[407-25-0] · C4F6O3 · Trifluoroacetic Anhydride · (MW 210.04)
(activating agent; oxidation)
Alternate Name: TFAA.
Physical Data: mp -65 °C; bp 39-40 °C; d 1.487 g cm-3.
Solubility: sol C6H6, CH2Cl2, Et2O, DMF, THF, MeCN.
Form Supplied in: colorless liquid; commercially available.
Analysis of Reagent Purity: by standard analytical techniques.
Preparative Methods: by distilling Trifluoroacetic Acid from Phosphorus(V) Oxide.1
Handling, Storage, and Precautions: corrosive and moisture sensitive; toxic by inhalation; should be freshly distilled prior to reaction. Use in a fume hood.
Mixed anhydrides may be prepared by reaction of carboxylic acids with trifluoroacetic anhydride.2 The method has been used widely as a means of activating carboxyl groups to nucleophilic attack. The method has also been highly useful in Friedel-Crafts acylation of arenes (eqs 1 and 2).3,4 Sulfonic acids are also activated to nucleophilic attack; substituted sulfones result. Intramolecular Friedel-Crafts reactions are also facilitated, but only for formation of six-membered rings.5
Anhydrides of diacids are prepared in (about) 90% yield by reaction with TFAA in ether.6 The method involves formation of the monotrifluoroacetyl mixed anhydride, which may be converted to the cyclic anhydride by heating under vacuum (eq 3).7
An inversion of alkene geometry is made possible by the reaction of their derived epoxides with lithium halides and TFAA (eq 4);8 the products of this reaction are the corresponding halohydrin trifluoroacetates, which undergo a syn elimination upon reaction with Lithium Iodide.
Primary alkanols and 2-alkenols are converted into the corresponding halides in high yield by a one-pot, two-step reaction via transformation into intermediate trifluoroacetates, followed by nucleophilic substitution with lithium halides (eq 5).9
Sulfoxides are reduced to sulfides under mild conditions with Trifluoroacetic Anhydride-Sodium Iodide (eq 6).10
Primary amides are converted under mild conditions to the corresponding nitriles using TFAA in pyridine (eq 7).11 Similarly, aldoximes are converted to nitriles by TFAA in pyridine (eq 8).12
TFAA in triethylamine can be used for the dehydration of aldols to enones where other methods are less successful (eq 9).13 When Acetic Anhydride is employed instead of TFAA, the reaction proceeds slowly.
The Pummerer rearrangement of sulfoxides to a-acyloxy sulfides, induced by TFAA, has been used as a means of converting sulfoxides to aldehydes (eq 10).14
Methyl aryl sulfides are converted in a mild, one-pot, three-step procedure via Pummerer rearrangement of the corresponding sulfoxides, and without purification of intermediates, to provide arylthiols in excellent yields (eq 11).15
Trifluoroacetoxydimethylsulfonium trifluoroacetate is prepared in situ from Dimethyl Sulfoxide and TFAA below -50 °C and reacts rapidly with alcohols in the presence of Triethylamine to give the corresponding carbonyl compounds (eq 12).16
TFAA/DMSO also efficiently converts vicinal diols to the corresponding a-dicarbonyl compounds or derivatives thereof (eq 13).17 Unlike the Swern oxidant (Dimethyl Sulfoxide-Oxalyl Chloride), this reagent mixture gives good yields for halogenated substrates. The preparation of previously inaccessible compounds (such as s-homo-ortho-benzoquinones) is thus facilitated.
Undesired electrophilic chlorination as a side-reaction in Swern oxidations is avoided by use of TFAA in place of oxalyl chloride.18 See also Dimethyl Sulfoxide-Trifluoroacetic Anhydride.
Enamines of a-amino acids react rapidly with TFAA to give pyrrole derivatives (eq 14).19
The reaction of TFAA with triethylamine N-oxide leads to formation of the trifluoroacetate salt of N,N-dimethylformaldimmonium ion. This ion is a superior reagent in the Mannich reaction.20
TFAA is used to prepare trifluoroacetamides from amines; these amides may be used in Gabriel-type reactions. The use of TFAA delivers an amide of enhanced acidity and which is easily hydrolyzed in situ, thereby allowing a one-pot alkylation process (eq 15).21
Reaction of TFAA with ammonium nitrate provides an in situ source of trifluoroacetyl nitrate, which has been used for the nitration of enol acetates22 and as an N-nitrating agent.23
TFAA efficiently cleaves N-tosyl protecting groups from histidine (eq 16).24
Joseph Sweeney & Gemma Perkins
University of Bristol, UK