Mechanism nucleophilic trifluoromethylation

Scheme 2.127 Mechanism of the nucleophilic trifluoromethylation of carbonyl compounds by Me3SiCF3 [59, 65],...

A. Nucleophilic Reactions of the P=0 Group.—Tris(trifluoromethyl)-phosphine oxide (33) reacts with hexamethyldisiloxane to give a phos-phorane, whose n.m.r. spectrum at — 140 °C shows non-equivalent trifluoromethyl groups. Although this unusual reaction clearly involves nucleophilic attack of the phosphoryl oxygen on silicon at some stage of the reaction, a full study of the mechanism has not been published. Tertiary phosphine oxides can be converted cleanly into dichlorophos-phoranes (34) by treatment with two moles of phosphorus pentachloride. Alkylation of the sodium salt of tetraphenylmethylenediphosphine dioxide (35) with alkyl halides, in dimethyl sulphoxide, has been reported to... 

The addition of a nucleophile to an aromatic ring, followed by elimination of a substituent, results in nucleophilic substitution. The major energetic requirement for this mechanism is formation of the addition intermediate. The addition step is greatly facilitated by strongly electron-attracting substituents, and nitroaromatics are the best reactants for nucleophilic aromatic substitution. Other EWGs such as cyano, acetyl, and trifluoromethyl also enhance reactivity. 

The enhanced reactivity of 3-cyano-, 3-sulfonyl-, and 3-(trifluoromethyl)allyl chlorides compared with that of allyl or 2-buten-l-yl chloride can also be explained by a mechanism analogous to that sketched in Scheme 4.43, in which the nucleophile... 

The same mechanism has been proposed for the reaction of diazo compounds with either fluorine or trifluoromethyl hypofluorite (Scheme 3). Thus, nucleophilic attack of the polarized diazo compound at the fluorine atom of fluorine or trifluoromethyl hypofluorite, followed by reaction of the intermediate with X (F or CF3O ) yields the g w-diIluoro compound or the fluoro(trifluoromethoxy) derivative. 

An example of cleavage ot the sulfur-oxygen bond in trifluoromethane-sulfonic ester has been reported Trifluoromethyl triflate reacts with neutral or anionic nucleophiles with elimination of carbonyl difluonde and formation of trifluoromethanesulfonyl fluoride [57] (equation 37) The mechanism of this reaction involves elimination of fluoride ion, which is a chain earner in the substitution of fluorine for the trifluoromethoxy group... 

Thiolates are powerful nucleophilic reagents. However, we observed no reaction when trifluoromethyl bromide is bubbled through a potassium thiophenoxide solution in DMF at room temperature. This failure was in agreement with the inertness reputation of this halide. Assuming that a mechanism involving radical anions (Fig. 4, X = Br) could occur, a minimal concentration of the halide should be necessary to maintain the chain process. In order to increase the amount of trifluoromethyl bromide in solution, we performed the reaction under pressure. Indeed, condensation occurred at room temperature in a glass apparatus under 2-3 bars (Fig. 5) (refs. 16,17). Inhibition of this condensation by nitrobenzene was clearly observed, in agreement with the SET process (Fig 4, X = Br). A similar trifluoromethylation of thiols by trifluoromethyl bromide in liquid ammonia under UV irradiation has also been described (ref. 18). 

Either mechanism explains why trifluoroacetylation of the nucleophile does not occur. Protonation of the anhydride would occur selectively at the more electron-rich carbonyl oxygen, rather than at the carbonyl flanked by the very electron-with-drawing trifluoromethyl group. Similarly, cleavage of the unsymmetrical anhydride would occur to give the more stable acylium ion. The trifluoroacetylium ion would be highly unstable. 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

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