Trifluoroperacetic Acid1

[359-48-8]  · C2HF3O3  · Trifluoroperacetic Acid  · (MW 130.03)

(electrophilic reagent capable of reacting with many functional groups; delivers oxygen to alkenes, arenes, and amines;1 useful reagent for Baeyer-Villiger oxidation of ketones27,44)

Alternate Names: TFPAA; peroxytrifluoroacetic acid.

Solubility: sol CH2Cl2, dichloroethane, ether, sulfolane, acetonitrile.

Form Supplied in: not available commercially.

Analysis of Reagent Purity: assay using iodometry.2

Preparative Methods: the preparation and handling of TFPAA should be carried out behind a safety shield. A mixture of Trifluoroacetic Anhydride (46.2 g; 0.22 mole) and CH2Cl2 (50 mL) is cooled with stirring in an ice bath. 90% H2O2 (caution: for hazards see Hydrogen Peroxide) (5.40 mL, 0.20 mol) is added in 1 mL portions over a period of 10 min. When the mixture has become homogeneous, it is allowed to warm to rt and then again cooled to 0 °C.3 TFPAA prepared from 30% aqueous H2O2 and Trifluoroacetic Acid has been used for some reactions.4-6 Hydrogen peroxide of high concentration (70%) is not widely available due to hazards involved in handling, storage, and transportation. The commercially available Hydrogen Peroxide-Urea (UHP) system, which is safe to handle, has been introduced recently as a substitute for anhydrous H2O2 in the preparation of TFPAA.2,7,8

Purification: in the preparation of TFPAA, a slight excess of trifluoroacetic anhydride is used to ensure that no water is present in the reagent. The reaction between H2O2 and trifluoroacetic anhydride is very fast; the reagent is ready for use after the reactants have been mixed and the solution has become homogeneous. No special purification steps are employed. Suitable buffers (Na2CO3, Na2HPO4) are used to neutralize the highly reactive and strongly acidic trifluoroacetic acid which is present along with TFPAA in the reagent.

Handling, Storage, and Precautions: the reagent can be stored at -20 °C for several weeks9 and exhibits no loss in active oxygen content after 24 h in refluxing CH2Cl2.40 However, since it can be prepared in a short time, the usual practice is to prepare the reagent when needed. Note that solutions of TFPAA in CH2Cl2 can lose activity by evaporation of the volatile peracid.41 Since peroxy acids are potentially explosive, care is required while carrying out the reactions and also during workup of the reaction mixture. Solvent removal from excess H2O2-CF3CO2H experiments can result in explosions; the peroxide must be destroyed by addition of MnO2 (until a potassium iodide test is negative) before solvent removal.10a For a further discussion of safety, see Luxon.10b This reagent should only be handled in a fume hood.

General Considerations.

Trifluoroperacetic acid oxidizes simple alkenes, alkenes carrying a variety of functional groups (such as ethers, alcohols, esters, ketones, and amides), aromatic compounds, alkanes,11 amines and N-heterocycles. Ketones undergo oxygen insertion reactions (Baeyer-Villiger oxidation).

Epoxidations of Alkenes.

Due to the presence of the strongly electron withdrawing CF3 group, TFPAA is the most powerful organic peroxy acid and as such is more reactive than performic21 or 3,5-dinitroperbenzoic acids.41 It reacts readily even with electron-poor alkenes to furnish the corresponding epoxides (see m-Chloroperbenzoic Acid).

Trifluoroacetic acid is a strong acid which opens epoxides readily.12,44 Since TFPAA is a much weaker acid than trifluoroacetic acid (pKa 3.7 vs. 0.3), the latter reagent can be selectively neutralized with Na2CO3 or Na2HPO4, leading to the isolation of epoxides in high yields. When the substrate is highly reactive, Na2CO3 is used as buffer; when the substrate reacts sluggishly, Na2HPO4 is used as buffer.12 The TFPAA reagent is rapidly decomposed by Na2CO3.

Since monosubstituted alkenes are not electron rich, they react sluggishly with the standard organic peroxy acids. By contrast, the monosubstituted alkene 1-pentene (1) is epoxidized efficiently by TFPAA (eq 1).12 TFPAA prepared from 0.3 mol of 90% H2O2 and 0.36 mol of trifluoroacetic anhydride in CH2Cl2 is added during 30 min to a stirred mixture of (1) (0.2 mol), Na2CO3 (0.9 mol), and CH2Cl2 (200 mL). Since the alkene is volatile the reaction flask is fitted with an efficient ice water-cooled condenser. The reaction mixture boils during the addition of the peracid. After all the reagent has been added, the reaction mixture is heated under reflux for 30 min, cooled, and the insoluble salts are removed by centrifugation. The salt is thoroughly washed with CH2Cl2. Fractional distillation of the combined CH2Cl2 extracts furnishes the epoxide (2) in 81% yield.

The alkene (3), which is resistant to epoxidation by m-CPBA or Peracetic Acid, has been epoxidized with TFPAA to furnish in 83% yield a mixture of esters (4) and (5) (eq 2).13 Esters (4) and (5) undergo facile deacylation when chromatographed on silica gel to furnish alcohols (6) and (7).

Epoxidation of allyldiphenylphosphine oxide (8) with TFPAA furnishes in quantitative yield the corresponding epoxide, 2-(diphenylphosphinoylmethyl)oxirane; m-CPBA epoxidation of (8) furnishes the epoxide in only 56% yield.14 Epoxide (9) is obtained in 80% yield through regio- and stereoselective epoxidation of the corresponding alkene with TFPAA in CH2Cl2 in the presence of Na2HPO4 buffer.15

The tertiary amine of (10) is expected to react more readily than the disubstituted double bond on treatment with an organic peracid. Selective epoxidation of the double bond in (10) was achieved by initially treating it with CF3CO2H. This led to salt formation due to protonation of the amine. Epoxidation of the salt with TFPAA and subsequent workup furnished the epoxide (11) (eq 3).16

Alkenes have been epoxidized efficiently employing TFPAA prepared by the UHP method (eq 4).2

a,b-Unsaturated esters and a,b-unsaturated ketones are resistant to epoxidation by organic peracids since the double bonds are not electron rich; however, these compounds can be epoxidized by TFPAA. 1-Acetylcyclohexene17 and methyl methacrylate12 furnish the corresponding epoxides in 50% and 84% yields, respectively, when treated with TFPAA/Na2HPO4 in CH2Cl2 (reflux for about 0.5 h). The a,b-unsaturated ester (12) has been epoxidized stereoselectively by TFPAA (eq 5).18 With m-CPBA, this epoxidation requires a higher reaction temperature which results in the formation of a complex mixture.

With organic peracids, allyl alcohols form hydrogen bonds involving the hydrogen of the alcohol, as in (13).19 Ganem has suggested that, with TFPAA, allylic ethers form hydrogen bonds involving the hydrogen of the peracid (14).

Epoxidation of (15) having an allylic ether substituent axially oriented is syn selective (syn:anti epoxidation = 12.4:1) (eq 6);19 this selectivity is due to the formation of the hydrogen bond of the type shown in (14). The stereoselectivity in the epoxidation of (15) is solvent dependent. When (15) is epoxidized in THF (which disrupts hydrogen bonding) the ratio of syn:anti epoxides obtained is 1:12. The epoxidation of the allyl alcohol (16) with TFPAA is highly syn selective (syn:anti epoxidation = 100:1); the syn selectivity in the epoxidation of (16) with m-CPBA is much less (syn:anti epoxidation = 5.2:1).

The diol (17) is epoxidized stereoselectively to furnish (18) (eq 7).20

Oxidation of Alkenes to Diols and Ketones.

Alkenes react readily with a CF3CO3H/CF3CO2H mixture to furnish hydroxy trifluoroacetates, e.g. (19) -> (20) (eq 8).21 In this reaction, high molecular weight byproducts are formed due to the condensation of hydroxy trifluoroacetates with the epoxides formed from alkenes. The formation of the byproduct can be avoided by adding triethylammonium trifluoroacetate. After the formation of the glycol ester is complete, the solvent is evaporated under reduced pressure and the crude ester is subjected to methanolysis to furnish the vicinal diol (21). a,b-Unsaturated esters are also hydroxylated by this procedure.

The allyl alcohol (22) reacted readily with TFPAA to furnish the 1,3-dioxolane (23) (eq 9).8 This reaction could not be carried out with m-CPBA even in refluxing ethylene dichloride. The homoallyl alcohol (22) (R1 = H, R2 = OH) was reacted with TFPAA prepared from commercially available urea-hydrogen peroxide; the major product formed was the dioxolane (23) (R1 = H, R2 = OH).

(±)-Allosamizoline (25) has been synthesized from the (dimethylamino)oxazoline (24).22 5.4 M TFPAA in CF3CO2H is added carefully to (24) at 0 °C. The reaction mixture is evaporated in vacuum and the resulting mixture of epoxides is solvolyzed by heating with 10% aqueous CF3CO2H at 40 °C. Hydrogenolysis (Pd/C, H2, MeOH) of the solvolysis product furnishes pure (±)-(25) (overall yield 67%) and the epoxide (26) (yield 16%).

Epoxidation of sterically congested alkenes occurs with TFPAA under basic conditions (eq 10).45

Treatment of tetrasubstituted alkenes with TFPAA/BF3 furnishes ketones via rearrangement. 1,2-Dimethylcyclohexene has been transformed to the ketone (27) (eq 11);23 the reagents TFPAA and 47% Boron Trifluoride Etherate are added simultaneously.

Arene Oxidation.

Arenes are exhaustively oxidized to aliphatic carboxylic acids. Heteroaromatic systems, such as pyridine, quinoline, and dibenzothiophene, are quantitatively oxidized to their N-oxides and sulfone rather than undergo ring oxidation. The heteroatom oxidation deactivates the ring towards electrophilic attack by TFPAA.6 Benzene undergoes direct catalytic oxidation to phenyl trifluoroacetate using a TFPAA/CoIII reagent.24

With BF3.

The combination TFPAA/Boron Trifluoride is a potent electrophilic oxidant for p-systems.46 As a source of positive hydroxyl, it is used to convert aromatics into cyclohexadienones (eq 12)26a and phenols,25 and alkenes into ketones (eq 13).26b See also eq 11 above.

Baeyer-Villiger Oxidation.

On treatment with organic peroxy acids, ketones undergo oxygen insertion reactions to furnish esters (see m-Chloroperbenzoic Acid).44 This reaction, known as the Baeyer-Villiger rearrangement, has several applications and has been reviewed recently.27 When carrying out this oxidation with TFPAA, Na2HPO4 buffer is added to prevent the reaction between trifluoroacetic acid and the Baeyer-Villiger product. The ketone (28) reacts with TFPAA to furnish brassinolide tetracetate (29) (eq 14).28 The migration of C-7 rather than C-5 carbon in this oxidation is due to the effect of the acetate groups at C-2 and C-3. A systematic study of the Baeyer-Villiger reaction of 5a-cholestan-6-ones having substituents at C-1, C-2, and C-3 has been carried out.29

The oxidations of the ketone (30) and a-tetralone (31) have been reported (eqs 15 and 16).30,2 Epimerization of a-substituents is generally not observed when ketones are oxidized with buffered TFPAA.42

Complete stereospecificity and high regioselectivity (25:1) is observed in the oxidation of an erythro ketone (eq 17). Oxidation of the threo ketone is also stereospecific but gives a 5:3 mixture of ester regioisomers.47

Heteroatom Oxidations.

Aromatic primary amines carrying electron-withdrawing groups are oxidized efficiently by TFPAA to the corresponding nitro compounds (eq 18).21,31 The amine dissolved in CH2Cl2 is added to the peracid. The above oxidation cannot be carried out with aromatic amines such as p-anisidine, which are unusually sensitive to electrophilic attack; for these sensitive amines, peracetic acid is the preferred oxidant.

Oxidation of 2,3,4,5,6-pentachloroaniline with TFPAA in CHCl3-water at rt furnishes, in 78% yield, 2,3,4,5,6-pentachloronitrosobenzene.32 The electron-deficient heterocycle (32) furnishes the N-oxide (33) on oxidation with TFPAA prepared from urea-hydrogen peroxide (eq 19).7 Electron-deficient pyridines are oxidized to the corresponding N-oxides with TFPAA; perbenzoic and peracetic acid are not effective for this transformation.43

Oxidation of the isoxazoline (34) furnishes the hydroxy ester (35) (eq 20) via an initial oxaziridine intermediate.33

Nitro compounds have many applications in organic chemistry.34 Strained polynitro polycyclic compounds are of interest as a new class of energetic materials.35 Since oximes are readily available, their oxidation to nitro compounds has been studied. Oxidation of the oxime (36) furnishes a mixture of nitro compounds; the major component is the cis isomer (eq 21).36 During the oxidation of oximes, ketones are obtained as byproducts. Hindered oximes such as camphor oxime are not oxidized by TFPAA.

Oximes yield primary, secondary, and alicyclic nitroalkanes (72%),48 and a-chloro ketoximes give a-nitroalkenes (31-66%).49

Oxidation of the oxime (37) furnishes a mixture of endo,endo and exo,exo isomers (eq 22).35b Oximes have been converted to nitro compounds using a multistep method.35a Sodium Perborate in glacial acetic acid oxidizes oximes to nitro compounds.37

a-Unsubstituted a,b-epoxy ketoximes are oxidized to g-hydroxy-a-nitroalkenes (eq 23).38 Aldoximes are oxidized to nitroalkanes (60-80%) with the reagent prepared from urea-H2O2 and trifluoroacetic anhydride. Ketoximes fail to react with this reagent system.50

Nitroso compounds are oxidized to the corresponding nitro compounds (eq 24)39 or to nitramines.40,51 30% H2O2 is added to a solution of the nitrosopyrimidine (38) in CF3CO3H during 1.5 h. After workup the nitro compound (39) is obtained in high yield; in this reaction, oxidative hydrolytic desulfurization is observed.

Miscellaneous Reactions.

Aromatic azines are oxidized to their azine monoxides with TFPAA.52 Organosulfides can be oxidized by TFPAA to either sulfoxides or sulfones under mild conditions in high yield.5,53

Related Reagents.

m-Chloroperbenzoic Acid; Hydrogen Peroxide-Urea; Peracetic Acid; Perbenzoic Acid.


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Kenneth C. Caster

Union Carbide Corporation, South Charleston, WV, USA

A. Somasekar Rao & H. Rama Mohan

Indian Institute of Chemical Technology, Hyderabad, India



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