Stereochemistry and Chirality

Stereochemistry Notes

Chirality Definition
- An object is achiral if the object and its mirror image are identical.
- A chiral object is one that cannot be superposed on its mirror image.

Chiral molecules
- Chiral molecules are those that cannot be superimposed with their mirror images.
- Enantiomers:
- One enantiomer can cause birth defects, while the other may cure conditions like morning sickness.
- Example:
- Tretoquinol
- One enantiomer acts as a bronchodilator; the other inhibits platelet aggregation.
Drug Development Statistics
- 66% of all drugs in development are chiral.
- 51% are studied as a single enantiomer.
- In 2008, of the $475 billion in global sales of pharmaceutical products, $205 billion was attributed to single enantiomer drugs.

Isomers:
- Different compounds with the same molecular formula.
- Constitutional Isomers:
- Isomers having the same molecular formula but different connectivity (atoms connected in different orders).
- Examples:
  - C4H10: Butane vs. 2-Methylpropane vs. 1-Chloropropane vs. 2-Chloropropane.
  - C2H6O: Ethanol vs. Methoxymethane.
  - C4H8O2: Butanoic acid vs. Methyl propanoate.
Stereoisomers:
- Not constitutional isomers.
- Have the same connectivity but differ in the spatial arrangement of their atoms.
- This aspect of molecular structure is termed stereochemistry.

Stereoisomers subcategories:
- Enantiomers:
- Stereoisomers whose molecules are nonsuperposable mirror images of each other.
- Diastereomers:
- Stereoisomers whose molecules are not mirror images of each other.
Geometric Isomers (Cis & Trans):
- Example of diastereomers with different spatial arrangements.

Subdivision of isomers:
- Isomers
- Constitutional Isomers
- Stereoisomers
  - Enantiomers
  - Diastereomers

Enantiomers only arise from chiral compounds.
A chiral molecule is NOT superposable on its mirror image. The relationship between a chiral molecule and its mirror image is referred to as enantiomeric.

A molecule typically becomes chiral if it contains a carbon atom bonded to four different groups, termed an asymmetric carbon or chirality center, often indicated with an asterisk (*).
- IUPAC terminology prefers chirality center.

Tetrahedral stereogenic centers are chiral.
Trigonal stereogenic centers typically lead to achiral compounds.
- Example: Cis and trans alkene isomers which possess trigonal stereogenic centers.

Example:
- ( + )-Limonene found in oranges vs. ( - )-Limonene in lemons.
The activity of drugs can vary between enantiomers, potentially leading to severe consequences:
- Thalidomide Case:
- Used before 1963 to treat morning sickness; later found to cause severe birth defects in children.

A molecule is not chiral if it possesses a plane of symmetry.
A plane of symmetry is an imaginary plane that bisects a molecule so that both halves are mirror images.
Any molecule demonstrating a plane of symmetry in its most symmetrical conformation will be classified as achiral.

Assign Priorities: Identify the four different groups on the stereocenter from highest to lowest priority based on atomic number.
Next Atoms if Needed: If priority cannot be determined, look at the next set of atoms in the unassigned groups, continuing until a decision can be made.
Visualize Orientation: Visualize the molecule so that the lowest priority group is directed away from you, then trace the path from highest to lowest priority:
- Clockwise = (R)
- Counter-clockwise = (S).
Double/Triple Bonds: For groups with double or triple bonds, assign priorities as if those atoms were duplicated/triplicated.

Characteristics:
- Enantiomers are mirror images that are not superposable.
- They have identical physical properties (e.g., melting point, boiling point, refractive index, etc.), but they interact differently with chiral substances.
Optical Activity:
- The property of chiral substances rotating the plane of polarization of plane-polarized light.
Measurement:
- A polarimeter is used to measure optical activity and calculate specific rotation. The formula for specific rotation (0b) is given by:
  [ ext{}] = rac{ ext{observed rotation}}{ ext{temperature} imes ext{concentration of sample (g/mL)} imes ext{length of cell (dm)}}
Racemization: When equal amounts of both enantiomers exist in a mixture, this is referred to as a racemic mixture. Such a mixture does not cause a net rotation of plane-polarized light.

An enantiomerically pure substance consists only of one enantiomer and shows a specific rotation of 100%.
Example: (S)-(+)-2-butanol has a specific rotation of +13.52. A mixture of enantiomers with specific rotation less than +13.52 shows an enantiomeric excess less than 100%.

Definition: Diastereomers are stereoisomers that are not enantiomers and can exhibit substantially different chemical and physical properties.
Diastereomeric relationships can notably include structures with more than one chirality center, wherein the total number of stereoisomers is given by 2^n where n equals the number of stereocenters.

Definition: Meso compounds with two stereocenters do not always result in four stereoisomers because some can be achiral due to the presence of a plane of symmetry.
- Example: 2,3-dichlorobutane has two stereocenters, yet has only three stereoisomers due to one being achiral (meso structure).
Naming Compounds: When naming compounds with multiple chirality centers, evaluate each center systematically, similar to the R/S nomenclature for single centers.

The understanding of chiral molecules and their implications, particularly in biological systems and pharmaceuticals, is critical due to the profound effects that enantiomers can have on drug efficacy and safety. Awareness of stereochemistry, chirality centers, and isomer classifications, alongside the methodologies of naming and testing chirality, provides a comprehensive view of molecular behavior in organic chemistry.