1. Chiroptical properties

Any material which rotates the plane of the polarized light is termed "optically active." Compounds featuring chiral centers are optically active unless they possess symmetry plane or a symmetry center (see above). An isomer of optically active compound can rotate the plane of polarized light to the left (levorotatory), in which case it will be designated (l, or -), or to the right (dextrorotatory) in which case it will be termed (d, or +).

There are following properties associated with enantiomerism:

1. Enantiomeric molecules interact in a different manner with another enantiomeric molecules (such as biological receptors, but also with simple chiral organic molecules); it regards both weak interaction such as forming weak complexes, as well as chemical reactions (bond breaking or forming).
2. Enantiomers can not be distinguished by their interactions with achiral molecules, nor by their physical properties measured by techniques other than those using in-plane-, or circularly-polarized light.

Several rules for specifying chirality have been adopted from the time of van't Hoff. The L/D systems relies on the chemical correlation of the configuration of the chiral center to D-glyceraldehyde. The compounds which can be correlated without inverting the chiral center are named D (capital D), those correlated to its enantiomer are designated as L (capital L).

IMPORTANT NOTE: Although D-glyceraldehyde is dextrorotatory (rotates the plane of polarized light to the right), the compounds correlated to D-glyceraldehyde do not have to be dextrorotatory, i.e. could rotate light to the left. Therefore, D-prefix is not correlated with the (+) or (-) specific rotation, and the D-compound can be l, (or -), and vice versa L-compound can be d (or +). This nomenclature system is slowly being abandoned in favor of the Cahn-Ingold-Prelog (CIP) nomenclature, with the exception where the DL-nomenclature has been used traditionally, and is more useful (D-carbohydrates or L-aminoacids).

EXAMPLE:

However, only S-configuration has pharmacologic properties. The demonstration(video) of superposition between the S and R configurations indicates that they are enantiomers. They are nonsuperposable mirror reflection of each other.

NOTE: In the movie and picture below, the hydrogen atoms of the methyl group and the benzene ring are not shown.

QuickTime(196K)

To see how Ibuprofen and other drugs interact with Cyclooxygenase enzyme. Please look at the image of Cyclooxygenase here.

2. Cahn-Ingold-Prelog Rules

For the tetrahedral chiral center C with four inequivalent substituents the rule is adopted for designation of chirality.

• First ligands are ordered by the ligand precedence rules as 1,2,3 & 4.
• The central atom and three ligands are viewed from the direction of C4 vector where 4 is a ligand of lowest precedence.
• If the ligands 1-3 are ordered such that the movement from the ligand of the highest precedence (1) to the third (3) passing the second (2) in between is in the clockwise direction (sequence 123) the configuration is designated as R (rectus, written in italic, capital). On the other hand if the same requires movement in the anti clockwise direction the configuration is designated as S (sinister). The configurational designation is preceded by the number specifying the location of the chiral center, i.e. 2R with one chiral center at the 2-position and R configuration, or 2R, 3S, 4R with multiple chiral centers.

3. Ligand precedence rules

1. Ligands of the higher atomic number precede those with lower ones, e.g. Br precedes Cl (Br>Cl).
2. For ligands with the same type of atoms linked to the center C, the precedence is determined based on the atomic numbers of ligands in the next sphere, e.g. ligand with C-O sequence precedes C-C. If no difference is detected, the determination is based on the distinction in the next spheres, and search is continued until the difference is detected.
3. The coordination number of non-hydrogen atoms is assumed to be 4, i.e. atoms bonded with multiple bonds are considered to be bonded to multiple atoms, e.g. carbonyl carbon is treated as if it was bonded to two oxygen atoms, and carboxyl carbon as if it was bonded to three oxygens (these are then called phantom atoms). Ligand duplication is also necessary in the cases of cyclic systems.
   
4. Ligands of the same atomic number, but a higher atomic mass precede those with a lower atomic mass, e.g. D precedes H (D>H). This criterion applies only after the previous ones were exhausted.
5. For compounds where only configurational (not constitutional) differences between ligands are detected, the following rules apply:
   • The olefinic ligand that has the chiral center and another ligand on the same side of the double bond (cis) precedes the one with the trans-configuration.
   • Ligands with R,R or S,S precede R,S or S,R.
   • R precedes S.
   

WORKSHEET PROBLEMS

• WORKSHEET A & B

4. Helical Chirality

Certain natural, as well as unnatural linear polymers assume helical conformation: e.g. right-handed B-DNA, left-handed Z-DNA, protein alpha-helices. The hydrated lipids can form chiral mesophases, whereby chirality is due to small rotation of each layer versus the adjacent layers in the multilayer stack. These macromolecules or aggregates are said to have helical chirality.

The chirality of such compounds is determined by determining the screw sense of the helix. If the screw is right handed the chirality is P(plus), if it is left handed the chirality is M(minus). Conformations of simple chain compounds can also be treated as if they had helical chirality.

5. Z/E Geometry of Double Bonds

The same Prelog's precedence rules, as discussed earlier, apply to geometrical isomers of olefinic compounds and alicyclic compounds. Precedence of ligands at both nodes of the double bonds is determined pairwise. If both higher precedence ligands are on the same side of the double bond the configuration is Z, if on the opposite sides the configuration is E.

6. cis/trans Geometry of Alicyclic Compounds

The cyclic systems use the traditional cis/trans nomenclature. When specifying geometry (cis/trans) the precedence of substituents is also determined based on the precedence rules set forth earlier. The situation is simple in the case of disubstituted systems, however, in the case of multiple substitution the geometry of the ring system has to be specified with respect to a selected reference indicated by the the symbol "r" (italic). Example:

7. Relative Configurations in Compounds with Multiple Chiral Centers.

The most unambiguous notation employs Prelog's descriptors R,S. For example for D-glucose (below) the correct specification of chirality is 2R, 3S, 4R, 5S. Note that only R,S descriptors are italicized and the chirality is specified with the numerical prefix denoting this position.

The configuration of racemic compounds is specified by using RS notation for each chiral center. Note that the relative configurations have to be preserved in order to correspond to a given diastereomers Thus racemic glucose would be described as 2RS, 3SR, 4RS, 5SR. (in contrast, 2SR, 3SR, 4RS, 5SR would correspond to racemic mannose).

The use of CIP nomenclature requires assignment of R,S descriptors for every center. The quicker way (older and a more ambiguous one) is by using threo/erythro nomenclature. This notation is based on the four-carbon sugars threose and erythrose. It requires vertical projection of the sugar main chain; threo-compounds are defined as those that have two ligands of higher precedence on each carbon atom on the opposite sides of the chain, erythro on the same side. The ambiguity arises from the question what should be used as the main chain.

8. Mezo Compounds and Pseudoasymmetry.

However, since such a compound also has a plane of symmetry it is, in fact, achiral as a whole. The central atom is termed a pseudoasymmetric center. The configuration of such atom is determined according to normal precedence rules assuming that R precedes S.

In contrast, in molecules in which the two ligands of the central atom have the same configuration the central atom is achiral, but the molecule as a whole is chiral. The pseudoasymmetry can also exist with chiral axes instead of centers. The chirality of a pseudoasymmetric carbon is specified with the lower case r/s descriptors.

Which of the following statements are true:

1. Compounds with multiple chiral centers are chiral
2. Compounds with multiple axes of symmetry are achiral
3. Compounds with plane of symmetry are achiral
4. Compounds composed of two chiral fragments are chiral
5. The dl-prefix specifies configuration
6. The cis/trans-prefix specifies configuration
7. Cis/trans compounds of the same constitutions are diastereomers
8. Threo/erythro compounds are constitutional isomers
9. Constitution is a composite term including structure, configuration and conformation.
10. Compounds with carbon atom with three different substituents are chiral
11. Tertiary amines with three different substituents are chiral
12. The E-conformers of peptides are more stable due to intramolecular hydrogen bonding.
13. Mezo-compounds are achiral
14. Compounds which can be reflected through mirror plane are chiral
15. Mirror images of a compound are enantiomers