Stereoisomerism

Introduction

Stereoisomerism is a fundamental concept in organic chemistry that deals with the spatial arrangement of atoms in molecules. Molecules with the same molecular formula and connectivity can differ in the three-dimensional orientation of their atoms, leading to different physical and chemical properties.

Isomerism Review

Types of Isomers

• Isomers are different compounds that have the same molecular formula.

• There are two general types of isomers:

Stereochemistry’s Origin

Historical Background

• Louis Pasteur studied tartaric acid crystals isolated from wine grapes.

• He separated two types of mirror-image crystals by hand using tweezers under a microscope.

• Although the crystals were made of the same material, they differed in their optical properties.

Key Example: Tartaric acid salts exist as enantiomers, which are non-superimposable mirror images.

Stereochemistry Importance

Biological and Pharmaceutical Relevance

• Stereochemistry can determine the biological activity of molecules.

• Thalidomide is a classic example: the (R)-enantiomer is a sedative, while the (S)-enantiomer is teratogenic (causes birth defects).

• Regulatory oversight (e.g., by Dr. Frances Kelsey at the FDA) prevented tragedies by ensuring drug safety regarding stereochemistry.

Identifying Isomers

Classification of Isomers

• Isomers can be classified as constitutional isomers, stereoisomers, or identical structures.

• Conformational isomers are the same compound in different rotational states.

• Cis/trans (geometric) isomers are a type of stereoisomerism found in alkenes and cycloalkanes.

Symmetry and Chirality

Chirality

• Chirality is a property of an object or molecule that makes it non-superimposable on its mirror image.

• An achiral object is superimposable with its mirror image.

• A chiral center (usually a carbon) is bonded to four different groups.

• The total number of stereoisomers for a molecule is , where is the number of chiral centers.

Example: A carbon atom bonded to Cl, Br, OH, and H is a chiral center.

Identifying Chiral Centers

Determining Chirality

• To identify chiral centers, look for tetrahedral carbons attached to four different groups.

• Chiral molecules lack a plane of symmetry.

Types of Stereoisomers

Enantiomers and Diastereomers

• Enantiomers: Non-superimposable mirror images. Only chiral compounds can have enantiomers.

• Diastereomers: Stereoisomers that are not mirror images of each other.

Example: (R,R)-tartaric acid and (S,S)-tartaric acid are enantiomers.

Classifying Stereoisomers

• Determine if molecules are identical, enantiomers, or diastereomers by comparing their spatial arrangement and mirror images.

Assigning R/S Designations

Cahn-Ingold-Prelog System

• Assign priorities to the four groups attached to a chiral center based on atomic number (highest atomic number = highest priority).

• Orient the molecule so the lowest priority group is facing away from you.

• Trace a path from priority 1 → 2 → 3:

  • If the path is clockwise, the configuration is R (rectus).

  • If the path is counterclockwise, the configuration is S (sinister).

Special Cases: For tie-breaking, compare the next set of atoms along the chain. Double bonds count as two single bonds, triple bonds as three.

Meso Compounds

Definition and Properties

• Meso compounds have chiral centers but are achiral due to an internal plane of symmetry.

• Meso compounds have fewer stereoisomers than predicted by .

Example: 2,3-butanediol with a plane of symmetry is a meso compound.

Optical Activity

Interaction with Polarized Light

• Enantiomers rotate plane-polarized light in equal but opposite directions.

• Optical activity is measured using a polarimeter.

• The degree of rotation depends on sample concentration and path length.

Specific Rotation Formula:

• = specific rotation

• = observed rotation (degrees)

• = path length (dm)

• = concentration (g/mL)

Standard measurements are taken at 1 g/mL concentration and 1 dm path length, with temperature and wavelength specified.

Racemic Mixtures

Definition and Properties

• A racemic mixture contains equal amounts of both enantiomers.

• Racemic mixtures are optically inactive (net rotation = 0°).

• If one enantiomer is in excess, the mixture will show optical activity, but less than the pure enantiomer.

Summary Table: Types of Stereoisomers

Additional info: The notes also reference the use of models and visual aids for understanding stereochemistry, and highlight the importance of stereochemistry in drug safety and regulatory policy.