Stereochemistry

The part of chemistry that deals with structure in three dimensions is called stereochemistry. One aspect of stereochemistry is stereoisomers: same chemical formula but differ in the way atoms oriented in space. Stereochemistry is presented by reviewing the work of the five pioneers listed above.

Jean-Baptiste Biot (1774-1862)
The history of stereochemistry begins in 1815 when Biot performed experiments using "polarized light." Ordinary light consists of light vibrating in numerous planes. However, when ordinary light is filtered, a single plane of polarized light can be obtained. Biot passed polarized light through various solutions and noted that certain solutions such as sugar can rotate polarized light. He also found the degree of rotation is a direct measure of the concentration of the solution. Substances capable of rotating a plane of polarized light were designated "optically active." It took more than 30 years to understand the cause of rotation of polarized light.

Louis Pasteur (1822-1895)
In 1848 Pasteur resolved (separated) an optically inactive substance (tartaric acid) into two optically active components. Each of the optically active components had properties identical to tartaric acid (density, melting point, solubility, etc.) except that one of the components rotated the polarized light clockwise (+) while the other component rotated the polarized light by the same amount counterclockwise (-). Pasteur made a proposal that still stands as the foundation of stereochemistry: The twin molecules of tartaric acid were mirror images of each other!
Additional research by Pasteur revealed that one component of tartaric acid could be utilized for nutrition by micro-organisms but the other could not. On the basis of these experiments, Pasteur concluded that biological properties of chemical substances depend not only on the nature of the atoms comprising the molecules but also on the manner in which these atoms are arranged in space.

Jacobus van't Hoff (1852-1911)
In 1874 as a student at University of Utrecht, van't Hoff proposed the tetrahedral carbon. His proposal was based upon evidence of isomer number: Conversion of CH₄ into CH₃Y (Y=Cl,Br,F,I,OH,etc.)
generates only one structure. When CH₃Y converted into CH₂YZ (CH₂Cl₂,CH₂ClBr,CH₂BrF,etc.), only one structure has ever been observed. van't Hoff realized that the four hydrogens in CH₄ had to be equivalent (same environment) and a geometrical square was ruled out because it would form the two structures shown below:

For tetrahedral CH₄, the four equivalent hydrogens are in corners with H-C-H angles of 109.5°

The tetrahedral carbon not only collaborated the absence of isomers CH₃Y and CH₂YZ, but also predicted the existence of mirror image isomers. When carbon makes four single bonds with four different groups such as CHFClBr, nonsuperimposable mirror-image molecules (enantiomers) exist:

These enantiomers display virtually identical physical properties except for the direction of rotation of polarized light. An equal mixture of the mirror image twins is optically inactive since rotations cancel one another. A carbon with four different groups is said to possess a "chiral center." Examples of molecules containing one or more chiral centers are indicated by red asterisk. Although hydrogen atoms are not shown, assume they are present to give carbon four bonds.

As the number of chiral centers (C*) increase, so do the number of stereoisomers (same structure but different orientation in space). The maximum number of stereoisomers possible is 2^x where x is number of chiral centers per molecule. The table shows number of stereoisomers for structures I-V:

Structure I II III IV V

Number 2 3 4 8 10

Emil Fisher (1852-1919)
In 1894 Fisher performed one of the most remarkable feats in the history of chemistry: He identified the 16 stereoisomers for the aldohexoses (C₆H₁₂O₆), the most prominent member being D-glucose.

Fisher used cross representations (now called Fisher projections) to distinguish three dimensional shapes. Fisher projections are shown for D and Lglucose (D/L another Fisher innovation).

Vladmir Prelog (1906-1998)
Prelog was awarded Nobel Prize in chemistry (1975) for research into the stereochemistry of alkaloids, antibiotics, enzymes, and other natural compounds. He designed the stereochemical distinctions used today for mirror image configurations: R/S designations for enantiomers and Z/E for geometric isomers.

Enantiomer Uniqueness
Derived from the Greek word "enantio" meaning opposite, enantiomers are nonsuperimposable mirror image structures. Because they possess identical physical properties--except for the direction of rotation of polarized light--they are often viewed as a single entity. But enantiomers can exhibit distinct chemical behavior when subjected to a chiral environment, that is, any environment consisting of a single enantiomer. Here are a few examples to demonstrate the point:

In the 1960s, many pregnant women who had taken racemic thalidomide gave birth to deformed babies. Ensuing investigations showed only the right-handed version of the drug to cause the same birth defects in rat embryos.
Sold over the counter in a number of pain remedies such as Advil and Nuprin, ibuprofen contains therapeutic activity only in the (+) isomer.
Our bodies can only metabolize (+) glucose and not (-) glucose.
(+) leucine tastes sweet while (-) leucine bitter.
Our bodies can utilize only (-) amino acids.

According to the modern receptor-site theory, drugs attach themselves to specific sites by means of three dimensional bonding capabilities. The fit of a drug onto a receptor site was compared by Fisher to the fit of a key into a lock: The right drug is the "key" which can fit the receptor "lock" and turn on the desired biological response. Sometimes two slightly different keys will fit inside the same lock, but only one will open the door.
When subjected to a chiral environment such as the human body, how are mirror image twins differentiated? Discrimination between enantiomers, called chiral recognition, depends on the degree of interaction exhibited between each enantiomer and the chiral bonding site. In a way, chiral recognition resembles the matching of a right hand with a right-handed glove. The illustration below represents interactions between chiral bonding site -CXYZ and enantiomers CWXYZ. For one enantiomer, a three-point interaction is possible at X-X, Y-Y, and Z-Z; the other enantiomer can only accommodate a two-point interaction at X-X and Y-Y with the same chiral binding site. In this instance, chiral recognition relies on the absence of a Z-Z fit in conjunction with the other two interactions.

Many substances utilized by living organisms are optically active (amino acids, carbohydrates, enzymes). Chemists say, "It takes optical activity to get optical activity." So how did optically active substances (single enantiomers) originate? Consider transforming ethanol into an optically active substance:

The hydrogens attached to the carbon bearing the OH group are said to be heterotopic (different positions). Substitution for one or the other leads to a single enantiomer. The hydrogen leading to the R-configuration is designated H_R and the S-configuration H_S. Our enzymes are able to metabolize ethanol by exclusive removal of H_R. But an enzyme (chiral site) needs to interact with the other three groups (CH₃, OH, and H_S) to make H_R susceptible for elimination.

Physics cannot account for the origin of matter/energy and chemistry can't account for the origin of optically active substances. Theories to explain the generation of optical activity include spontaneous resolution of enantiomers, asymmetric synthesis (preparation of a single enantiomer), single enantiomer evolution, or some kind of intervention (supernatural, aliens, meteorite,?).