ChemPep Generic Term Stereochemistry

The two optical isomers of alanine

The two enantiomers of bromochlorofluoromethaneThe symmetry of a molecule (or any other object) determines whether it is chiral. A molecule is achiral (not chiral) if and only if it has an axis of improper rotation; that is, an n-fold rotation (rotation by 360°/n) followed by a reflection in the plane perpendicular to this axis which maps the molecule onto itself. (See chirality (mathematics).) A simplified rule applies to tetrahedrally-bonded carbon, as shown in the illustration: if all four substituents are different, the molecule is chiral. A chiral molecule is not necessarily asymmetric, that is, devoid of any symmetry elements, as it can have, for example, rotational symmetry.

Contents

1. History
2. Naming conventions
    2.1. By configuration: R- and S-
    2.2. By optical activity: (+)- and (−)-
    2.3. By configuration: D- and L-
3. Types
4. Properties of enantiomers
5. Chirality in biology
6. Chirality in drugs
7. Chirality in inorganic chemistry
8. Chirality of amines
9. Chemical chirality in literature
10. References & notes
11. External links

1. History

The term optical activity derives from the interaction of chiral materials with polarized light. A solution of the (−)-form of an optical isomer rotates the plane of polarization of a beam of plane polarized light in a counterclockwise direction, vice-versa for the (+) optical isomer. The property was first observed by Jean-Baptiste Biot in 1815 [1], and gained considerable importance in the sugar industry, analytical chemistry, and pharmaceuticals. Louis Pasteur deduced in 1848 that this phenomenon has a molecular basis[2]. Artificial composite materials displaying the analog of optical activity but in the microwave regime were introduced by J.C. Bose in 1898 [3], and gained considerable attention from the mid-1980s [4].

The word “racemic” is derived from the Latin word for grape; the term having its origins in the work of Louis Pasteur who isolated racemic tartaric acid from wine.

2. Naming conventions

2.1. By configuration: R- and S-

For chemists, the R/S system is the most important nomenclature system for denoting enantiomers which does not involve a reference molecule such as glyceraldehyde. It labels each chiral center R or S according to a system by which its substituents are each assigned a priority, according to the Cahn Ingold Prelog priority rules, based on atomic number. If the center is oriented so that the lowest-priority of the four is pointed away from a viewer, the viewer will then see two possibilities: if the priority of the remaining three substitutents decreases in clockwise direction, it is labeled R (for Rectus), if it decreases in counterclockwise direction, it is S (for Sinistrus).

This system labels each chiral center in a molecule (and also has an extension to chiral molecules not involving chiral centers). It thus has greater generality than the D/L system, and can label, for example, an (R,R) isomer versus an (R,S) — diastereomers.

The R/S system has no fixed relation to the (+)/(−) system. An R isomer can be either dextrorotatory or levorotatory, depending on its exact substituents.

The R/S system also has no fixed relation to the D/L system. For example, the side-chain one of serine contains a hydroxy group, -OH. If a thiol group, -SH, were swapped in for it, the D/L labeling would, by its definition, not be affected by the substitution. But this substitution would invert the molecule’s R / S labeling, due to the fact that the CIP priority of CH2OH is lower than that for CO2H but the CIP priority of CH2SH is higher than that for CO2H.

For this reason, the D/L system remains in common use in certain areas of biochemistry, such as amino acid and carbohydrate chemistry, because it is convenient to have the same chiral label for all of the commonly-occurring structures of a given type of structure in higher organisms. In the D/L system, they are all L; in the R / S system, they are mostly S but there are some common exceptions.

2.2. By optical activity: (+)- and (−)-

An enantiomer can be named by the direction in which it rotates the plane of polarized light. If it rotates the light clockwise (as seen by a viewer towards whom the light is traveling), that enantiomer is labeled (+). Its mirror-image is labeled (−). The (+) and (−) isomers have also been termed d- and l-, respectively (for dextrorotatory and levorotatory). This labeling is easy to confuse with D- and L-.

2.3. By configuration: D- and L-

An optical isomer can be named by the spatial configuration of its atoms. The D/L system does this by relating the molecule to glyceraldehyde. Glyceraldehyde is chiral itself, and its two isomers are labeled D and L. Certain chemical manipulations can be performed on glyceraldehyde without affecting its configuration, and its historical use for this purpose (possibly combined with its convenience as one of the smallest commonly-used chiral molecules) has resulted in its use for nomenclature. In this system, compounds are named by analogy to glyceraldehyde, which generally produces unambiguous designations, but is easiest to see in the small biomolecules similar to glyceraldehyde. One example is the amino acid alanine: alanine has two optical isomers, and they are labeled according to which isomer of glyceraldehyde they come from. Glycine, the amino acid derived from glyceraldehyde, incidentally, has no optical activity as it is not chiral (achiral). Alanine, however, is chiral.

The D/L labeling is unrelated to (+)/(−); it does not indicate which enantiomer is dextrorotatory and which is levorotatory. Rather, it says that the compound’s stereochemistry is related to that of the dextrorotatory or levorotatory enantiomer of glyceraldehyde. Nine of the nineteen L-amino acids commonly found in proteins are dextrorotatory (at a wavelength of 589 nm), and D-fructose is also referred to as levulose because it is levorotatory.

The dextrorotatory isomer of glyceraldehyde is in fact the D isomer, but this was a lucky guess.[citation needed] At the time this system was established, there was no way to tell which configuration was dextrorotatory.[citation needed] (If the guess had turned out wrong, the labeling situation would now be even more confusing.)[citation needed]

A rule of thumb for determining the D/L isomeric form of an amino acid is the “CORN” rule. The groups:

COOH, R, NH2 and H (where R is a variant carbon chain)

are arranged around the chiral center carbon atom. Sighting with the hydrogen atom away from the viewer, if these groups are arranged clockwise around the carbon atom, then it is the D-form. If counter-clockwise, it is the L-form.

3. Types

Most commonly, chiral molecules have point chirality, centering around a single atom, usually carbon, which has four different substituents. The two enantiomers of such compounds are said to have different absolute configurations at this center. This center is thus stereogenic (i.e., a grouping within a molecular entity that may be considered a focus of stereoisomerism), and is exemplified by the α-carbon of amino acids. A molecule can have multiple chiral centers without being chiral overall if there is a symmetry element (a mirror plane or inversion center) which relates the two (or more) chiral centers. Such a molecule is called a meso compound. It is also possible for a molecule to be chiral without having actual point chirality. Commonly encountered examples include 1,1′-bi-2-naphthol (BINOL) and 1,3-dichloro-allene which have axial chirality, and (E)-cyclooctene which has planar chirality.

It is important to keep in mind that molecules which are dissolved in solution or are in the gas phase usually have considerable flexibility and thus may adopt a variety of different conformations. These various conformations are themselves almost always chiral. However, when assessing chirality, one must use a structural picture of the molecule which corresponds to just one chemical conformation – the most symmetric conformation possible.

When the optical rotation for an enantiomer is too low for practical measurement it is said to exhibit cryptochirality.

Even isotopic differences must be considered when examining chirality. Replacing one of the two 1H atoms at the CH2 position of benzyl alcohol with a deuterium (²H) makes that carbon a stereocenter. The resulting benzyl-α-d alcohol exists as two distinct enantiomers, which can be assigned by the usual stereochemical naming conventions. The S enantiomer has [α]D = +0.715°.[5]

4. Properties of enantiomers

Enantiomers are identical with respect to ordinary chemical reactions, but differences arise when they are in the presence of other chiral molecules or objects. Different enantiomers of chiral compounds often taste and smell different and have different effects as drugs – see below.

One chiral ‘object’ that interacts differently with the two enantiomers of a chiral compound is circularly polarised light: An enantiomer will absorb left- and right-circularly polarised light to differing degrees. This is the basis of circular dichroism (CD) spectroscopy. Usually the difference in absorptivity is relatively small (parts per thousand). CD spectroscopy is a powerful analytical technique for investigating the secondary structure of proteins and for determining the absolute configuratations of chiral compounds, particularly transition metal complexes. CD spectroscopy is replacing in polarimetry as a method for characterising chiral compounds, although the latter is still popular with sugar chemists.

5. Chirality in biology

Many biologically-active molecules are chiral, including the naturally-occurring amino acids (the building blocks of proteins), and sugars. Interestingly, in biological systems most of these compounds are of the same chirality: most amino acids are L and sugars are D. Typical naturally occurring proteins, made of L amino acids, are known as left-handed proteins, while D amino acids produce right-handed proteins.

The origin of this homochirality in biology is the subject of much debate. Most scientists believe that Earth’s life’s choice of chirality was purely random, and that it is possible that the chemistry of some alien forms of carbon-based life – assuming it exists – may have opposite chirality. However, a few scientists are looking for fundamental reasons that favor the chirality as here on earth, such as the weak nuclear force.[1]

Enzymes, which are chiral, often distinguish between the two enantiomers of a chiral substrate. Imagine an enzyme as having a glove-like cavity which binds a substrate. If this glove is right handed, then one enantiomer will fit inside and be bound while the other enantiomer will have a poor fit and is unlikely to bind.

D-form amino acids tend to taste sweet, whereas L-forms are usually tasteless. Spearmint leaves and caraway seeds respectively contain L-carvone and D-carvone – enantiomers of carvone. These smell different to most people because our olfactory receptors also contain chiral molecules which behave differently in the presence of different enantiomers.

6. Chirality in drugs

Many chiral drugs must be made with high enantiomeric purity due to potential side-effects of the other enantiomer. (The other enantiomer may also merely be inactive.)

• Thalidomide: Thalidomide is racemic. One enantiomer is effective against morning sickness while the other is teratogenic. Unfortunately, in this case administering just one of the enantiomers to a pregnant patient does not help to as the two enantiomers are readily interconverted in vivo. Thus, if a person is given either enantiomer, both the D and L isomers will eventually be present in the patient’s serum.

• Ethambutol: Whereas one enantiomer is used to treat tuberculosis, the other causes blindness.

• Naproxen: One enantiomer is used to treat arthritis pain, but the other causes liver poisoning with no analgesic effect.

• Steroid receptor sites also show stereoisomer specificity.

• Penicillin’s activity is stereoselective. The antibiotic only works on peptide links of D-alanine which occur in the cell walls of bacteria – but not in humans. The antibiotic can kill only the bacteria, and not us, because we don’t have these D-amino acids.

7. Chirality in inorganic chemistry

Many coordination compounds are chiral; for example the well-known [Ru(2,2′-bipyridine)3]2+ complex in which the three bipyridine ligands adopt a chiral propeller-like arrangement [6]. In this case, the Ru atom may be regarded as a stereogenic centre, with the complex having point chirality. The two enantiomers of complexes such as [Ru(2,2′-bipyridine)3]2+ may be designated as Λ (left-handed twist of the propeller described by the ligands) and Δ (right-handed twist). Hexol is a chiral cobalt complex which was first investigated by Alfred Werner. Resolved hexol is significant as being the first compound devoid of carbon to display optical activity.

8. Chirality of amines

Tertiary amines (see image) are chiral in a way similar to carbon compounds: the nitrogen atom bears four distinct substituents counting the lone pair. However, the energy barrier for the inversion of the stereocenter is typically about 30 kJ/mol, which means that the two stereoisomers are rapidly interconverted at room temperature. As a result, amines such as NHRR’ cannot be resolved optically and NRR’R” can only be resolved when the R, R’, and R” groups are constrained in cyclic structures.