THE TRIFLUOROMETHYL GROUP

The trifluoromethyl group has become an important structural component of many bioactive compounds, mainly because of its polar influence and its effect on the lipophilicity of compounds. 

NMR Spectra of Compounds Containing the CF3 Group - General Considerations 

Guide to Fluorine NMR for Organic Chemists, Second Edition. William R. Dolbier, Jr. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

FIGURE 5.1. Examples of bioactive compounds containing a CF3 group 

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Attack at the meta position leads to a more stable intermediate than attack at either the ortho or the para position and so meta substitution predominates Even the inter mediate corresponding to meta attack however is very unstable and is formed with dif ficulty The trifluoromethyl group is only one bond farther removed from the positive charge here than it is m the ortho and para intermediates and so still exerts a significant although somewhat diminished destabilizing inductive effect... 

As Table 12 2 indicates a variety of substituent types are meta directing and strongly deactivating We have already discussed one of these the trifluoromethyl group Several of the others have a carbonyl group attached directly to the aromatic ring... 

General Properties. The trifluoromethyl group is stable under different reaction conditions, eg, the multistep classical transformation of ben2ottifluoride to ttifluoroacetic acid features successive nitration, reduction, and oxidation. 

Reactions Involving the Trifluoromethyl Group. Aluminum chloride effects chlorinolysis of ben2otrifluoride to give ben2otrichloride (307). High yields of volatile acid fluorides are formed from ben2otrifluoride and perfluorocarboxyUc acids (308). 

Fluorination and iodination reactions are used relatively littie in dye synthesis. Fluorinated species include the trifluoromethyl group, which can be obtained from the trichi oromethyl group by the action of hydrogen fluoride or antimony pentafluoride, and various fluorotria2iQyl and pyrimidyl reactive systems for reactive dyes, eg, Cibacron F dyes. 

Steric factors would ordinarily be expected to induce a preference for the larger group to move outward and thus generate the -isomer. It was observed, however, that in the case of l,2,3,4-tetrafluoro-tran5-3,4-bis(trifluoromethyl)cyclobutene, ring opening occurred with an inward rotation of the trifluoromethyl groups. ... 

The reaction ot tormamides with sulfur tetrafluoride in the presence of potassium fluoride leads to replacement of both carbonyl oxygen and hydrogen with fluorine. The formyl group is directly converted into the trifluoromethyl group A-(trifluoromethyl)amines are formed in near quantitative yields [233] (equation 121)... 

Hydrolysis of the trifluoromethyl group of 2 tnfluoiomethylimidazoles is promoted by the formation of the anion, which readily eliminates fluoride. The resultant ditluorodiazafulvene then easily adds water The remaining steps in the hydrolysis ate predictable When aqueous ammonia is used, 2-cyanoimidazoles result [40] (equation 4])... 

Recently developed trifluoromethylatmg agents capable of transferring the trifluoromethyl group as a cation to strongly nucleophilic compounds such as carbanions and sulfur and phosphorus nucleophiles are prepared from o-biphenyl trifluoromethyl sulfoxide [164] and are shown in equation 141... 

The bond between the trifluoromethyl group and boron is difficult to form Preparation of trifluoromethyl aminohoranes was successfully achieved by transfer of trifluoromethyl group from reagent 2, which was prepared in situ [107] (equation 85)... 

Similarly, 6-mercaptopurine in alkaline medium adds across the triple bond in 3,3,3-trifluoropropyne to form the carbon-sulfur bond to the carbon more remote from the trifluoromethyl group In trifluoromethyl-ferf-butyldiacetylene, the bond is formed to the carbon adjacent to the trifluoromethyl group [5] (equation 6)... 

Binucleophiles give regiospecific addition to trifluoromethylacetylene with and without subsequent cyclization. Initial attack by the softer nucleophile occurs preferentially at the carbon p to the trifluoromethyl group [6] (equation 7). 

The directing influence of the trifluoromethyl group also competes with that of the strongly electron-donating methoxyl group. Thus 2-methoxy-5-trifluoromethyl-l,4-benzoquinone (26) was treated with ethyl 3-aminocrotonate (5) to furnish 25% of each of the two possible isomeric indoles 27 and 28. °... 

Bischler-Napieralski reaction conditions can be attributed, again, to the destabilizing ability of the trifluoromethyl group to the cationic transition state of the acid catalyzed elimination. Formation of compound 29 was ultimately accomplished by base catalyzed methanol elimination-conditions conditions that are quite unusual for isoquinoline formation. 

Trihalomethyl groups have a-constants similar to those of the halogens but seem to be generally much less reactive than chlorine. However, convenient displacement of the former is often possible. Chlorine is more reactive than the trifluoromethyl group in 4-chloro-and 4,6-dichloro-2-trifluoromethylpyrimidine and the 5-nitro derivative of the latter thus ammonia or hydrosulfide ion gave the 4-and 4,6-analogs. In the isomeric 2,6-dichloro-5-nitro-4-trifluoro-... 

Toluene is more reactive the trifluoromethyl group is electron-withdrawing. 

Thenoyltrifluoroacetone(TTA), C4H3S,CO,CH2,COCF3. This is a crystalline solid, m.p. 43 °C it is, of course, a /1-diketone, and the trifluoromethyl group increases the acidity of the enol form so that extractions at low pH values are feasible. The reactivity of TTA is similar to that of acetylacetone it is generally used as a 0.1-0.5 M solution in benzene or toluene. The difference in extraction behaviour of hafnium and zirconium, and also among lanthanides and actinides, is especially noteworthy. 

The hydrophilic group numbers of the sodium sulfonate (SOj Na+) is +11.0, of methylene (CH2) groups (and also for the methyl group) -0.475, and of difluoromethylene (CF2) groups (also valid for the trifluoromethyl group)... 

The preparative reactions were conducted in sealed tubes in which — 1-3 g of the reagents had been placed. After the vessels had been maintained at the indicated temperatures for the designated times, the contents were removed, to be separated by fractional condensation and GLC. In addition to the (trifluoromethyl)Group 4A halides reported next, each sample contained unreacted (CFalaHg, the expected (tri-fluoromethyDmercuric halide, and the mercuric halide, identified by fluorine-NMR spectroscopy and mass spectrometry. 

The main products of photolysis of 3-trifluoromethyl-4-nitrophenol are 2,5 dihydroxy-benzoate produced by hydrolytic loss of the nitro group and oxidation of the trifluoromethyl group, together with a compound identified as a condensation product of the original compound and the dihydroxybenzoate (Figure 1.5) (Carey and Cox 1981). 

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