Enantiomeric purity by NMR

Chiral shift reagents are used for the determination of enantiomeric purity by NMR. Resonances of enantiomers give rise to different chemical shifts in the chiral environment,... 

Combining cryocooled probes and high magnetic fields enabled monitoring of enantiomeric purity by NMR of deuterium at natural abundance using liquid crystalline solvents. This allows for the discrimination between enantiomeric forms of compounds, which previously could not be resolved. 

Overall, Mosher s reagent, although still useful for the determination of enantiomeric purity by NMR spectroscopy, is not recommended for the determination of the absolute configuration of secondary alcohols by NMR. Such assignments should be made using other, more-reliable reagents. 

Figure 5. Determination of enantiomeric purity by enantioselective H-NMR spectroscopy. The N-methyl signals in the H-NMR spectrum obtained from 1.1 mg of indolinospirobenzoxazine 4 in CDClj at 400 MHz are shown. Scales give chemical shifts 5. Left ( (-4) in the presence of 9 equivalents of (Sy 1 -(9-anthryl)-2,2,2-trifluoroethanol. Right Enriched (+ >4 in the presence of 11 equivalents of the same alcohol electronic integration yields an enantiomeric purity of 42 3%.

The enantiomers of camphorcarboxylic and sulfonic acids are used for resolution of enantiomers from racemic chiral amines and alcohols via diastereomeric salts and esters, respectively. Europium(III)- and praseodymium(III)-chelates of hydroxy-methylenecamphor derivatives are suitable chiral shift reagents for the determination of enantiomeric purity by integration of NMR spectra, because they exchange ligands with enantiomeric substrates such as alcohols and amines, thus forming diastereomeric chelates characterized by different spectra. 

Enantiomers cannot be distinguished in an achiral medium by their NMR spectra because their resonances are chemical shift equivalent (isochronous). In contrast, diastereomers may be distinguished because certain resonances are chemical shift non-equivalent (anisochronous). Determination of enantiomeric purity using NMR requires the intervention of a chiral auxiliary to convert an enantiomeric mixture into a mixture of diastereomers. Provided that the magnitude of the observed chemical shift non-equivalence is sufficient to give baseline... 

Szawkalo J, Zawadzka A, Wojtasiewicz K, Leniewski A, Drabowicz J, Czarnocki Z. First enantioselective synthesis of the antitumour alkaloid (+)-crispine A and determination of its enantiomeric purity by IH NMR. Tetrahedron Asymm. 2005 16(22) 3619-3621. 

Acylation of various oxygen functions by use of common and commercially available fluonnated carboxylic acid denvatives such as trifluoroacetic anhydride or the corresponding acyl halides have already been discussed sufficiently in the first edition [10] Therefore only exceptional observations will be described in this section In the past 15 years, many denvatizations of various nonfluonnated oxygen compounds by fluoroacylation were made for analytical purposes. Thus Mosher s acid chlorides for example became ready-to-use reagents for the determination of the enantiomeric purity of alcohols and amines by NMR or gas-liquid chromatographic (GLC) techniques [//] (equation 1)... 

Thus, the enantiomeric contents in a pair of sulphoxides can be determined by the NMR chemical shifts in the methine or methylene protons in the two diastereomeric complexes which are stabilized by the hydrogen bond between the hydroxyl and the sulphinyl groups147-151 (Scheme 13). Similarly, the enantiomeric purity and absolute configurations of chiral sulphinate ester can be determined by measuring the H NMR shifts in the presence of the optically active alcohols152. 

The pyrroline-iV-oxide 411 lost enantiomeric purity in the deprotection step. The THP protecting group could be deprotected under very mild conditions using Amberlyst 15 in methanol. However, the mixture was obtained in low yield accompanied by partial or total racemization as indicated by variation of specific rotation. Racemization also occurred during purification by silica gel chromatography or recrystallization. The lack of configurational stability of the nitrone 411 may be explained with the occurrence of a fast (not detectable by NMR), nitrone-hydroxyenamine tautomerism (Scheme 91). 

Compound 22 can be conveniently prepared in multigram quantities and has been found to be useful for assessing the enantiomeric purity of 1,2-glycols. Because the ketal carbon represents a new chiral center, the formation of four diastereomers is possible. However, the diastereomeric pair 23a and 23b (or 23c and 23d) shows 1 1 peak height in 13C NMR or equal peak areas in HPLC the diastereomer composition measured by the ratio of 23a to 23b or 23c to 23d reflects the enantiomer composition of the original 1,2-glycol. 

The enantiomeric purity of vinylsilane (S)-3a and (R)-3c are determined to be >95% ee by 1H-NMR (400 MHz) on the derived mandelate ester, obtained by a DCC-promoted coupling to (R)-O-acetylmandelic acid, and absolute stereochemical assignment is accomplished by 1H NMR analysis of the derived (R)-O-acetyl-mandelate esters. For details of this procedure see the published method of Trost.3... 

Barretta and coworkers63 reported a direct determination of the enantiomeric purity of chiral trisubstituted allenes by using permethylated cyclodextrin as a chiral solvating agent. They found that the heptakis ft-cyclodextrin TRIMEB discussed above can be successfully used as a chiral solvating agent (CSA) for the NMR determination of the enantiomeric purity of trisubstituted allenes llOa-f. An accurate analysis of the experimental conditions (molar ratio aliene/TRIMEB, temperature and solvent) required to optimize the enantioseparation has been carried out. The XH NMR spectra of TRIMEB, allenes llOa-f, and the mixtures TRIMEB/allene have been recorded at 300 MHz in CD3OD as solvent. 

The enantiomeric purity was checked by the H-NMR method of Mislow and Raban (60). The absolute configurations of the major alcohol isomers were all R. 

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