same reaction using environmentally less desirable tri-n-butyltin hydride (TBTH) in benzene, less quantity of BTF than that of benzene can be used because of slower hydrogen atom transfer from TTMSS than that from TBTH toward primary alkyl radicals. Also, electron-transfer reactions promoted by tris(p-bromophenyl)aminium hexachloroantimonate (TBPA) and FeCl₃ were conducted in BTF. Then, TBPA was found to be effective in BTF comparably to that in methylene chloride. In addition, an interesting observation that FeCl₃ promoted reaction was accelerated by the addition of imidazolium salt was made. All the results suggest that BTF is a tolerable solvent for free radical reaction with TTMSS and electron-transfer reactions using TBPA as well as FeCl₃.