Enantiomers polarimetry

The analytical capability of these matrices has been demonstrated for chiral amines [12, 13]. The procedure is illustrated in Fig. 8-4 for the separation of NapEtNH " CIO . Concentrated methanol/dichloromethane solutions of the racemic mixture were placed on a column containing the chiral macrocycle host. The enantiomers of the ammonium salts were resolved chromatographically with mixtures of methanol and dichloromethane as the mobile phase. The amounts of R and S salts in each fraction were determined by polarimetry. Because the chiral supported macrocycle interacts more strongly with S salts, the R salt passes through the column first and the S salt last, as seen in Fig. 8-4. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

A particular case of this kinetic system is the racemisation of an enantiomeric compound, i.e. Equation 4.4 where A and B are enantiomers, and k = k 1( the rate constant for enan-tiomerisation. The rate constant for the approach to equilibrium, measurable by polarimetry, is the rate constant for racemisation, which is twice the rate constant for enantiomerisation, kmc = 2h [11]. 

Polarimetry coupled to a liquid chromatograph has been used to determine the optical purity of drugs [113-121]. The advantages of this approach for determining optical purity is that the enantiomers do not need to be resolved and only eluates which give rise to optical rotation or circular dichro-ism are detected. This advantage makes on-line polarimetry inherently more accurate than conventional polarimetry because minor interfering compo-... 

HPLC was used to evaluate the enantiomeric resolution of dihydrope-pidine enantiomers (including nimodipine), using phenylcarbamates of polysaccharides as a chiral stationary phase [35]. A column (25 cm x 4.6 mm) packed with the arylcarbamate derivatives of amylase, cellulose, and xylem was used. Detection was effected using polarimetry at 435 nm. Using xylem bis-(3,5-dichlorophenylcarbamate) and a mobile phase (flow rate of 0.5 mL/min) of 0.1%, diethylamine in hexane-propan-2-ol (17 3) yielded separation of nimodipine. 

When possible, the resolution of enantiomers due to restricted rotation allows the study of racemization rates by polarimetry. This time-honored... 

Dimethyl-l-(aryl)pyrimidine-2(l//)-(thio)ones (134a-d) were resolved into enantiomers with D-camphor-10-sulfonic acid and their barriers to racemization determined by polarimetry (80JCS(P1)1599). These barriers deserve comment, since their trend is opposite to what is expected (Scheme 98). 

Differences in enantiomers become apparent in their interactions with other chiral molecules, such as enzymes. Still, we need a simple method to distinguish between enantiomers and measure their purity in the laboratory. Polarimetry is a common method used to distinguish between enantiomers, based on their ability to rotate the plane of polarized light in opposite directions. For example, the two enantiomers of thyroid hormone are shown below. The (5) enantiomer has a powerful effect on the metabolic rate of all the cells in the body. The (R) enantiomer is useless. In the laboratory, we distinguish between the enantiomers by observing that the active one rotates the plane of polarized light to the left. 

Just as solvents can serve as CSRs, it is possible to use enantiomerically pure solvents to provide the asymmetric environment necessary to differentiate enantiomers. This then allows us to determine the relative amount of two enantiomers in a mixture of them, something that is otherwise difficult to accomplish without resorting to polarimetry. Enantiomerically pure alcohol (R)-10-11 has been used as a solvent to differentiate the enantiomers of aminoester 10-1412 ... 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

In the laboratory, the technique of polarimetry is used to distinguish between enantiomers and to measure the extent to which each enantiomer rotates the plane of plane-polarised light. 

Dextrorotatory enantiomer predominates absolute configuration unknown. Determined by polarimetry. 

It is apparent from the preceding chapter that the analysis of enantiomers (by whatever means) addresses only part of the problem often, a stereoselective reaction produces a mixture of diastereomers, and polarimetry is an inappropriate technique. Thus, asymmetric synthesis requires the means for the analysis of both enantiomeric and diastereomeric mixtures. Ultimately, the ratio of isomers and the cofifiguration of each new stereocenter should be determined. 

If polarimetry is to be used for the analysis of enantiomers, is the specific rotation of the pure enantiomer known with certainty, or will it have to be determined ... 

The optical purity is usually, but not always, equal to enantiomer excess. In order for the two to be equal, it is necessary that there be no aggregation. It is possible, for example, that a homochiral or heterochiral dimer (see Glossary, Section 1.6, for definitions) would refract the circularly polarized light differently than the monomer (or each other). In 1968 [19] Krow and Hill showed that the specific rotation of (S)-2-ethyl-2-methylsuccinic acid (85% ee) varies markedly with concentration, and even changes from levorotatory to dextrorotatory upon dilution. In 1969 [20], Horeau followed up on Krow and Hill s observation, and showed that the optical purity (at constant concentration) and enantiomer excess of (5)-2-ethyl-2-methylsuccinic acid were unequal except when enantiomerically pure or completely racemic. This deviation from linearity is known as the Horeau effect, and its possible occurence should be remembered when determining enantiomeric purity by polarimetry. 

The discovery of the anomalies mentioned above are partly responsible for the declining popularity of polarimetry for the determination of enantiomer ratios. Even if the experimentalist is alert to these sources of error, the possibility still exists that an early determination of specific rotation, against which a new value must be compared, is itself in error. Thus, caution is advised. Nevertheless, if used carefully, polarimetry can provide a simple, efficient, and inexpensive method for the analysis of enantiomeric purity. 

Aimed at investigating the taste enhancing activity of the individual enantiomers of alapyridaine, enantiopure 1 was prepared upon reductive animation of 5-(hydroxymethyl)-2-furanaldehyde and L-alanine with Raney nickel/hydrogen. This reaction resulted in the corresponding ( S)-A -(1-carboxyethyl)-2-hydroxymethyl-5-(methylamino)furan (Figure 7). The latter was converted into the target pyridinium betain compound by mild oxidation with bromine in water/methanol to yield (+)-(iS)-l. Similarly, the reaction with D-alanine resulted in (-)-(R)-l. After purification, the presence of (5)-l and (R)-1 was proven by polarimetry, revealing optical rotations of +40.2° and -38.6°, respectively (72). 

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