Molecular Chirality Enantiomers

In organic chemistry, chirality most often occurs in molecules that contain a carbon that is attached to four different groups. An example is bromochlorofluoromethane (BrClFCH). 

A molecule with four different groups attached to a single carbon is chiral. Its two mirror-image forms are not superimposable. 

The mirror images of bromochlorofluoromethane have the same constitution. That is, the atoms are connected in the same order. But they differ in the arrangement of their atoms in space they are stereoisomers. Stereoisomers that are related as an object and its nonsu-perimposable mirror image are classified as enantiomers. The word enantiomer describes a particular relationship between two objects. One cannot look at a single molecule in isolation and ask if it is an enantiomer any more than one can look at an individual human being and ask, Is that person a cousin Furthermore, just as an object has one, and only one, mirror image, a chiral molecule can have one, and only one, enantiomer. 

The surest test for chirality is a careful examination of mirror-image forms for superimposability. Working with models provides the best practice in dealing with molecules as three-dimensional objects and is strongly recommended. 

Bromochlorofluoromethane is a known compound, and samples selectively enriched in each enantiomer have been described in the chemical literature. In 1989 two chemists at the Polytechnic Institute of New York University described a method for the preparation of BrClFCH that is predominantly one enantiomer. 

Thomson (Lord Kelvin) coined a word for this property. He defined an object as chiral if it is not superposable on its mirror image. Applying Thomson s term to chemistry, we say that a molecule is chiral if its two mirror-image forms are not superposable in three dimensions. The work chiral is derived from the Greek word cheir, meaning hand, and it is entirely appropriate to speak of the handedness of molecules. The opposite of chiral is achiral. A molecule that is superposable on its mirror image is achiral. 

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Mezey PG, Ponec R, Amat L, Carbo-Dorca R. Quantum similarity approach to the characterization of molecular chirality. Enantiomer 1999 4 371-378. 

In chemoinformatics, chirality is taken into account by many structural representation schemes, in order that a specific enantiomer can be imambiguously specified. A challenging task is the automatic detection of chirality in a molecular structure, which was solved for the case of chiral atoms, but not for chirality arising from other stereogenic units. Beyond labeling, quantitative descriptors of molecular chirahty are required for the prediction of chiral properties such as biological activity or enantioselectivity in chemical reactions) from the molecular structure. These descriptors, and how chemoinformatics can be used to automatically detect, specify, and represent molecular chirality, are described in more detail in Chapter 8. 

Chirality codes are used to represent molecular chirality by a fixed number of de-.scriptors. Thc.se descriptors can then be correlated with molecular properties by way of statistical methods or artificial neural networks, for example. The importance of using descriptors that take different values for opposite enantiomers resides in the fact that observable properties are often different for opposite enantiomers. 

The three water ligands located at meridional positions of the J ,J -DBFOX/Ph aqua complexes may be replaced by another molecule of DBFOX/Ph ligand if steric hindrance is negligible. Based on molecular model inspection, the hetero-chiral enantiomer S,S-DBFOX/Ph looks like a candidate to replace the water ligands to form the heterochiral meso-2 l complex J ,J -DBFOX/Ph-S,S-DBFOX/... 

Ever since Pasteur s work with enantiomers of sodium ammonium tartrate, the interaction of polarized light has provided a powerful, physical probe of molecular chirality [18]. What we may consider to be conventional circular dichroism (CD) arises from the different absorption of left- and right-circularly polarized light by target molecules of a specific handedness [19, 20]. However, absorption measurements made with randomly oriented samples provide a dichroism difference signal that is typically rather small. The chirally induced asymmetry or dichroism can be expressed as a Kuhn g-factor [21] defined as ... 

Aires-de-Sousa, J., Gasteiger, J. New description of molecular chirality and its applications to the prediction of the preferred enantiomer in stereoselective reactions. J. Chem. Inf. Comput. Sci. 2001, 41, 369-375. 

The experimentally observable phenomenon of optical activity is usually considered in the context of variation of molecular chirality arising from a particular stereochemical configuration at a particular atom such that the molecule has no improper rotation S axis. Molecules with opposite chirality configurations are enantiomers and show oppositely signed optical activity. Molecules differing only in conformation are called conformers or rotational isomers. In most cases, the difference in energy between rotational isomeric states is very small, such that at ambient temperature all are populated and no optical activity results. However, if one particular conformer is stabilized, for example, by restriction of rotation about a bond, the molecule can become chiral, and thus optically active. 

Consequences of Molecular Chirality. A mixture containing an equal number of molecules of enantiomers is known as a racemic modification. The preparation and reactions of these modifications (as well as the individual enantiomers themselves) represent important aspects of the study of stereochemistry. 

It is clear from the above examples that the presence of chiral centers in molecules leads to stereoisomers. There is another type of molecule which itself is chiral but has no chiral center. The molecular chirality arises from the presence of a screw axis in the molecule. Allenes and biphenyls are common examples of such compounds, and because they are chiral, they exist as enantiomers. 

Hund, one of the pioneers in quantum mechanics, had a fundamental question of relation between the molecular chirality and optical activity [78]. He proposed that all chiral molecules in a double well potential are energetically inequivalent due to a mixed parity state between symmetric and antisymmetric forms. If the quantum tunnelling barrier is sufficiently small, such chiral molecules oscillate between one enantiomer and the other enantiomer with time through spatial inversion and exist in a superposed structure, as exemplified in Figs. 19 and 24. Hund s theory may be responsible for dynamic helicity, dynamic racemization, and epimerization. 

Since Pasteur s time, stereochemistry has experienced an enormous intellectual growth and has also found widespread industrial application. In recent years, a spate of articles, reviews, books, and international conferences and symposia have dealt with the role of chirality in chemistry, and three new journals have been specifically devoted to this topic Chirality, by Wiley-Liss in 1989, Tetrahedron Asymmetry, by Pergamon Press in 1990, and Enantiomer, by Gordon and Breach in 1996. Much of the research reported in these media, though motivated to some degree by market forces—notably by the demand of pharmaceutical industry for enantiopure drugs4—serves as a reminder that molecular chirality remains the centerpiece of stereochemistry and allied branches of science. 

The oldest example of molecular chiral recognition described by Pasteur [1] is the separation of enantiomers based on diastereoisomeric salt formation and subsequent fractionated crystallisation. The principle of the enantiomeric differentation is that one of the salts formed with a chiral reagent is less soluble than the other, and thus precipitates from the solution. This enrichment of one of the enantiomers leads to the optical resolution... 

Even nowadays, particularly in industrial processes, the separation of enantiomers of racemic acids and bases is based on this molecular chiral recognition. The less soluble, i.e. the more stable of these diastereomer salts crystallizes even if the chiral agent in the better soluble salt is replaced by an achiral reagent of similar chemical character, or eventually eliminated, or substituated by a solvent. In this case, a mixture enriched with the more stable diastereomer can be isolated by filtration from the solution of the achiral salt of the enantiomeric mixture or the free enantiomers [2,3]... 

In addition SFE has the advantage of beeing carried out at low temperature, and thus it does not cause racemization or thermal decomposition of the enantiomers. In our previous work we have observed the molecular chiral recignition in supercritical carbon dioxide for several compounds [5], The present study was designed to explore the applicability of supercritical carbon dioxide for extraction ofibuprofen and cw-chrysanthemic acid. 

Louis Pasteur was the first scientist to study the effect of molecular chirality on the crystal structure of organic compoimds [23], finding that the resolved enantiomers of sodium ammonium tartrate could be obtained in a crystalline form that featured nonsuperimposable hemihedral facets (see Fig. 9.1). Pasteur was quite surprised to learn that when he conducted the crystallization of racemic sodium ammonium tartrate at temperatures below 28 °C, he also obtained crystals of that contained nonsuperimposable hemihedral facets. He was able to manually separate the left-handed crystals from the right-handed ones, and foimd that these separated forms were optically active upon dissolution. More surprising was the discovery that when the crystallization was conducted at temperatures exceeding 28 °C, he obtained crystals having different morphologies that did not contain the hemihedral crystal facets (also illustrated in Fig. 9.1). Later workers established that this was a case of crystal polymorphism. 

The relationship between a chiral object and its mirror-related object is called enantiomerism. A knowledge of the existence of enantiomers was one of the reasons that van t Hoff and Le Bel proposed, as described in Chapter 1, that the four valences of carbon are spatially directed to the corners of a regular tetrahedron.The only difference between a pair of enantiomers is that, if one can be described as a left-handed form, the other will be a right-handed form they have identical chemical formulae. The major physical property that allows one to distinguish between enantiomers is the direction in which they, or their solutions, rotate the plane of polarized light, that is, when they are studied in the chiral environment provided by the polarized light. It is important to note that a molecule is not necessarily chiral just because it contains an asymmetric center, or that it is necessarily achiral because it lacks such an asymmetric center. These are not the criteria for molecular chirality. The test for chirality in a molecule is the nonsuperimposability of the object on its mirror image. 

The transfer of chiral information from the nanoscale adsorbed motif to the macroscale organisation of adsorbates leads to another consequence, namely, that switching molecular chirality should also flip the organisational chirality. When enantiopure (5, 5)-TA is adsorbed on Cu(llO), the RAIRS spectra are identical to those of the (R,R) enantiomer, showing that the chemical nature of the adsorbed species is the same for both enantiomers. However, STM and TF.F.D data show that the mirror organisation is now created, yielding a (9 0,-1 2) overlayer (Fig. 5.4). A change in... 

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