Chiral molecules, separation

The Cahn-Ingold-Prelog (CIP) rules stand as the official way to specify chirahty of molecular structures [35, 36] (see also Section 2.8), but can we measure the chirality of a chiral molecule. Can one say that one structure is more chiral than another. These questions are associated in a chemist s mind with some of the experimentally observed properties of chiral compounds. For example, the racemic mixture of one pail of specific enantiomers may be more clearly separated in a given chiral chromatographic system than the racemic mixture of another compound. Or, the difference in pharmacological properties for a particular pair of enantiomers may be greater than for another pair. Or, one chiral compound may rotate the plane of polarized light more than another. Several theoretical quantitative measures of chirality have been developed and have been reviewed elsewhere [37-40]. 

In Section 4.2.1 it will be pointed out that hydrogen peroxide (Figure 4.1 la) has only one symmetry element, a C2 axis, and is therefore a chiral molecule although the enantiomers have never been separated. The complex ion [Co(ethylenediamine)3], discussed in Section 4.2.4 and shown in Figure 4.11(f), is also chiral, having only a C3 axis and three C2 axes. 

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases. 

Liquid membranes can be constituted by liquid chiral selectors used directly [170] or by solutions of the chiral molecules in polar or apolar solvents. This later possibility can also be an advantage since it allows the modulation of the separation con-... 

KR is the total or partial separation of two enantiomers from a racemic mixture [5]. KR is based on the different reaction rates of the enantiomers with a chiral molecule (a reagent, a catalyst, etc). In the ideal case, the difference in reactivity is large, and one of the enantiomers reacts very fast to give the product, whereas the other does not react at all (Figure 4.1). 

A closely related method does not require conversion of enantiomers to diastereomers but relies on the fact that (in principle, at least) enantiomers have different NMR spectra in a chiral solvent, or when mixed with a chiral molecule (in which case transient diastereomeric species may form). In such cases, the peaks may be separated enough to permit the proportions of enantiomers to be determined from their intensities. Another variation, which gives better results in many cases, is to use an achiral solvent but with the addition of a chiral lanthanide shift reagent such as tris[3-trifiuoroacetyl-Lanthanide shift reagents have the property of spreading NMR peaks of compounds with which they can form coordination compounds, for examples, alcohols, carbonyl compounds, amines, and so on. Chiral lanthanide shift reagents shift the peaks of the two enantiomers of many such compounds to different extents. 

Here, ry is the separation between the molecules resolved along the helix axis and is the angle between an appropriate molecular axis in the two chiral molecules. For this system the C axis closest to the symmetry axes of the constituent Gay-Berne molecules is used. In the chiral nematic phase G2(r ) is periodic with a periodicity equal to half the pitch of the helix. For this system, like that with a point chiral centre, the pitch of the helix is approximately twice the dimensions of the simulation box. This clearly shows the influence of the periodic boundary conditions on the structure of the phase formed [74]. As we would expect simulations using the atropisomer with the opposite helicity simply reverses the sense of the helix. 

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

High performance capillary electrophoresis in its current form is a new technique. Its feasibility has been proven by the analysis and separation of small ions, drugs, chiral molecules, polymers, and biopolymers.93 We are learning more every day about the small tricks of the trade of the technique, and the efficiency and reproducibility of the methods are improving. 

A number of specialised stationary phases have been developed for the separation of chiral compounds. They are known as chiral stationary phases (CSPs) and consist of chiral molecules, usually bonded to microparticulate silica. The mechanism by which such CSPs discriminate between enantiomers (their chiral recognition, or enantioselectivity) is a matter of some debate, but it is known that a number of competing interactions can be involved. Columns packed with CSPs have recently become available commercially. They are some three to five times more expensive than conventional hplc columns, and some types can be used only with a restricted range of mobile phases. Some examples of CSPs are given below ... 

Complexation with Chiral Metal Complexes. This idea was first suggested by Feibush et al.44 The separation is realized by the dynamic formation of diastereomeric complexes between gaseous chiral molecules and the chiral stationary phase in the coordination sphere of metal complexes. A few typical examples of metal complexes used in chiral stationary phase chromatography are presented in Figure 1-13.45... 

The dissimilar association of enantiomers with another chiral molecule (Figure 4.18) also allows their determination if the molecule is part of a chromatographic system. The unequal interactions result in different rates of migration of the enantiomers through the column. The chiral molecule may be a component of the mobile phase or the stationary phase of the system. Typical examples of the separation of... 

For example22, separation of enantiomers of chiral molecules (amines, alcohols, amino acids) is possible by using a chiral stationary phase obtained from 10-undecenyl esters of Af-(2-naphthyl)-a-amino acids (4). Amino groups are of fundamental importance in this practical application of the chiral recognition. 

Finally, reference must be made to the important and interesting chiral crystal structures. There are two classes of symmetry elements those, such as inversion centers and mirror planes, that can interrelate. enantiomeric chiral molecules, and those, like rotation axes, that cannot. If the space group of the crystal is one that has only symmetry elements of the latter type, then the structure is a chiral one and all the constituent molecules are homochiral the dissymmetry of the molecules may be difficult to detect but, in principle, it is present. In general, if one enantiomer of a chiral compound is crystallized, it must form a chiral structure. A racemic mixture may crystallize as a racemic compound, or it may spontaneously resolve to give separate crystals of each enantiomer. The chemical consequences of an achiral substance crystallizing in a homochiral molecular assembly are perhaps the most intriguing of the stereochemical aspects of solid-state chemistry. 

Chiral method development is often referred to as one of the most difficult fields in terms of development time. Interaction with a chiral selector is required to achieve separation but the enantioselectivity of a given selector for a given chiral molecule is a priori unknown. For some compounds, it can take several days to find suitable separation conditions when using sequential approaches. Therefore, industry most often defines generic separation strategies, which are often kept internally or are... 

In recent years, for analytical purposes the direct approach has become the most popular. Therefore, only this approach will be discussed in the next sections. With the direct approach, the enantiomers are placed in a chiral environment, since only chiral molecules can distinguish between enantiomers. The separation of the enantiomers is based on the complex formation of labile diastereoisomers between the enantiomers and a chiral auxiliary, the so-called chiral selector. The separation can only be accomplished if the complexes possess different stability constants. The chiral selectors can be either chiral molecules that are bound to the chromatographic sorbent and thus form a CSP, or chiral molecules that are added to the mobile phase, called chiral mobile phase additives (CMPA). The combination of several chiral selectors in the mobile phase, and of chiral mobile and stationary phases is also feasible. 

By adding a chiral molecule to the mobile phase, the direct separation of enantiomers can be obtained on an achiral stationary phase. This... 

Several CD derivatives (charged and uncharged) are available which should allow the separation of most chiral molecules with at least one of them. However, due to the complexity of chiral recognition mechanisms, the determination of the best selector based on the analyte structure is challenging. Eurthermore, separations using CDs are influenced by numerous factors, so that no general rule can be applied for the successful resolution of enantiomers. ... 

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