As the anhydride will form trifluoroacetic acid in contact with water, an excess of the anhydride also serves to remove the solvent from the peroxide reactant:[9]
A more dilute hydrogen peroxide solution (30%) can be used to form trifluoroperacetic acid for some reactions from trifluoroacetic acid.[2]
CF 3COOH + H 2O 2 → CF 3COOOH + H 2O
In order to avoid the danger of handling pure or highly concentrated solutions of hydrogen peroxide, hydrogen peroxide – urea can be used to give the peracid.[5] This method involves no water, so it gives a completely anhydrous peracid,[10] which is an advantage when the presence of water leads to side reactions during certain oxidation reactions.[11]
In cases where a pH buffering agent is needed for a synthesis and where the presence of water is tolerated, another approach has been developed. Reacting trifluoroacetic anhydride with sodium percarbonate, 2Na 2CO 3·3H 2O 2, yields trifluoroperacetic acid and sodium carbonate, obviating the need for an additional buffer.[5][12]
Trifluoroperacetic acid can also be generated in situ,[13] allowing it to react promptly with the target substrate rather than pre-synthesizing a batch of the reagent for later use.
Trifluoroperacetic acid is primarily used as an oxidising agent.[5][7] In September 1953, the Journal of the American Chemical Society published work by William D. Emmons and Arthur F. Ferris reporting that this reagent, generated in situ, was capable of oxidising anilinetonitrobenzene.[13] Over the following two years, Emmons reported a preparative method for this reagent and published six further manuscripts in this journal on its applications;[14][15][16] Emmons is remembered in part as the pioneer[6] and developer[7] of trifluoroperacetic acid as a laboratory reagent, which has since become useful as a reagent for many different types of synthetic reactions.
One example is the formation of the hypervalent iodine compound (bis(trifluoroacetoxy)iodo)benzene, (CF 3COO) 2IC 6H 5 which is used to carry out the Hofmann rearrangement under acidic conditions.[17] The hypervalent compound is accessible in two ways, and which is chosen usually depends on what materials are available: it can be prepared from its acetate analogue by an exchange reaction,[18] or by reacting iodobenzene with a combination of trifluoroperacetic acid and trifluoroacetic acid:[17]
Trifluoroperacetic acid is one of the strongest reagents used for Baeyer–Villiger oxidations, as a consequence of its high acidity relative to similar peracids and peroxides.[19]: 17 This reaction converts ketones to either straight-chain estersorlactones, and is named for Adolf von Baeyer and Victor Villiger, who first reported it 1899.[1] The reaction is believed to proceed via a Criegee intermediate[5] and demonstrates good regioselectivity and chemoselectivity for the position of oxygen atom insertion, along with retention of stereochemistry at the adjacent position, as can be seen in the following example. The disodium phosphate (Na 2HPO 4) is added as a pH buffer[2] to prevent the highly acidic trifluoroacetic acid byproduct from causing hydrolysis[20]ortransesterification[21] of the ester product.
The high reactivity of trifluoroperacetic acid relative to other peroxy acids allows it to successfully oxidize relatively electron-poor alkenes such as 1-hexene and α,β-unsaturated esters such as methyl methacrylate, substrates that are generally resistant to peroxy-acid epoxidation.[2] Including additional buffered trifluoroacetic acid in the mixture gives a vicinal hydroxy–trifluoroacetate structure instead of an epoxide, which can be converted to the diol by treatment with acidic methanol, such as in the following conversion of 1-dodecene to 1,2-dodecanediol.[2]
The preparation of the isomeric compound sporol involved a similar dioxolane formation. In this case, the use of trifluoroperacetic acid derived from hydrogen peroxide, which therefore presumably contained traces of water, gave mostly a hemiacetal rather than the closed-ring dioxolane. The use of the urea complex, which gave a water-free material, successfully gave the dioxolane as the major product.[11] The dioxolane is expanded to the 1,3-dioxane system found in sporol at a later step in the synthesis.[25]
Functional groups containing heteroatoms in low oxidation states can be oxidised by trifluoroperacetic acid.[5][7] Common cases include the oxidation of iodine (for example, the formation of the hypervalent iodine compound from iodobenzene mentioned earlier), nitrogen, sulfur, and selenium.
In the case of chalcogen elements, sulfide moieties (R–S–R) can be oxidised by trifluoroperacetic acid to sulfoxide (R–S(O)–R) and/or sulfone (R–S(O)2–R) forms, depending on the conditions used.[5] In the analogous selenium system, trifluoroperacetic acid oxidation of selenoethers (R–Se–R) produces selones (R–Se(O)2–R) without the formation of the related selenoxides (R–Se(O)–R) as an isolable product,[3] a reaction which is particularly effective when the R is an aryl group.[29] A general approach to the formation of sulfinyl chlorides (RS(O)Cl) is the reaction of the corresponding thiol with sulfuryl chloride (SO 2Cl 2). In cases where the sulfenyl chloride (RSCl) results instead, a subsequent trifluoroperacetic acid oxidation affords the desired product, as in the case of 2,2,2-trifluoro-1,1-diphenylethanethiol:[30]
The trifluoroperacetic acid oxidation of thiophene illustrates competing pathways for reaction, with both S-oxidation and epoxidation being possible.[31][Note 2] The major pathway initially forms the sulfoxide, but this chemical promptly undergoes a Diels-Alder-type dimerisation before any further oxidation occurs—neither thiophene-S-oxide or thiophene-S,S-dioxide are found among the products of the reaction.[5][31] The dimer can then be oxidized further, converting one of the S-oxide moieties to an S,S-dioxide. In the minor reaction pathway, a Prilezhaev epoxidation[22] results in the formation of thiophene-2,3-epoxide that rapidly rearranges to the isomer thiophene-2-one.[31]Trapping experiments[35] demonstrate that this epoxide pathway is not an alternative reaction of the S-oxide intermediate, and isotopic labeling experiments demonstrate that a 1,2-hydride shift (anNIH shift) occurs and thus that a cationic intermediate is involved.[31] The choice of trifluoroperacetic acid preparation method is important as water suppresses the minor reaction pathway, likely because it acts as a competing base.[31]
For alkenes, the reaction gives a ketone product, though the mechanistic process is not simply epoxidation followed by a BF3-catalyzed Wagner–Meerwein rearrangement:[36]
For aromatics, an example demonstrated in an Organic Syntheses report is the conversion of hexamethylbenzene to 2,3,4,5,6,6-hexamethyl-2,4-cyclohexadienone:[9]
In addition to simple oxidation of aromatic rings to form carbonyl compounds (see § Oxidation with acidic rearrangement), trifluoroperacetic acid can fully cleave the carbon–carbon bonds within the ring. Unlike other oxidations of alkylaromatic structures, which yield benzoic acids and related compounds by cleavage of the alkyl chain at the reactive benzylic position, trifluoroperacetic acid causes an "inverse oxidation", cleaving the aromatic ring itself while leaving the alkyl group intact.[37][38]
This selectivity for certain types of bonds allows it to be used to decompose complex mixtures of hydrocarbons, such as coal, in order to determine structural details.[39][37]
Aromatic systems containing heteroatoms are resistant to this ring-opening as heteroatom oxidation occurs preferentially and deactivates the ring towards electrophilic attack by the peroxy acid. For example, purines, pyridines, and quinolines instead form N-oxides,[5] while sulfur systems like octafluorodibenzothiophene are converted to sulfones.[7][40]
Aromatic systems with ring-activating substituents can be oxidised to form phenols instead of undergoing a ring-opening reaction. Mesitylene, for example, reacts with trifluoroperacetic acid to form mesitol (2,4,6-trimethylphenol).[7] Researchers attempting to form a lactone by Baeyer–Villiger oxidation of 7-oxodeacetamidocolchicine were unable to prepare the desired product, but did achieve oxidation of the aromatic ring to produce a phenol-derivative in high yield:[5][41]
^Three condensed structural formulae are used to represent trifluoroperacetic acid, CF 3COOOH, CF 3CO 3H, and CF 3C(O)OOH. They are equivalent and can be used interchangeably.
^Such competitions can have biochemical significance. For example, it is known that the loop diuretic pharmaceutical agent tienilic acid acts as a suicide substrate at cytochrome P450 enzymes and that the process involves thiophene oxidation, but the oxidation pathway responsible remains unclear despite considerable research activity.[32][33][34]
^Cooper, Mark S.; Heaney, Harry; Newbold, Amanda J.; Sanderson, William R. (1990). "Oxidation Reactions Using Urea–Hydrogen Peroxide; A Safe Alternative to Anhydrous Hydrogen Peroxide". Synlett. 1990 (9): 533–535. doi:10.1055/s-1990-21156. S2CID196724921.
^ abcdZiegler, Fredrick E.; Metcalf, Chester A.; Nangia, Ashwini; Schulte, Gayle (1993). "Structure and total synthesis of sporol and neosporol". J. Am. Chem. Soc.115 (7): 2581–2589. doi:10.1021/ja00060a006.
^Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. (1978). "Carbon-carbon bond formation promoted by transition metal carbonyls. 19. General synthesis of tropane alkaloids via the polybromo ketone-iron carbonyl reaction". J. Am. Chem. Soc.100 (6): 1786–1791. doi:10.1021/ja00474a021.
^ abPirrung, Michael C.; Morehead, Andrew T.; Young, Bruce G., eds. (2000). "10. Neosporol, Sporol". Part B: Bicyclic and Tricyclic Sesquiterpenes. The Total Synthesis of Natural Products. Vol. 11. John Wiley & Sons. pp. 222–224. ISBN978-0-470-12963-0.
^Brooke, G. M.; Burdon, J.; Tatlow, J. C. (1961). "Aromatic polyfluoro-compounds. Part VII. The reaction of pentafluoronitrobenzene with ammonia". J. Chem. Soc.: 802–807. doi:10.1039/JR9610000802.
^Williams, W. Michael; Dolbier, William R. (1969). "Thermal and photochemical rearrangements of azine oxides. I. Pyrolytic decomposition to nitriles". J. Org. Chem.34 (1): 155–157. doi:10.1021/jo00838a034.
^Mansuy, Daniel; Valadon, Philippe; Erdelmeier, Irene; López Garcia, Pilar; Amar, Claudine; Girault, Jean-Pierre; Dansette, Patrick M. (1991). "Thiophene S-Oxides as new Reactive Metabolites: Formation by Cytochrome P-450 Dependent Oxidation and Reaction with Nucleophiles". J. Am. Chem. Soc.113 (20): 7825–7826. doi:10.1021/ja00020a089.
^Hart, Harold; Lerner, Lawrence R. (1967). "Oxidations with peroxytrifluoroacetic acid-boron trifluoride. IX. Direct oxidation of alkenes to ketones using peroxytrifluoroacetic acid–boron fluoride". J. Org. Chem.32 (9): 2669–2673. doi:10.1021/jo01284a004.
^Chambers, R. D.; Cunningham, J. A.; Spring, D. J. (1968). "Polyfluoroaryl organometallic compounds. Part VIII. Synthesis of and nucleophilic substitution in octafluorodibenzofuran". J. Chem. Soc. C: 1560–1565. doi:10.1039/J39680001560.
^Berg, Ulf; Bladha, Håkan; Mpamposa, Konstantinos (2004). "Stereochemical variations on the colchicine motif. Peracid oxidation of thiocolchicone. Synthesis, conformation and inhibition of microtubule assembly". Org. Biomol. Chem.2 (14): 2125–2130. doi:10.1039/B402840F. PMID15254641.