Theoretical study of the reaction of CF3O radicals with CO

The potential energy surface for the reaction of the CF₃O radicals with CO was investigated. The geometries and vibrational frequencies of the reactants, transition states, intermediates, and products were calculated at the UB3LYP/6-311+G(2d,p), UB3LYP/6-311+G(3df,2p) and UMP2/6-311+G(2d,p) levels of theory. The energies were improved by using the G2M(CC2) and G3B3 methods. The calculation suggests the reaction proceeds via either the fluorine abstraction of CF₃O by CO to produce FCO + CF₂O with a high energy barrier or the barrierless association of the reactants to form the trans-CF₃OCO intermediate. The trans-CF₃OCO is predicted to undergo subsequent isomerization to cis-CF₃OCO or dissociate directly to the products FCO + CF₂O and CF₃ + CO₂. The collisional stabilization of trans-CF₃OCO is dominant at room temperature, while trans-CF₃OCO isomerizing to cis-CF₃OCO followed by dissociating to CF₃ + CO₂ is accessible when temperature rises. The reason for only trans-CF₃OCO without cis-CF₃OCO observable in Ashen’s experiment [S.V. Ahsen, J. Hufen, H. Willner, J.S. Francisco, Chem. Eur. J. 8 (2002) 1189] is cis-CF₃OCO can be produced only via the isomerization of trans-CF₃OCO, and its yield is inappreciable at a low experimental temperature. The enthalpies of formation for the two conformations of CF₃OCO have been deduced: (trans-CF₃OCO) = −196.25 kcal mol⁻¹, (trans-CF₃OCO) = −197.46 kcal mol⁻¹, (cis-CF₃OCO) = −193.64 kcal mol⁻¹, and (cis-CF₃OCO) = −194.90 kcal mol⁻¹.     

A reexamination of the pyrolysis of bis trifluoromethyl peroxide. Addendum: Concerning D(CF3O2-CF3) and D(CF3-O2)

Earlier arguments concerning D(CF₃O₂-CF₃) and D(CF₃-O₂) are shown to be probably wrong. New values of 86 and 49 kcal/mol, respectively, are derived. C–O bond strengths are compared between CF₃- and CH₃-containing compounds.     

Synthesis of Lanthanide–Alkylaluminium Bimetallic Complexes and Studies on Their Catalytic Activities for Polymerization of Some Polar Monomers

Three new lanthanide (Ln)–alkylaluminium (Al) bimetallic complexes with the formula [(μ-CF₃CO₂)₂Ln(μ-CF₃CHO₂)AlR₂ · 2THF]₂ (Ln=Nd, Y, R=i-C₄H₉ (i-Bu); Ln=Eu, R=C₂H₅(Et); THF=tetrahydrofuran) were synthesized by the reaction of Ln(CF₃CO₂)₃ (Ln=Nd, Y) with HAl (i-Bu)₂ and of Eu(CF₃CO₂)₃ with AlEt₃, respectively. Their crystal structures were determined by X-ray diffraction at 233 K. [(μ-CF₃CO₂)₂Nd (μ-CF₃CHO₂)Al(i-Bu)₂ · 2THF]₂ (Nd–Al) and [(μ-CF₃CO₂)₂Y(μ-CF₃CHO₂)Al(i- Bu)₂ · 2THF]₂ (Y–Al) are isomorphous and crystallize in space group P 1 with a =12.441(3) Å [12.347(5) Å for Y–Al], b =12.832(3) Å [12.832(4) Å], c =11.334(3) Å [11.292(8) Å], α=104.93 (2)° [104.45(4)°], β=98.47(2)° [98.81(4)°], γ=64.60(2)° [64.30(3)°], R =0.519 [0.113], R _w=0.0532 [0.110], Z =1 and [(μ-CF₃CO₂)₂Eu(CF₃ CHO₂)AlEt₂ · 2THF]₂(Eu–Al) in space group P 2₁/ n with a =11.913(6) Å, b =14.051(9) Å, c =17.920(9) Å, α=101.88(11)°, β=γ=90°, R =0.0509, R _w=0.0471 and Z =2. The six CF₃CO     

Copper-Catalyzed Regioselective [3+3] Annulations of Alkynyl Ketimines with α-Cyano Ketones: the Synthesis of Polysubstituted 4H-Pyran Derivatives with a CF3-Containing Quaternary Center

Regioselective [3+3] annulation of alkynyl ketimines with α-cyano ketones for the synthesis of polysubstituted 4H-pyran derivatives with a quaternary CF₃-containing center has been realized by using Cu(OAc)₂ as the catalyst. The novel strategy tolerates a wide range of α-CF₃ alkynyl ketimines and α-cyano ketones with both aryl and alkyl substitutents. A preliminary asymmetric synthesis of chiral product 3 has been attempted by using copper and chiral thiourea as the cocatalyst with excellent yields (86-99 %) and good enantioselectivities (71–78 % ee). Furthermore, product 3 aa could be obtained on a gram-scale reaction with 75 % yield and 99 % ee after recrystallization. Several products were also transformed readily. Control experiments indicate that the reaction involves a process with a base-catalyzed or chiral thiourea-catalyzed Mannich-type reaction followed by a highly regioselective copper-catalyzed ring-closing reaction on the alkynyl moiety in a 6-endo-dig fashion.     

Synthetic efforts towards the synthesis of fluorinated C-glycosidic analogues of α-galactosylceramides

An overview of the work realized by the group regarding the synthesis of fluorinated C-glycosides is described. The various strategies that were investigated allowed the synthesis of CF₂-glycosides for many carbohydrate series (glucose, mannose and galactose) and for any pseudo-anomeric center configuration (α or β). This work culminated in an efficient preparation of a synthetically useful α-CF₂-galactoside intermediate and its conversion to α-CF₂-galactoconjugates. A synthesis of α-CF₂-galactosylceramide, based on this last methodology, is currently investigated.     

3-Fluoroalkyl (CF3, CHF2, CH2F) Cyclobutane-Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties

Synthesis and physicochemical characterization of all possible cis- and trans-1,3-disubstituted cyclobutane-derived amines and carboxylic acids bearing mono-, di- and trifluoromethyl groups at the C-3 position is disclosed. Tetramethylammonium fluoride (TMAF)- or morpholinosulfur trifluoride (Morph-DAST)-mediated nucleophilic fluorination of appropriate cis- and trans-diastereomeric substrates was used as the key step for the preparation of CH₂F- and CHF₂-substituted derivatives. To obtain the corresponding cis- and trans-isomeric CF₃-substituted derivatives, resolution of known 3-(trifluoromethyl)cyclobutanecarboxylic acid (obtained as a mixture of diastereomers) was applied. The proposed procedures were suitable for the preparation of corresponding fluoroalkyl-substituted cyclobutane-derived amines and carboxylic acids on up to 50 g scale. All 12 building blocks obtained were characterized by measuring dissociation constants (pK_a) and lipophilicities (LogP, for model derivatives) to evaluate the effect of the fluoroalkyl substituents on their physicochemical properties relevant to further drug discovery applications.     

Trifluoromethyl- and difluoromethyl-β-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids

Enantiopure 1-acyl-3-hydroxyl-4-CF₂H-azetidin-2-ones and 1-acyl-3-hydroxy-4-CF₃-azetidin-2-ones serve as versatile intermediates for the syntheses of CF₂- and CF₃-containing α-hydroxy-β-amino acids, dipeptides, and taxoid anticancer agents. Both enantiomers of 3-hydroxy-4-CF₂H-β-lactams can be obtained in high yields through the diethylaminosulfur trifluoride (DAST) reaction of the corresponding enantiopure 4-formyl-β-lactam that is prepared through [2+2] cycloaddition of acetoxyketene to a 3-methyl-2-butenaldimine, followed by enzymatic optical resolution and ozonolysis. (+)-3-Hydroxy-4-CF₃-β-lactams and (−)-3-hydroxy-4-CF₃-β-lactams can also be readily obtained in enantiopure form through [2+2] cycloaddition of a CF₃-imine with a ketene, followed by enzymatic optical resolution. Practical processes for the preparations of these enantiopure 3-hydroxy-4-R_f-β-lactams as well as their synthetic applications are described.     

A Convergent,Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp3)−H Activation

Trifluoromethyl-bearing 5-membered rings are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust C(sp³)−H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium-catalyzed α-CF₃-α-alkyl carbene insertion into C(sp³)−H bonds of a broad range of substrates to access 7 types of CF₃-bearing saturated 5-membered carbo- and heterocycles. The reaction is particularly effective for benzylic C−H insertion exerting good site-, diastereo- and enantiocontrol, and applicable to the synthesis of chiral CF₃ analogues of bioactive molecules. Ruthenium α-CF₃-α-alkyl carbene complexes underwent stoichiometric reactions to give C−H insertion products, lending evidence for the involvement of metal α-CF₃-α-alkyl carbene species in the catalytic cycle. DFT calculations revealed that the π⋅⋅⋅π attraction and intra-carbene C−H⋅⋅⋅F hydrogen bond elucidate the origin of selectivity of the benzylic C−H insertion reactions.     

Azidoperfluoroalkanes: Synthesis and Application in Copper(I)‐Catalyzed Azide–Alkyne Cycloaddition

We report an efficient and scalable synthesis of azidotrifluoromethane (CF₃N₃) and longer perfluorocarbon‐chain analogues (R_FN₃; R_F=C₂F₅, ⁿ C₃F₇, ⁿ C₈F₁₇), which enables the direct insertion of CF₃ and perfluoroalkyl groups into triazole ring systems. The azidoperfluoroalkanes show good reactivity with terminal alkynes in copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC), giving access to rare and stable N ‐perfluoroalkyl triazoles. Azidoperfluoroalkanes are thermally stable and the efficiency of their preparation should be attractive for discovery programs.     

Kinetics of the gas‐phase reactions of cyclo‐CF2CFXCHXCHX – (X = H,F, Cl) with OH radicals at 253–328 K

Rate constants were determined for the reactions of OH radicals with halogenated cyclobutanes cyclo‐CF₂CF₂CHFCH₂? (k₁), trans‐cyclo‐CF₂CF₂CHClCHF? (k₂), cyclo‐CF₂CFClCH₂CH₂? (k₃), trans‐cyclo‐CF₂CFClCHClCH₂? (k₄), and cis‐cyclo‐CF₂CFClCHClCH₂? (k₅) by using a relative rate method. OH radicals were prepared by photolysis of ozone at a UV wavelength (254 nm) in 200 Torr of a sample reference H₂O? O₃? O₂? He gas mixture in an 11.5‐dm³ temperature‐controlled reaction chamber. Rate constants of k₁ = (5.52 ± 1.32) × 10^?13 exp[–(1050 ± 70)/T], k₂ = (3.37 ± 0.88) × 10^?13 exp[–(850 ± 80)/T], k₃ = (9.54 ± 4.34) × 10^?13 exp[–(1000 ± 140)/T], k₄ = (5.47 ± 0.90) × 10^?13 exp[–(720 ± 50)/T], and k₅ = (5.21 ± 0.88) × 10^?13 exp[–(630 ± 50)/T] cm³ molecule^?1 s^?1 were obtained at 253–328 K. The errors reported are ± 2 standard deviations, and represent precision only. Potential systematic errors associated with uncertainties in the reference rate constants could add an additional 10%–15% uncertainty to the uncertainty of k₁–k₅. The reactivity trends of these OH radical reactions were analyzed by using a collision theory–based kinetic equation. The rate constants k₁–k₅ as well as those of related halogenated cyclobutane analogues were found to be strongly correlated with their C? H bond dissociation enthalpies. We consider the dominant tropospheric loss process for the halogenated cyclobutanes studied here to be by reaction with the OH radicals, and atmospheric lifetimes of 3.2, 2.5, 1.5, 0.9, and 0.7 years are calculated for cyclo‐CF₂CF₂CHFCH₂? , trans‐cyclo‐CF₂CF₂CHClCHF? , cyclo‐CF₂CFClCH₂CH₂? , trans‐cyclo‐CF₂CFClCHClCH₂? , and cis‐cyclo‐CF₂CFClCHClCH₂? , respectively, by scaling from the lifetime of CH₃CCl₃. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 41: 532–542, 2009     

An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF₃CCl₃ afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF₃-β-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H₂O system initiated intramolecular cyclization to afford 2-CF₃-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF₃-indole.     

Trifluoromethylation of carbon and boron with CF3SiMe3/NMe4F: formation of NMe4[trans-CF3CFCFB(CF3)3]

Trimethylamine-trifluoroethenyl-bis(trifluoromethyl)borane [F₂CCF(CF₃)₂B·NMe₃] (1) reacts with NMe₄[(CF₃)₂SiMe₃] in THF solution to form trimethylamine-bis(trifluoromethyl)pentafluoropropenylborane [trans-CF₃CFCF(CF₃)₂B·NMe₃] (3), the fluoroborate NMe₄[trans-CF₃CFCF(CF₃)₂BF] (4), the novel borates NMe₄[trans-CF₃CFCFB(CF₃)₃] (5) and NMe₄[cyclo-(CF₃)₂BCF₂CFCF₂CF₃] (6).     

Copolymerization of butadiene and styrene with a gadolinium tricarboxylate catalyst

Homo- and copolymerizations of butadiene (BD) and styrene (St) were carried out by gadolinium catalysts having various tricarboxylate ligands [Gd(OCOR)₃: R = CH₃, CH₂Cl, CHCl₂, CCl₃, and CF₃], to investigate the effects of ligands and discuss the cis polymerization mechanism. Polymerization of BD with Gd(OCOR)₃—(i—Bu)₃Al—Et₂AlCl catalysts was carried out in hexane at 50°C. By each catalyst, poly(BD) having a high cis content (cis = 97–99%) in 22–85% yields for 2–24 h were obtained. The ligands with low pKa values increased the polymerization activity as follows: R of Gd(OCOR)₃: CF₃ > CCl₃ > CHCl₂ > CH₂Cl ～ CH₃. On the other hand, in the polymerization of St or copolymerization of BD and St under similar conditions, the highest activity was attained by a Gd(OCOCCI₃)₃- based catalyst. The difference in the optimum ligand among the homo- and copolymerization of BD and St was discussed on the basis of energy levels of the catalysts. In the copolymers of BD and St, the cis-1,4 content of the BD unit decreased with increasing St content. Furthermore, according to the diad analysis of copolymers (St content ～ 14.5 mol %) by ¹³C NMR spectroscopy, the low cis value of the BD unit was observed in the St-BD diad (cis/trans/vinyl = 24/53/23), while the high cis value of the BD unit remained in the BD-BD diad (cis/trans/vinyl = 89/10/1). These results suggest that the terminal BD unit is controlled by the cis configuration by the coordination between the penultimate cis vinylene unit and the gadolinium metal catalyst, whereas the presence of the penultimate St unit interferes with cis polymerization of the terminal BD unit. The difference in the coordination mechanism in the course of polymerization between rare earth metal and transition metal catalysts such as the Ni(acac)₂ and Co(acac)₃-based catalyst was also discussed. © 1995 John Wiley & Sons, Inc.     

Novel perfluoroalkylated oligo(oxyethylene) methyl ethers with high hemocompatibility and excellent co-emulsifying properties for potential biomedical uses

Two series of novel perfluoroalkylated amphiphilic compounds were synthesized from monomethyl ethers of mono-, di- and tri-(oxyethylene) glycols. The first series CH₃(OCH₂CH₂)_nOCH₂CH(OH)CH₂-CF₂(CF₂CF₂)_nCF₃ (n = 1-3) bearing the hydroxy group at the spacer between hydrophilic and hydrophobic parts was prepared by the reactions of the monomethyl ethers with 2-(perfluoroalkylmethyl)oxiranes in 76-97% yields. The second series CH₃(OCH₂CH₂)_nOCH₂CH₂CH₂-CF₂(CF₂CF₂)_nCF₃ (n = 1-3) possessing the non-hydroxylated spacer was synthesized from allyl methyl ethers of oligo(oxyethylene) glycols using radical additions of perfluoroalkyl iodides and subsequent selective reductions of the C-I bond in the adducts in overall yields of 23-69%. Some of the novel amphiphilic compounds displayed very low hemolytic activity to erythrocytes and excellent co-emulsifying properties on testing on perfluorodecalin/Pluronic F-68 microemulsions. 1-O-(2-Hydroxy-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-d-xylitol was prepared by a novelized synthesis and employed as a standard compound in the testing.     

Formation of a trans-cycloadduct from the reaction of difluorocarbene with cis-difluorostilbene

The photochemical isomerization of trans and cis-difluorostilbenes has been studied. In the presence of a photosensitizer (biacetyl, 0.05 mol·^?1) about 75% of the trans form can be converted into the crystalline cis form. The reactions of difluorocarbene (CF₂) from the Seyferth reagent (PhHgCF₃) with cis- and trans-stilbene obey the Skell rule, i. e., stereospecific cycloaddition. However, although the reaction of CF₂ with trans-1,2-difluorostilbene yields trans-1,2-diphenyl-perfluorocyclopropane (9) as the only isolable product, the reaction of CF₂ with cis-difluorostilbene also gives the same trans-cycloadduct as the only isolable product. A possible mechanistic path involving the homolytic cleavage of the highly activated cyclopropane C—C bond facing the CF₂ group is discussed.     

Copolymerization of ethylene and cyclopentene with bis(β‐enaminoketonato) titanium complexes

The copolymerizations of ethylene and cyclopentene with bis(β‐enaminoketonato) titanium complexes {[(Ph)NC(R₂)CHC(R₁)O]₂TiCl₂; R₁ = CF₃ and R₂ = CH₃ for 1a , R₁ = Ph and R₂ = CF₃ for 1b ; and R₁ = t‐Bu and R₂ = CF₃ for 1c } activated with modified methylaluminoxane (MMAO) as a cocatalyst were investigated. High‐molecular‐weight copolymers with cis‐1,2‐cyclopentene units were obtained. The catalyst activity, cyclopentene incorporation, polymer molecular weight, and polydispersity could be controlled over a wide range through the variation of the catalyst structure and reaction parameters, such as the Al/Ti molar ratio, cyclopentene feed concentration, and polymerization reaction temperature. The complex 1b /MMAO catalyst system exhibited the characteristics of a quasi‐living ethylene polymerization and an ethylene–cyclopentene copolymerization and allowed the synthesis of polyethylene‐block‐poly(ethylene‐co‐cyclopentene) diblock copolymer. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1681–1689, 2005     

Janus Face All-cis 1,2,4,5-tetrakis(trifluoromethyl)- and All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)- Cyclohexanes

We report the synthesis of all-cis 1,2,4,5-tetrakis (trifluoromethyl)- and all-cis 1,2,3,4,5,6-hexakis (trifluoromethyl)- cyclohexanes by direct hydrogenation of precursor tetrakis- or hexakis- (trifluoromethyl)benzenes. The resultant cyclohexanes have a stereochemistry such that all the CF₃ groups are on the same face of the cyclohexyl ring. All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane is the most sterically demanding of the all-cis hexakis substituted cyclohexanes prepared to date, with a barrier (ΔG) to ring inversion calculated at 27 kcal mol⁻¹. The X-ray structure of all-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane displays a flattened chair conformation and the electrostatic profile of this compound reveals a large diffuse negative density on the fluorine face and a focused positive density on the hydrogen face. The electropositive hydrogen face can co-ordinate chloride (K≈10³) and to a lesser extent fluoride and iodide ions. Dehydrofluorination promoted decomposition occurs with fluoride ion acting as a base.     

Rapid access to CF3-containing heterocycles

The silyl-Prins and aza-silyl-Prins reactions have been employed for the preparation of 6-CF₃-substituted dihydropyrans and 6-CF₃-substituted tetrahydropyridines. The product heterocycles have been further elaborated to a number of products, including CF₃-substituted pipecolates and hydroxylated pyrans and piperidines.     

The influence of sodium trifluoroacetate on the acidity function of solutions of trifluoroacetic acid in N,N-dimethylformamide

The influence of CF₃COONa on the acidity function (H ₀) and IR spectra of the CF₃COOH-N,N-dimethylformamide (DMF)-CF₃COONa system ([CF₃COOH] ≤ [DMF], [CF₃COONa] = 0–3 M) and H ₀ of solutions of the salt in 100% CF₃COOH ([CF₃COONa] = 0–1.2 M) was studied. The addition of the salt to 100% CF₃COOH insignificantly changed solution acidity; H ₀ passed a minimum at [CF₃COONa] = 0.7 M because of the formation of (CF₃COO…H…OOCCF₃)^? anions and destruction of acid associates in the presence of the salt. Changes in the acidity of solutions of CF₃COOH in DMF caused by the addition of the salt depended on the n = [CF₃COOH]/[DMF] ratio. At n = 1, the salt almost did not influence H ₀. At n < 1, a substantial decrease in the acidity of solutions was observed, because the salt increased the degree of proton transfer in CF₃COO…H…OC(H)N(CH₃)₂ quasi-ion pairs solvated by DMF molecules.     

Vibrational relaxation and dissociation in the perfluoromethyl halides,CF3Cl,CF3Br,andCF3I

The processes of vibrational relaxation and unimolecular dissociation of the perfluoromethyl halides CF₃Cl, CF₃Br, and CF₃I have been studied in the shock tube with the laser-schlieren technique. Vibrational relaxation was resolved in pure CF₃Cl and CF₃Br (400–484 K and 400–500 K, respectively), and in the mixtures; 2% CF₃Cl/Kr (500–1000 K), 10% CF₃Cl/Kr (440–670 K), 4% CF₃Br/Kr (450–850 K), and 2% CF₃I/Kr (620–860 K). Relaxation in the pure gases is extremely rapid, but shows a well-resolved, accurately exponential decay which provides very precise relaxation times in close agreement with ultrasonic results. Relaxation times as short as 0.1 μs-atm can be resolved, showing the method has a resolution within a factor 2–3 of the best ultrasonic methods. Relaxation dilute in rare gas shows a complex double exponential behavior consistent with a two-stage series process. Rates of CF₃(SINGLEBOND)X fission in these mixtures were measured over 1800–3000 K, P<0.55 atm, for CF₃Cl; 1600–2500 K, P<0.55 atm, in CF₃Br; and 1260–2100 K, P<0.34 atm, in CF₃I. Rates for dissociation were derived from a full profile modeling using a secondary mechanism of six CF₃ reactions. RRKM analysis showed all dissociations to lie near the low pressure limit. Using literature barriers, these rates are best fit with (ΔE)_all=−270 cm⁻¹ for CF₃Cl, 〈ΔE〉_down=0.3 T for CF₃Br, and 〈ΔE〉_down=800 cm⁻¹ for CF₃F. All these transfers are on the large side, similar to those found in other halogenated methanes. © 1997 John Wiley & Sons, Inc.