Agent, chiral resolving

A group attached to a chiral carbon normally has the same chemical shift whether the chiral carbon has RoiS configuration. However, the group can be made diastereotopic in the NMR (have different chemical shifts) when the racemic parent compound is treated with an optically pure chiral resolving agent to produce diastereomers. In this case, the group is no longer found in two enantiomers but in two different diastereomers, and its chemical shift is different in each environment. 

For instance, if the partly resolved amine -phenylethylamine, a mixture containing both the R and S enantiomers, is mixed with optically pure (S)-(4-)-0-acetyhnandelic aeid in an NMR tube containing CDCI3, two diastereomers form  

The doublets which appear may be integrated in order to determine the pereentages of the R and S amines in the mixture. In the example, the NMR spectmm was determined with a mixture made by dissolving equal quantities (a 50/50 mixture) of the original umesolved ( )-a-phenyl-ethylamine and a student s resolved produet, which contained predominantly (iS)-(-)-a-phenyl-ethylamine. 

We have seen that the spectra of enantiomers, acquired under normal conditions, are identical. The NMR spectrometer does not differentiate between optically pure samples, and racemic ones. The wording is carefully chosen, particularly normal conditions , because it is often possible to distinguish enantiomers, by running their spectra in abnormal conditions - in the presence of a chiral resolving agent. Perhaps the best known of these is (-)2,2,2,trifluoro-l-(9-anthryl) ethanol, abbreviated understandably to TFAE. (W.H. Pirkle and D.J. Hoover, Top. Stereochem., 1982,13, 263). Structure 7.4 shows its structure. 

The use of TFAE is demonstrated in Spectrum 7.4, which shows the appearance of proton b , before and after the addition of 30 mg of (+)TFAE to the solution. (This is the region of interest - it is usually protons nearest the chiral centre, which show the greatest difference in chemical shifts in the pair of 

Another useful reagent of this type is chiral binaphthol (see Structure 7.5). 

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). 

Optically pure mandelic acid (see Structure 7.6) can be a useful chiral resolving agent where the compound you are looking at has a basic centre, as it can form an acid-base pair with it, which is a stronger form of association. This compound is of sparing solubility in CDCI3 however and can precipitate out your compound if, as is often the case, its protonated form is of low solubility in CDCI3. 

FIGURE 8.22 The lOO-MHz NMR spectrum of 1-hexanol with 0.29-mole equivalent of Eu(dpm)3 added. (From Sanders, J. K. M., and D. H. Williams, Chemical Communications (1910) 442. Reprinted by permission.) 

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The methyl groups in the amine portion of the salts are attached to a steieocenter, S in one case and R in the other. As a result, the methyl groups thanselves are now diastereotopic, and they have diffoent chemical shifts. In this case, the R isomer is downfield, and the S isomer is upheld. Since the methyl groups are adjacent to a methine (CH) group, they appear as doublets at approximately 1.1 and 1.2 ppm, respectively, in the NMR spectrum of the mixture (the exact chemical shifts vary shghtly with concentration) (Fig. 8.23). 

These doublets may be integrated to determine the exact percentages of the R and S amines in the mixture. In the example shown, the NMR spectrum was determined with a mixture made by dissolving 

FIGURE 6.23 The 300-MHz H spectrum of a 50-50 mixture of (5 )-a-phenylethylamine from a resolution and unresolved (racemic) Ot-phenylethylamine in CDCI3 with the chiral resolving agent (5 )-(+)-0-acetylmandelic acid added. 

Similarly, an optically pure amine can be used as a chiral resolving agent to analyze the optical purity of a chiral carboxylic acid. For example, addition of optically pure (S)-(-)-a-phenylethylamine to a CDCI3 solution of O-acetytmandeUc acid will form diastereomeric salts as illnstrated above. In this case, one would look for the two doublets (one for each enantiomer) from the Ph-CH-OAc methine between 5 and 6 ppm in the NMR spectrum. 

When one needs to determine the optical purity of a compound that is not amenable to salt formation (i.e., not a carboxylic acid or amine), analysis by NMR becomes slightly more difficult. It is frequently necessary to determine the enantiomeric excesses of chiral secondary alcohols, for example. In these cases, derivatization of the alcohol through covalent attachment of an optically pure auxiliary provides the mixture of diastereomers for analysis. This requires reacting a (usually small, a few milligrams) sample of sample alcohol with the optically pure derivatizing agent. Sometimes, purification of the products is necessary. In the example shown below, a chiral secondary alcohol is reacted with (5)-2-methoxyphenylacetic acid [(5)-MPA] using dicyclohexylcarbodiimide (DCC) to form diastereomeric esters. After workup, the NMR spectrum of product mixture is acquired, and the res- 

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The most direct method is the separation of the enantiomers by HPLC using chiral columns. It has the advantage that there is no risk of contamination from chiral resolving agents. The formation of diastereoisomers... 

In a related study, Rieke and Guijarro studied the configurational stability of the zinc-carbon bond in 2-butylzinc bromide and (l-phenylprop-2-yl)zinc bromide, using a bis(oxazoline) as a chiral resolving agent.72 From their data, the authors determined the A 6 of inversion at the secondary carbon of (l-phenylprop-2-yl)zinc bromide to be 113.8 kj mol-1. 

JB Vincent, G Vigh. Nonaqueous capillary electrophoretic separation of enantiomers using the single isomer heptakis(2,3-diacetyl-6-sulfato)-cyclodex-trin as chiral-resolving agent. J Chromatogr A 816 233—241, 1998. 

A Family of Single-Isomer, Sulfated y-Cyclodextrin Chiral Resolving Agents for Capillary Electrophoresis, Anal. Chem. 2000, 72, 310. 

An overwhelming majority of classic resolutions still involve the formation of diastereomeric salts of the racemate with a chiral acid or base (Table 6.1). These chiral-resolving agents are relatively inexpensive and readily available in large quantities (Table 6.2). They also tend to form salts with good crystalline properties.8... 

Chiral acids or bases are tested for salt formation with the target racemate in a variety of solvents. The selected diastereomeric salt must crystallize well, and there must be an appreciable difference in solubility between the two diastereoisomers in an appropriate solvent. This type of selection process is still a matter of trial and error, although knowledge about the target racemate and the available chiral-resolving agents and experience with the art of crystallization does provide significant help.9-11... 

Hydrolysis of (R)-butan-2-ol tartrate gives (R)-butan-2-ol and ( + )-tartaric acid, and hydrolysis of (S)-butan-2-ol tartrate gives (,S )-butan-2-ol and ( + )-tartaric acid. The recovered tartaric acid would probably be thrown away, since it is cheap and nontoxic. Many other chiral resolving agents are expensive, so they must be carefully recovered and recycled. 

Chromatography of radiochemically homogeneous terpenoids has been reviewed useful gas-chromatographic techniques reported include the use of polyphenyl ether in g.c.-m.s. of 23 monoterpenoid hydrocarbons,the use of 3,4,5-trimethoxybenzylhydrazine for pre-column removal of aldehydes and ketones, and the resolution of some bicyclic alcohols and ketones by co-injection with a volatile chiral resolving agent. 

A chiral resolving agent is a chiral mobile-phase additive or a chiral stationary phase that preferentially complexes one of the enantiomers. 

Such mirror images are called enantiomers. Either chiral mobile-phase additives or chiral stationary phases are required for these separations. Preferential com-plexation between the chiral resolving agent (additive or stationary phase) and one of the isomers results in a separation of the enantiomers. The chiral resolving agent must have chiral character itself to recognize the chiral nature of the solute. 

Chiral stationary phases have received the most attention. Here, a chiral agent is immobilized on the surface of a solid support. Several different modes of interaction can occur between the chiral resolving agent and the solute." In one type, the interactions are due to attractive forces such as those between ir bonds, hydrogen bonds, or dipoles. In another type, the solute can fit into chiral cavities in the stationary phase to form inclusion complexes. No matter what the mode, the ability to separate these very closely related compounds is of extreme importance in many fields. Figure 32-16 shows the separation of a racemic mixture of an ester on a chiral stationary phase. Note the excellent resolution of the R and S enantiomers. 

Resolution of racemic mixtures using a chiral resolving agent is based on the formation of two diastereoisomeric entities, usually salts differing in their solubility, leading to preferential crystallization of one of them (Figure 13.3). The chemical nature of the racemate usually defines the compatible chemical character of the... 

The choice of an appropriate sheath liquid and its flow rate is essential to achieve good performance. This choice is a compromise between separation (to maintain an efficient electrophoretic separation) and ionization performances (to assist droplet formation and spray stability). Most CE-ESI-MS applications described in the literature for the analysis of protonated compounds use a sheath liquid containing a mixture of organic solvent, water and formic or acetic acid. In method development, the impact of the nature of the sheath liquid on the expected chiral separation can be evaluated by placing it in the outlet vial. The solubility of the chiral resolving agent in the sheath liquid has to be carefully investigated to avoid its precipitation at the spray needle. 

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