Enantiomeric purity determination

Monobasic solutes that have no carbinyl hydrogens may also show nonequivalence. 3-Methyl-2-butanone, 4-methyl-2-pentanone, 2-methylpropanal, methyl 2-methylbutyrate, 2,2,6,6-tetramethyl-piperidine, methyldiisopropylcarbinol, and methylethyl-n-butyl-carbinol in TFAE-saturated benzene all show nonequivalence of sufficient magnitude (0.01-0,03 ppm) to allow nonequivalence sense determination at 220 MHz. An especially striking example is that provided by pyrazolines 26. With only a severalfold excess of (S)-TFAE, 3(5),5(S)-enriched samples of these compounds show nonequivalence in their methyl resonances (downfield sense for the singlets and upfield sense for the triplets) sufficient for enantiomeric purity determination at 90 MHz (52). 

In general, the observation of opposite senses of nonequivalence for substituents on opposite faces of the plane defined by primary and secondary interactions will be the hallmark of a normal solvation model. Deviations are of no consequence for enantiomeric purity determinations but should raise questions concerning the validity of the usual model for the assignment of absolute configuration based on the observed senses of nonequivalence. Since knowledge of solute structure often allows anticipation of such third interactions, ... 

The use of chiral lanthanide shift reagents (CLSRs) for NMR enantiomeric purity determination has become very popular (6) since the first of these compounds (54a) was reported by Whitesides and Lewis (96). Reagents 54b [Eu(hfbc)3 or Eu(hfc)3] and 54c [Eu(facam)3 or Eu(tfc)3] subsequently independently introduced by Fraser (97) and Goering (98), are most widely used, and are commercially available. 

For enantiomeric purity determination, the CSA and CLSR techniques are complementary. When both methods work for a given solute, the CSA method is the more easily implemented. 

Dolezalova, M. and Tkaczykova, M., HPLC enantioselective separation of aromatic amino and hydrazino acids on a teicoplanin stationary phase and the enantiomeric purity determination of L-isomers used as drugs. Chirality, 11, 394, 1999. 

Sanger-van de Griend, C. E., Ek, A. G., Widahl-Nasman, M. E., and Andersson, E. K. M. (2006). Method development for the enantiomeric purity determination of low concentrations of adrenaline in local anaesthetic solutions by capillary electrophoresis. /. Pharm. Biomed. Anal. 41, 77—83. 

Marini, R. D., Servais, A.-C., Rozet, E., Chiap, P., Boulanger, B., Rudaz, S., Crommen, J., Hubert, P., and Fillet, M. (2006). Nonaqueous capillary electrophoresis method for the enantiomeric purity determination of 5-timolol using heptakis(2,3-di-0-methyl-6-0-sulfo)-p-cyclodextrin validation using the accuracy profile strategy and estimation of uncertainty. /. Chromatogr. A 1120(1—2), 102-111. 

Muijselaar, P. G., hammers, N. G. E M., and Gerding, T. K. (2004). Development and validation of a capillary electrophoresis method for the enantiomeric purity determination of SLV307, a basic potential antipsychotic compound. Electrophoresis 25(16), 2854—2859. 

Blanco, M., Gonzalez, J. M., Torras, E., and Valverde, I. (2003). Enantiomeric purity determination of ketoprofen by capillary electrophoresis development and validation of the method. Anal. Bioanal. Chem. 375(1), 157-163. 

Huang et al. [96] developed a method for the enantiomeric purity determination of (6 )-ornidazole in raw material and injection solution that was used in an preclinical study. In this publication, a mobile phase of n-hexane, MeOH, and 2-PrOH (95 4 1) was used with a Chiralcel OB-H column. No chiral impurity (/ )-ornidazole was detected above the LOD (0.05%) in either the raw material or the injection solution (see Figure 17.4D and E). The separation of the racemate is presented in Figure 17.4A, and the minor peak in Figure 17.4B corresponds to an enantiomeric impurity of 0.5%. 

The precision of enantiomeric purity determinations by gas chromatography is high123 124-1 >s. This statement holds not only for small enantiomeric purities ( 0% ee), e.g., in the differentiation of a true racemate from enantiomerically slightly enriched mixtures (in reactions devoted to the amplification of optical activity under prebiotic conditions), but also for very high enantiomeric purities (— 100% ee), with detection of 1.0 to 0.1% (and less) of enantiomeric impurities (see Section 3.1.5.8). It is always advantageous if the enantiomer present as an impurity is eluted as the first peak from the gas chromatographic column (Section 3.1.5.3.). This is achieved by the proper selection of the chirality of the nonracemic stationary phase147-188 which, unfortunately, is not possible for the cyclodextrin phases. 

The idea of two sequential detectors, one conventional the other chiroptical, is the basis of a third strategy for enantiomeric purity determinations using HPLC. It differs from the previous two by not involving a chiral separation. In it the enantiomers co-elute and the total amount is determined from an absorbance measurement. Subsequently a chiroptical... 

An interesting feature of this study is the enantiomeric purity analysis of the products. By converting the amine functionality of the pyrrolidine to a 3,5-dinitrobenzamide, the substrate can be analyzed by chiral HPLC. To date, the 3,5-dinitrobenzamide of 2-substituted pyrrolidines that the submitters have prepared have beer baseline-resolved by the Pirkle S-N1 N-Naphthylleucine column. This approach obviates the need for MPTA-derivativization which has been previously employed in enantiomeric purity determinations.3 5... 

Enantiomeric purities determined by capillary GC analysis of the (-)-menthyloxycarbonyl derivative, and have been corrected by adding 1% to the experimentally observed values to correspond to values for optically pure catalyst. ... 

The unique ability of the optical rotation detector to respond to the sign of rotation allows precise enantiomeric purity determination even if the enantiomers are only partially resolved. The sign of rotation is also useful in establishing enantiomer elution order. 

Because the optical rotation detectors only respond to optically active compounds, enantiomeric purity determination to precisions of better than 0.5% can be achieved and is possible in even the complex mixtures. The detection can also be used as part of a flow injection analysis system to determine amount and enantiomeric purity of a drug in dosage form. 

Advances in ILs have made synthesis of chiral ILs a subject of intense study in recent years.The popularity stems from the fact that it is possible to use chiral ILs as chiral solvents for optical resolutions, for asymmetric induction in synthesis and as chiral stationary phase in chromatography. It may also be possible to use chiral IL to replace the solvent as well as the added carbohydrate compound for tire enantiomeric purity determination method. Specifically, the chiral IL with its high solubility... 

KA Assi, BJ Clark, KD Altria. Enantiomeric purity determination of propanolol by capillary electrophoresis using dual cyclodextrins and a polyacrylamide-coated capillary. Electrophoresis 20 2723-2725, 1999. 

Yamamoto, A., Akiba, N., Kodama, S., Matsunaga, A., Kato, K., and Nakazawa, H., Enantiomeric purity determination of malic acid in apple juices by multibeam circular dichroism detection, J. Chromatogr. A, 928, 139, 2001. 

---