Trifluoroacetic Acid

CF3CO2H

[76-05-1]  · C2HF3O2  · Trifluoroacetic Acid  · (MW 114.03)

(solvent; acid catalyst for diverse organic transformations, including solvolysis,9 rearrangements,3 reductions,17 oxidations,22 and trifluoromethylation8,16)

Alternate Name: TFA.

Physical Data: 1 freely flowing clear liquid, mp -15.4 °C, bp 72 °C; pKa 0.23 (25 °C, H2O); d 1.480 g cm-3. Trifluoroacetic acid and water form an azeotrope, bp 105.5 °C, 20.8% water.

Solubility: miscible with water and most organic solvents, but has limited solubility in alkanes (with more than six carbons) and carbon disulfide.

Form Supplied in: neat liquid; commercially available.

Purification: distilled from traces of (CF3CO)2O or P2O5; KMnO4 has caused serious explosions.33

Handling, Storage, and Precautions: 2 is a strong organic acid. It is extremely corrosive and especially destructive to tissue of mucous membranes. Inhalation is a major hazard. Use of a NIOSH/MSHA approved respirator is recommended. Use in a fume hood with gloves and protective clothing to avoid contact. TFA is hygroscopic. Listed incompatibilities include oxidizing and reducing agents; however, literature references report the use of both types of reagents with TFA. TFA should never be mixed with basic solvents or acid-sensitive materials. The acute toxicity of TFA is low.

Acid-Catalyzed Rearrangements.

There are many examples of rearrangements catalyzed by TFA, including acid-catalyzed epoxide ring opening (eq 1),3 biomimetic cyclizations (eq 2),4 Cope rearrangements (eq 3),5 and natural product synthesis (eq 4).6 The cited references are given as examples; a comprehensive listing is beyond the scope of this publication. Often these reactions are initiated through protonation and dehydration to provide a cationic intermediate for cyclization. TFA is a general catalyst for most acid-catalyzed rearrangements. The physical properties of TFA may provide benefits over alternative acids. The volatility of this catalyst will allow product isolation by simple solvent evaporation. Less volatile alternatives, such as Sulfuric Acid or p-Toluenesulfonic Acid, may require neutralization or an extractive workup. Owing to the low nucleophilicity of trifluoroacetate anion, TFA has been used as a solvent for basic research into solvolysis mechanisms.7

Synthesis of Trifluoromethyl Organic and Organometallic Compounds.

The reaction of TFA with Grignard reagents is general for the formation of trifluoromethyl ketones (eq 5).8 The reaction is useful only with readily available Grignard reagents, as 1 equiv of organometallic reagent is consumed deprotonating TFA. The best yields are obtained using 2.5-3.0 mol of Grignard reagent per equiv of TFA. Phenyl, alkynyl, and normal alkyl Grignard reagents give superior results. Strongly reducing Grignard reagents, such as Isopropylmagnesium Bromide, tend to produce trifluoromethyl alcohols from reduction of the initially formed ketone.

The condensation of Mercury(II) Oxide with 2 mol of TFA produces Mercury(II) Trifluoroacetate. Thermal decarboxylation in the presence of carbonate followed by sublimation yields bis(trifluoromethyl)mercury.9 Treatment of bis(trifluoromethyl)mercury with Cu0 in NMP or DMA produces a stable trifluoromethylcopper reagent.10 Addition of an aromatic or benzylic halide leads to displacement and incorporation of the trifluoromethyl group (eq 6). Alternatives for the introduction of a trifluoromethyl group as a nucleophile are limited. The trifluoromethyl derivatives of lithium and magnesium are unknown, probably due to fluoride elimination to produce difluorocarbene.11 Bis(trifluoromethyl)mercury has been used to synthesize trifluoromethyl organometallic derivatives of germanium,12 tin,13 zinc,14 and cadmium.15

Direct trifluoromethylation of electron-poor aromatic and heterocyclic systems can be accomplished by treatment with TFA and Xenon(II) Fluoride.16 The initial reaction is thought to produce Xe(O2CCF3)2 which undergoes decomposition to yield carbon dioxide, xenon, and trifluoromethyl radicals. Aromatic and heterocyclic compounds can react with the trifluoromethyl radicals, often with a high degree of selectivity. Yields of trifluoromethylated products vary between good to moderate, but the reaction allows entry into structures that would otherwise be difficult to synthesize. The chemistry has been extended to heterocyclic systems, as demonstrated with an intermediate reaction in the production of 5-(trifluoromethyl)-2-deoxyuridine, a known antiviral compound (eq 7).16

Reductions with Boron and Silicon Hydrides.

Sodium Borohydride,17 Sodium Cyanoborohydride,18 Borane-Tetrahydrofuran,19 and Triethylsilane20 have been used in conjunction with TFA to reduce a variety of functional groups. These reactions generally proceed by protonation of a functional group followed by delivery of hydride.

Of special note is the reduction of cobalt-complexed secondary a-alkynic alcohols with sodium borohydride and TFA.21 Oxidative decomposition of the resulting cobalt complex produces secondary alkynes in good to moderate yields. Production of the identical diastereomer from either epimeric alkynic alcohol is consistent with formation of a common intermediate by protonation and dehydration, followed by stereoselective hydride addition (eq 8).

Baeyer-Villiger Oxidations in TFA.

Trifluoroacetic acid has been reported to catalyze the action of m-Chloroperbenzoic Acid in the Baeyer-Villiger oxidation of cyclic and acyclic ketones.22

Trifluoroperacetic Acid (TFPAA) is remarkably efficient for the oxidation of ketones in the Baeyer-Villiger reaction.23 This reagent has been prepared from Trifluoroacetic Anhydride and concentrated Hydrogen Peroxide. Since 90% hydrogen peroxide is no longer available as a commercial reagent, alternatives are needed for classical oxidation procedures. A combination of TFA and sodium percarbonate has been used as a replacement for TFPAA in the Baeyer-Villiger reaction (eq 9).24 Yields vary between good to excellent. The procedure is not applicable to aliphatic ketones, as TFA esters are produced from transesterification with the solvent.

Cleavage of Nitrogen- and Oxygen-Protecting Groups.

Trifluoroacetic acid has found many applications in the removal of protecting groups. Examples include solvolysis under aqueous and anhydrous conditions. Groups that have been cleaved with TFA include N-Boc,25 N-benzyloxymethyl,26 benzyl ether,27 p-methoxybenzyl ether,28 t-butyl ether,29 t-butyloxymethyl ether,30 triphenylmethyl ether,31 and dimethyl acetals.32

Related Reagents.

Acetic Acid; Fluorosulfuric Acid; Formic Acid; Hydrochloric Acid; Hydrofluoric Acid; Oxalic Acid; Sulfuric Acid; p-Toluenesulfonic Acid; Trichloroacetic Acid; Triethylsilane-Trifluoroacetic Acid.


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Kirk F. Eidman

Scios Nova, Baltimore, MD, USA



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