NMR Determination of Enantiomeric Purity

Chiral heterocycles as reagents for NMR determination of enantiomeric purity 91CRV1441. 

Chiral Solvating Agent NEA is an effective chiral solvating agent for NMR determination of enantiomeric purity. The combination of enantiomerically pure NEA (3-5 mol excess) and racemic solute causes the NMR spectra of the diastereomerically solvated enantiomers to differ. Since NEA is an efficient hydrogen-bond acceptor, it solvates better if the solute is a hydrogen-bond donor. (R)-(+)-NEA has been used to determine the enantiomeric purity of a variety of substrates. ... 

When a chiral solute dissolves in a chiral solvent then a stereochemical interaction must be involved. The expense of using a chiral material as a bulk solvent for NMR determination of enantiomeric purity is rarely justified. A solvating agent is added in between 1 to 10 mole equivalents to a solution of the solute enantiomers in an achiral bulk... 

Pirkle WH, Tsipouras A. 3, 5-Dinitrobenzoyl amino acid esters. Broadly applicable chiral solvating agents for NMR determination of enantiomeric purity. Tetrahedron Lett. 1985 26 2989-2992. 

Offermann W, Mannschreck A. Chiral recognition of alkene and arene hydrocarbons by H and C NMR. Determination of enantiomeric purity. Tetrahedron Lett. 1981 22 3227 3230. 

As was already mentioned, the phenomenon of nonequivalence of NMR spectra of enantiomers in chiral solvents is a basis for the determination of enantiomeric purity of a variety of chiral sulfur compounds. This method, developed by Pirkle, has the advantage over other methods of being absolute that is, the chemical shift difference between enantiotopic nuclei induced by the chiral solvent increases with increasing optical purity of the solvent, whereas the relative intensities of the signals that are used to measure the enantiomeric composition of the solute are not affected. 

NMR spectroscopy the NMR spectrum of the sample in the presence of a chiral solvating agent (see Section 3.1.4.1.) or a chiral paramagnetic lanthanide shift reagent (see Section 3.1.4.2.2.) is recorded. The determination of enantiomeric purity rests on the nonequivalence of externally enantiotopic nuclei which are rendered externally diastereotopic in a non-racemic chiral environment. 

At present, polarimetry and allied techniques such as circular dichroism, NMR spectroscopy (employing nonracemic solvents or shift reagents) and various types of chromatography (employing nonracemic stationary or mobile phases) are the most widely used techniques for the direct determination of enantiomeric purities, and only these techniques are discussed further (see Sections 3.1.3. to 3.1.5.). 

The determination of enantiomeric purity (ee) by NMR spectroscopy is usually carried out with the help of a nonracemic chiral auxiliary compound. NMR methods not requiring a chiral auxiliary compound are also known and are based on self-association of the enantiomers or on their reaction with a bifunctional achiral compound (see Section 3.1.4.7.). 

NMR methods that do not require a chiral auxiliary compound for the determination of enantiomeric purities are based on... 

I.3. 2-Chloro-4-methyl-5-phenyl-l,3,2-oxazaphospholidine 2-Sulfide for the Determination of Enantiomeric Purities of Amines by a "P-NMR Technique... 

Determination of Enantiomeric Purity of Chiral Aldehydes Using F-NMR Spectroscopy of Their Diastereomeric Imidazolidines... 

The development of accurate methods for the determination of enantiomeric purity, which began in the late 1960 s, has been critical for the assessment of enantioselective synthesis. Thus a prerequisite in the enzyme-catalyzed kinetic resolution of racemates is a precise and reliable assessment of the degree of enantioselectivity (E), enantiomeric excess (ee) and conversion (c). Among these methods are 1) polarimetric methods, 2) gas chromatographic methods, 3) liquid chromatographic methods and 4) NMR spectroscopy. The most convenient and sensitive methods used are chiral GC and HPLC. 

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,... 

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%.

KV Anderson, H Bildspe, HJ Jakobsen. Determination of enantiomeric purity from solid-state 31P NMR of organophosphorus compounds. Magn Res Chem 28 S47-S51, 1990. 

MOSHER S ACID for Chirality Determination Synthesis and use of a-methoxy-a-(trifluoromethyl)phenylacetic acid (MTPA) 4, a chiral reagent for determination of enantiomeric purity of alcohols or amines by NMR. 

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