Trifluoro-1-phenylethanol

Scheme 21 Oxidation of 2,2,2-trifluoro-1 -phenylethanol with Ar3BiCl2-DBU oxidants [81]...

In 1965, Raban and Mislow [90] postulated that nuclei placed in an asymmetric magnetic field should show NMR nonequivalence. In 1966, Pirkle [91] first reported the validity of the prediction when it was shown that (5)-l-phenylmethylamine caused F-NMR nonequivalency of 2,2,2-trifluoro-1-phenylethanol in a carbon tetrachloride solution. In later studies, 2,2,2-trifluoro-l-(9-anthryl)ethanol, an NMR shift reagent, was used as a mobile-phase additive to separate 2,4-dinitrophenyl methyl sulfoxide on a silica gel column [92]. Later, one enantiomer of this fluoroalcohol was covalently attached to silica gel and used for resolution of a large number of solutes including sulfoxides, lactones, derivatives of alcohols, amines, amino acids, hydroxy acids, and mercaptans [93]. 

The CSAs that have been used most widely are 2,2,2-trifluoro-l-phenylethanol (TFPE, la), 2,2,2-trifluoro-l-(l-naphthyl)ethanol (TFNE, lb), 2,2,2-trifluoro-l-(9-anthryl)ethanol (TFAE, Ic), 1-phenylethylamine (PEA, 2a), and l-(l-naphthyl)ethylamine (NEA, 2b). Both enantiomers of TFPE, TFAE (9), PEA, and NEA are commercially available. The fluoroalcohols are relatively acidic and interact strongly with solutes having one or more basic sites (Sect. IV-B). Amines 2 have been used most often as CSAs for organic acids or other acidic solutes (Sect. IV-C). A number of analogs of TFAE have been studied (Sect. III-C). 

Interestingly, the newly developed Ar3BiCl2/DBU oxidants [Ar = p-nitrophenyl, p-(trifluoromethyl)phenyl] rapidly oxidize 2,2,2-trifluoro-l-phenylethanol [81], which is generally known to resist oxidation [85-87], to the corresponding trifluor-omethyl ketone within 5-50 min at room temperature (Scheme 21). The difference in the reaction rates among the bismuth(V) oxidants is in good agreement with the results obtained for the intermolecular competition experiments. 

In 1965, the determination of the enantiomeric purity (ee) by NMR spectroscopy using a chiral solvating agent (CSA)69- 73 was first postulated17 and demonstrated experimentally by Pirkle in 1967. An example is the nonequivalence of the proton and fluorine resonances of racemic 2,2,2-trifluoro-l-phenylethanol in the presence of optically active 1-phenylethanamine78 or l-(l-naphthyl)ethanamineS3 (Figure 5). 

Figure 5. NMR spectra of 2.2,2-trifluoro-l-phenylethanol (optically enriched) in 0 racemic and optically active l-(l-naphthyl)ethanaminc83.

Nafie LA, Cheng JC, Stephens PJ (1975) Vibrational circular dichroism of 2,2,2-trifluoro-l-phenylethanol. J Am Chem Soc 97 3842-3843... 

A number of optically active oxaziridines have been synthesized by the photolysis of the corresponding nitrones in (+) or (—)2,2,2-trifluoro-l-phenylethanol/ fluorotrichloromethane as solvents (Table 6). ... 

Thirdly, in the case of completely or partially racemic alcohols, it is possible to create diastereomeric esters by reaction with one enantiomer of a chiral carboxylic acid. One acid that gives consistently good results is Mosher s acid, 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (52) (see Dale et al.u). With a chiral alcohol, e.g. 1-phenylethanol, a pair of diastereoisomers, 53 and 54, is formed (Scheme 8.5). 

Although Lowry iu his classical treatise in 1935 discussed the possibility of detection of circular dichroism arising from molecular vibration transitions, only in the past two decades has it been possible to measure optical activity associated with infrared absorption transitions, CD maxima first being detected in the VCD spectrum for the C—H stretching modes of the enantiomers of 2,2,2-trifluoro-l-phenylethanol as the neat liqnid . This work was initiated with the view that such measurements would eventually yield information concerning absolute configurations and molecular conformations of... 

A soln. of benzaldehyde and tetra- -butylammonium bromide in DMF cooled to — 10° in a cell fitted with a foamy Ni cathode surrounding a sacrificial Zn rod anode, and electrolyzed at a constant current of 0.3 A with bromotrifluoromethane bubbling through the soln. for ca. 4-5 h 2,2,2-trifluoro-l-phenylethanol. Y 95%. The dissolving (sacrificial) zinc anode is essential in what is effectively an electro-assisted Barbier-type synthesis. The reaction is general with aldehydes, and reasonable yields are obtained with easily reducible ketones (preferably with added TMEDA). F.e.s. S. Si-bille et al.. Tetrahedron 45, 1423-8 (1989). 

With the exception of (2,2,2)-trifluoro-l-phenylethanol, which shows a very small twisting power of opposite handedness, all aromatic derivatives show a correlation between their absolute chirality (the R, S nomenclature is misleading owing to the different priority... 

The deviating case of (2,2,2)-trifluoro-l-phenylethanol can be understood by considering a different interacting configuration with the Schiff bases, characterized by a double hydrogen bond(18). 

Distinct NMR resonances were first observed for the enantiomers of 2,2,2-trifluoro-l-phenylethanol in the presence of (/ )-phenylethylamine. With (/ )-2-naphthylethylamine the magnitude of the non-equivalence was increased. A systematic study of a series of aryl alcohols in the presence of amines showed a consistent correlation between the sense of non-equivalence and the absolute configuration of the alcohol. From the simple solvation models proposed, the reciprocality of the CSA approach is evident, i.e. if chiral A can be used to assay racemic B then chiral B can be used to assay racemic A. With this in mind 1 -(9-anthryl)-2,2,2-trifluoroethanol (15a) was developed as a CSA for chiral amines. It is also effective with alcohols, lactones, a-amino acid esters, a-hydroxy acid esters and sulphoxides and is the most widely used chiral solvating agent. Other more specific solvating agents have been developed. Kagan has developed A -(3,5-dinitrobenzoyl)-l-phenylethylamine,forexample, as a CSA specifically for the assay of chiral sulphoxides prepared from sulphides by a modified Sharpless oxidation (section 6.3.2). 

Nitrile I-CyanO 2,2,2-trifluoro-I-phenylethanol. 2,2,2-Trifluoroacetophenone cyanohydrin CqH[Pg.608]

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