Trifluoromethyl groups hydrolysis

Trifluoromethyl groups are very resistant to hydrolysis, unless they are allylic or benzylic, or vicinal to a carbon linked to hydrogen. In the last case, elimination of hydrogen fluonde leads to the formation of a difluoromethylene group which is key to additional reactions... 

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])... 

Because of the strong electron-withdrawing effect of the trifluoromethyl group, trifluoroacetamides are subject to hydrolysis under mild conditions. This has permitted trifluoroacetyl groups to be used as amino-protecting groups in some situations. 

Various diastereomeric di-, tri-, and tetrapeptides that carry the sterically demanding trifluoromethyl group instead of the natural a-proton at different positions within these short peptide sequences have been designed, and their stability towards enzymatic hydrolysis has been investigated. The structures of the a-trifluoromethyl (aTfm)-substituted amino acids are shown in Scheme 1. From these studies we gained valuable information on how a-trifluoromethyl-substi-tuted peptides may interact with proteins. The aTfm amino acids used in this study combine the conformational restrictions [49-52] of C -dialkylation with the unique stereoelectronic properties of the fluorine atom and have shown interesting effects on peptide-enzyme interactions [53,54]. 

Hydrolysis of Trifluoromethyl Groups To Form Carboxy Groups... 

Aliphatic trifluoromethyl groups generally resist hydrolysis, both in acidic or alkaline media, unless adjacent to a C = C bond. Hydrolysis of a trifluoromethyl group attached to an aromatic nucleus requires rather energetic conditions. Thus, perfluoro(l,2-dimethylbenzene) is hydrolyzed by oleum to give tetrafluorophthalic acid (l).162... 

Alkaline hydrolysis of a trifluoromethyl group attached to an aromatic nucleus is assisted by the presence of an electron-donating substituent in the aromatic ring, especially in the 2- or 4-position.168-171... 

The electron-withdrawing power of the trifluoromethyl group in the 2,2,2-tn-fluoroethyl ether of 9-hydroxy-9-(dinitromethyl)fluorene considerably retards its hydrolysis compared with simple alkyl ethers [59] (equation 57)... 

This bibliographical survey shows the wide range of syntheses of the fluorinated difunctional compounds, whatever the position of the fluorinated substituent in the molecule. However, major efforts were developed, for example, to protect a group from hydrolysis in the case of esters protected by gera-trifluoromethyl groups. Actually, because of the electroattractive effects of the difluoromethyl groups in a position about the functions, the fluorinated polyesters and polyurethanes exhibit weak points which affect the applications of such polymers. 

Because of the activation of the benzene ring by electron-donating substituents, hydrolysis of the trifluoromethyl group linked to the aromatic ring occurs easier than without such assistance. 

Many N-unsubstituted pyrazoles 80 can be obtained from A-allyl-A-nitrosamides 79 (Scheme 46) <1990H(30)789>. Cyclocondensation of -alkoxyvinyl trifluoromethyl ketones 81 with thiosemicarbazide under mild conditions affords 4,5-dihydro-l//-pyrazole-l-thiocarboxamides 82, which can be easily dehydrated with concomitant thiocarboxamide group hydrolysis in concentrated sulfuric acid to give N-unsubstituted pyrazoles 83 (Scheme 47) <1998JFC(92)23>. 

Likewise, lipase-catalyzed hydrolysis of racemic lactam 99 gave both 100 and 101 in almost enantiomerically pure form (see Scheme 9.23). Conventional chemical conversion of the isobutenyl moiety of 101 to difluoromethyl and trifluoromethyl groups provided lactams 103 and 104, which were further transformed to dipeptide 106 by ring-opening coupling with amino esters [48]. 

Table IV contains selected examples of the enzymatic resolution of esters with various structures. As was discussed above, enhancement of the optical purity was possible by changing the acyl group or the enzyme (Run 1,2 or 6,7). Noteworthy is the fact that acetate 5 with a trifluoromethyl group was converted by lipase MY into the alcohol with (R) absolute configuration without exception in every case, when the stereochemistry has been determined. However, substrates with the other fluorine-containing substituents furnished alcohols whose asymmetric configuration depended on their structures. Particularly interesting is the relationship between Runs 4 and 5 (18), when resolution was accompanied with simultaneous separation of diastereomers. To the best of our knowledge, this is the first example of the type of resolution of both diastereomers and enantiomers by enzymatic hydrolysis in a single transformation.

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