Optical purity, by NMR

Optical purity, by NMR, 13, 14 Orbital correlation diagrams, 196-203 cycloaddition reactions, 197-196 Diels-Alder, 198 ethylene -E ethylene, 198 electrocyclic reactions, 198-200 butadienes, 199 hexatrienes, 199 limitations, 203 photochemical, 201 Woodward-Hoffinann, 197 Orbital energies, see also Energies, orbital degeneracy, 27, 90 Orbital interaction theory, 34-71 diagram, 40, 42, 47 limitations, 69-71 sigma bonds, 72-86 Orbitals... 

Wenzel TJ, Bogyo MS, Lebeau EL. Lanthanide-cyclodextrin complexes as probes for elucidating optical purity by NMR spectroscopy. J. Am. Chem. Soc. 1994 116 4858-4865. 

The list of drugs analyzed for optical purity by 1H NMR spectroscopy with lanthanide shift reagents is given in Table 10.7. 

The accuracy of the determination will depend upon the accuracy of peak areas used in the calculation, perhaps 2% - . For a crystalline complex, a single crystallization of material of >95% ee will almost certainly bring it to complete optical purity, in which case the absence of NMR signals for the minor diastereomer of the complex to within the limits of sensitivity of the NMR spectrometer will be the criterion for complete optical purity of the arsine. Since the displacement of an arsine from a configurationally homogeneous complex of this type is stereospecific with retention of configuration at arsenic and can be carried out under mild conditions, the arsine liberated will also be optically pure. However, to be certain of the optical purity of the arsine the diastereomer should be re-prepared on a small scale and checked once again for purity by NMR spectroscopy. 

The submitters report obtaining the product in 99% yield. The enantiomeric excess of the Mosher ester of 3 was measured to be 98% using a Chiralcel OD column (40% 2-propanol/hexane). This optical purity measurement substantiated the optical purity assessment made by 111 NMR studies of 3 and racemic 3 prepared using a different method3. Addition of the chiral shift reagent tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium (III) resulted in clear resolution of the respective aromatic proton signals for the two enantiomers, which was demonstrated with the racemate. Under similar conditions, NMR analysis of 3 showed that within the detectable limits of the experiment (ca. <3%), there was none of the disfavored enantiomer. 

Optically active (+)- and (—)-p-(/-propylmethylphenylstannyl) benzoic acids (56) and their methyl esters (57) were similarly prepared by Lequan four years later 38) (see Table 3). They are characterized by very low optical rotations. Furthermore, the diastereomeric brucine salts via which the acids were resolved, are characterized by almost identical NMR spectra that cannot be used to follow their separation so that no precise information is available about the optical purity of (56) and (57). 

This is a member of an interesting class of compounds which are chiral, without actually containing a defined chiral centre. They are chiral because their mirror images are non-superimposable. In the case of this molecule, there is no rotation about the bond between the two naphthol rings because of the steric interaction between the two hydroxyl groups, d and T forms can be isolated and are perfectly stable (Optical purity determination by H NMR, D. R Reynolds, J. C. Hollerton and S. A. Richards, in Analytical Applications of Spectroscopy, edited by C. S. Creaser and A. M. C. Davies, 1988, p346). 

The spectral properties of this product are the same as that of the racemate (see Note 10). The optical purity is higher than 98% as confirmed by 1H NMR of its salt with (L)-mandelic acid.7... 

Optical purity checked by NMR analysis of the MTPA ester. 

H) [a]D -64.1° (CHCI3), c 1.0). The optical purity of this adduct was 95% as determined by 200 MHz 1H NMR spectroscopy and GC analysis (capillary column PEG, 0.25 mm x 25 m, purchased from Gaskuro Kogyo Company, Ltd. in Japan) after conversion to the corresponding chiral acetal as follows A solution of the adduct, (2R,4R)-(-)-pentanediol (1.2 equiv, obtained from Wako Pure Chemical Industries), triethyl orthoformate (1.2 equiv), and p-toluenesulfonic acid monohydrate (as a 5 mM solution) in dry benzene is stirred at ambient temperature for 3 hr. The mixture is poured into saturated sodium bicarbonate and the product is extracted with ether. The... 

NMR spectroscopy was found to be a valuable technique for differentiation between the enantiomers of optically active compounds. The principles of the methods used to distinguish between enantiomers by means of NMR have been developed and reviewed by Mis-low and Raban (217). The best results from the point of view of the determination of optical purity and absolute configuration of chiral sulfur compounds, especially of sulfinyl compounds, have been obtained with the help of chiral solvents (218). Pirkle (86) was the first to demonstrate that enantiomeric sulfoxides have nonidentical NMR spectra when dissolved in chiral alcohols having the following general formula ... 

An interesting method for the estimation of optical purity of sulfoxides, which consists of the combination of chemical methods with NMR spectroscopy, was elaborated by Mislow and Raban (241). The optical purity is usually determined by the conversion of a mixture of enantiomers into a mixture of diastereomers, the ratio of which may be easily determined by NMR spectroscopy. In contrast to this, Mislow and Raban used as starting material for the synthesis of enantiomeric sulfoxides a diastereomeric mixture of pinacolyl p-toluenesulfinates 210. The ratio of the starting sulfinates 210 was 60.5 39.5, as evidenced by the H NMR spectrum. Since the Grignard reaction occurs with full stereospecificity, the ratio of enantiomers of the sulfoxide formed is expected to be almost identical to that of 210. This corresponds to a calculated optical purity of the sulfoxide of 20%. In this way the specific rotations of other alkyl or aryl p-tolyl sulfoxides can conveniently be determined. 

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. 

Recently, new examples of asymmetric induction in the Pummerer reaction of chiral sulfoxides have been described. Oae and Numata (301) reported that the optically active a-cyanomethyl p-tolyl sulfoxide 275 undergoes a typical Pummerer rearrangement upon heating with excess of acetic anhydride at 120°C, to give the optically active a-acetoxy sulfide 276. The optical purity at the chiral a-carbon center in 276, determined by means of H- NMR spectroscopy using a chiral shift reagent, was 29.8%. 

Simultaneous deprotection and cyclization of diols 60a and 60b with 3 M HCl in MeOH followed by acetylation yielded the 2,3-trans- ( 50%) (61a and 61b) and for the first time 2,3-cw-flavan-3-ol methylether acetate derivatives ( 20%) (62a and 62b) in excellent enantiomeric excesses (>99%). The optical purity was assessed by H NMR using [Eu(hfc)3] as chiral shift reagent. The absolute configuration of the derivatives of the tram- and cii-flavan-3-ol derivatives was assigned by comparison of CD data with those of authentic samples in the catechin or epicatechin series flavan-3-ols. Thus, the absolute configuration of the flavan-3-ol methyl ether acetates confirms the assigned configuration of the diols as derived from the Sharpless model. 

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). 

The optical purity of MTPA is checked conveniently using both readily available optically pure forms of phenylethylamine as a CDA15c. The H-NMR signal of the methyl group of the amine part is shifted for the (R,R) or (5,5)-diastereomer by 5 — 0.06 to higher field than for the (R.S) or (S, R) form (<5 = 1.46). A larger chemical shift difference of 5 = 0.15 can be observed in the l9F-NMR spectrum the trifluoromethyl group of the (R,R)- or (S.S)-diastereomer appears at S = 7.55 versus 7.30 for the (R,S) or (S,R) form, both dowmfield from trifluoroacctic acid. 

Like amino acids, the optical purity of sterically hindered a-substituted a-hydroxy acids can be determined by H NMR after reaction with (5)-2-chloropropanoyl chloride58. 

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