Optical isomers, determination

Infrared spectroscopy has broad appHcations for sensitive molecular speciation. Infrared frequencies depend on the masses of the atoms iavolved ia the various vibrational motions, and on the force constants and geometry of the bonds connecting them band shapes are determined by the rotational stmcture and hence by the molecular symmetry and moments of iaertia. The rovibrational spectmm of a gas thus provides direct molecular stmctural information, resulting ia very high specificity. The vibrational spectmm of any molecule is unique, except for those of optical isomers. Every molecule, except homonuclear diatomics such as O2, N2, and the halogens, has at least one vibrational absorption ia the iafrared. Several texts treat iafrared iastmmentation and techniques (22,36—38) and thek appHcations (39—42). 

Compounds analogous to the cobaltammines may be similarly obtained using chelating amines such as ethythenediamine or bipyridyl, and these too have played an important role in stereochemical studies. Thus ct5-[Co(cn)2(NH3)Cl] was resolved into d(+) and /(—) optical i.so-mers by Werner in 1911 thereby demonstrating. to all but the most determined doubters, its octahedral stereochemistry. More recently, the absolute configuration of one of the optical isomers of [Co(en)3] was determined (.sec Panel on p, 1125),... 

Then, as described in U.S. Patent 3,158,648, the optical isomers may be resolved as follows. 37 g of racemic a-methYl-3,4-dihYdroxYphenylalanine are slurried at 35°C in 100 cc of 1.0 N hydrochloric acid. The excess solids are filtered leaving a saturated solution containing 34.6 g of racemic amino acid of which about 61% is present as the hydrochloride. The solution Is then seeded at 35°C with 7 g of hydrated L-o -methYl-3,4-dihYdroxYphenYlalanine (6.2 g of anhydrous material). The mixture is then cooled to 20°C in 30 minutes and aged one hour at 20°C. The separated material Is isolated by filtration, washed twice with 10 cc of cold water and dried in vacuo. The yield of product is 14.1 g of L-a-methYl-3,4-di-hydroxyphenylalanine in the form of a sesquihydrate of 100% purity as determined by the rotation of the copper complex. 

Where the drug studied is a racemate, the pharmacokinetics, including potential interconversion, of the individual enantiomers should be investigated in Phase I clinical studies. Phase I or II data in the target population should indicate whether an achiral assay, or monitoring of only one optical isomer where a fixed ratio is confirmed, will be adequate for pharmacokinetic evaluation. If the racemate has already been marketed and the sponsor wishes to develop the single enantiomer, additional studies should include determination of any conversion to the other isomer and whether there is any difference in pharmacokinetics between the single enantiomer administered alone or as part of the racemate. 

Martens et al. [28] reported a system for resolving the optical isomers, and determining the enantiomeric purity of ( )-penicillamine by thin-layer chromatography. 

One of the important functions of the infrared spectroscopy is to determine the identity of two compounds. The infrared region 4000 cm-1 -650 cm-1 is of great importance in studying an organic compound. Since IR spectra contain a number of bands no two compounds will have the same IR spectrum (except optical isomers). Thus IR spectra may be regarded as finger print of a molecule. 

Normal-phase liquid chromatography is thus a steric-selective separation method. The molecular properties of steric isomers are not easily obtained and the molecular properties of optical isomers estimated by computational chemical calculation are the same. Therefore, the development of prediction methods for retention times in normal-phase liquid chromatography is difficult compared with reversed-phase liquid chromatography, where the hydrophobicity of the molecule is the predominant determinant of retention differences. When the molecular structure is known, the separation conditions in normal-phase LC can be estimated from Table 1.1, and from the solvent selectivity. A small-scale thin-layer liquid chromatographic separation is often a good tool to find a suitable eluent. When a silica gel column is used, the formation of a monolayer of water on the surface of the silica gel is an important technique. A water-saturated very non-polar solvent should be used as the base solvent, such as water-saturated w-hexane or isooctane. 

Newly used chiral surfactants often have a low critical micellar concentration, are highly soluble and can be synthesized both in L- and D-forms. This last feature makes it possible to easily change the migration order of the optical isomers, which is very interesting for the determination of the optical pnrity of drugs, where for quantification purposes it is favorable that the chiral impurity migrates before the main component. 

TcCl3(NCCH3) (C6H4Me-3)3 2], the reaction with phen, bipy, or terpy gave the dark blue (531) and [Tc(phen)3] + (532) or black [Tc(terpy)2] " (533), respectively, in good yields. The structure of (531) was determined. Both optical isomers were found to be present in the crystal. 

Major efforts to determine the structures of the optically active alkaloids were made with cryptaustoline iodide, and preliminary examination showed that the molecular formula could be expressed as CjgHjj(OH)(OCH3)3(NCH3)" I . Products obtained after Hofmann degradation and ozonolysis were identical with compounds obtained earlier by Robinson and Schopf from racemic 14, and the structure as one of the optical isomers of O-methylcryptaustoline iodide was established. 

Under all applied conditions only C 0F4g is formed, probably as three different optical isomers [24—26] (Figure 9.1). Gakh and co-workers determined the correct structure on the basis of F NMR spectroscopy [24]. The structure was confirmed by resolution of the X-ray crystal structure [25, 26]. This shows that, probably, all three optical isomers - namely the two enantiomeric forms with Dj-symmetry and the mesoform with Sg-symmetry- can be foimd in the crystal (Figure 9.1, structures 11 and 12). 

Only, a few sugars are found in Nature in the form of both optical isomers (for example, galactose and arabinose). It is intriguing to speculate on the special conditions that determine the presence of the rarer form (for instance, the limiting of D-fucose to certain plant and microbial products), and on the specific pathways involved in their metabolism. 

The structure of A1(acac)3 contains an octahedral A106 core, with At—O distance of 189.2 pm. Differences of the monoclinic a form and orthohombic y form (a racemate) lie chiefly in the orientations of molecules within the crystal bond distances are almost identical.181 Resolution of the optical isomers of Al(acac)3 has twice been achieved by column chromatography at low temperature.182183 The hexafluoro compound, Al[(OCCF3)2CH]3, m.p. 74 °C, is more volatile than Al(acac)3. Its structure, determined by vapour phase ED,184 reveals a slightly distorted A106 unit in which the A1—O distance of 189.3 pm is the same as that in Al(acac)3. Comparative studies have been made of the Raman spectra of M(acac)3 (M= Al, Ga or In)185 and of other j8-diketonates of these metals.186... 

The cone angles of optical isomers are, of course, identical, but it has been demonstrated that chiral phosphines in homogenous catalytic systems can determine a reaction pathway to form asymmetric products.199 Clearly the chirality of the phosphine is the determining factor in these systems, although other essential characteristics of the phosphine ligand s bulk and the it acidity still... 

Chiral separation by HPLC is a practically useful method not only for determining optical purity but also for obtaining optical isomers, and numerous CSPs are presently on the market. In order to achieve the efficient resolution of chiral compounds, we have to choose a suitable chiral column and eluent. The polysaccharide-based CSPs have a high chiral recognition ability and offer a high possibility for the successful resolution of racemates including aliphatic and aromatic compounds with or without functional groups under normal and reversed-phase conditions. 

---