Understanding Stereochemistry and Chirality

• Stereochemistry deals with the three-dimensional arrangement of atoms in molecules
• It focuses on stereoisomers, which have the same molecular formula and connectivity but different spatial arrangements
• Stereoisomers have distinct physical and chemical properties

Chirality

• Chirality refers to molecules that are non-superimposable on their mirror images
• A chiral molecule is not superimposable on its mirror image
• Achiral molecules are superimposable on their mirror images
• A chiral center is typically a carbon atom bonded to four different groups, also known as a stereocenter or asymmetric carbon
• The presence of one chiral center usually leads to a chiral molecule
• Molecules with multiple chiral centers can be chiral, achiral (meso compounds), or diastereomers
• Enantiomers are stereoisomers that are non-superimposable mirror images
• Enantiomers have identical physical properties, except for the direction in which they rotate plane-polarized light
• Diastereomers are stereoisomers that are not mirror images
• Diastereomers have different physical properties
• Optical activity refers to the ability of a chiral molecule to rotate the plane of plane-polarized light
• Dextrorotatory (d or +) enantiomers rotate the plane of polarized light clockwise
• Levorotatory (l or -) enantiomers rotate the plane of polarized light counterclockwise
• A racemic mixture is an equal mixture of two enantiomers, resulting in no net rotation of plane-polarized light
• Optical purity (enantiomeric excess) indicates the excess of one enantiomer in a mixture
• Enantiomeric excess (ee) is calculated as: ee = (|%R - %S|) where %R and %S are the percentages of the R and S enantiomers

Cahn-Ingold-Prelog (CIP) Priority Rules

• The Cahn-Ingold-Prelog (CIP) rules are used to assign absolute configurations (R or S) to chiral centers
• Assign priorities to the four groups attached to the chiral center based on atomic number: higher atomic number gets higher priority
• If atoms directly attached to the chiral center are the same, consider the next atoms along the chain until a difference is found
• Orient the molecule so that the lowest priority group (4) is pointing away from you
• Determine the direction of the path from the highest priority group (1) to the second (2) and third (3) priority groups
• If the path is clockwise, the chiral center is designated as R (rectus)
• If the path is counterclockwise, the chiral center is designated as S (sinister)
• In the case of multiple bonds, treat each multiple bond as if it were a single bond to multiple single atoms (e.g., -C=O is treated as -C(O)(O))

Fischer Projections

• Fischer projections are 2D representations of 3D molecules, commonly used for representing carbohydrates and amino acids
• The chiral carbon is at the intersection of two lines
• Horizontal lines represent bonds that project out of the plane of the paper (wedges)
• Vertical lines represent bonds that project into the plane of the paper (dashes)
• The carbon chain is drawn vertically, with the most oxidized carbon at the top
• To determine R/S configuration: if lowest priority is on a horizontal bond, assign configuration as normal, then invert the assignment
• Rotating a Fischer projection by 180° maintains the configuration
• Rotating a Fischer projection by 90° inverts the configuration

Meso Compounds

• Meso compounds are molecules with multiple chiral centers that are achiral due to an internal plane of symmetry
• Meso compounds have chiral centers, but the molecule is superimposable on its mirror image
• Meso compounds do not exhibit optical activity

Resolution of Enantiomers

• Resolution is the process of separating a racemic mixture into its pure enantiomers
• Resolution methods include:
  • Formation of diastereomeric salts: Reacting the racemic mixture with a chiral resolving agent to form diastereomeric salts, which can be separated based on differences in solubility
  • Chiral chromatography: Using a chiral stationary phase that selectively retains one enantiomer over the other
  • Kinetic resolution: Using a chiral catalyst or enzyme that reacts with one enantiomer faster than the other

Stereoisomers in Cyclic Systems

• Cyclic compounds can exhibit stereoisomerism due to restricted rotation
• Cis isomers have substituents on the same side of the ring
• Trans isomers have substituents on opposite sides of the ring
• Ring flipping in cyclohexane can interconvert conformers
• Substituents prefer to be in equatorial positions rather than axial positions to minimize steric strain
• Bulky groups like tert-butyl strongly prefer the equatorial position

Atropisomers

• Atropisomers are stereoisomers that result from restricted rotation about a single bond where steric hindrance prevents interconversion
• They are chiral due to the specific spatial arrangement that cannot easily rotate into another conformation
• Stable at room temperature, allowing for separation and characterization

Prochirality

• Prochirality describes molecules that can become chiral by a single chemical transformation
• Prochiral centers are typically sp3 hybridized atoms bonded to two identical groups
• Enantiotopic ligands are identical ligands on a prochiral center that, if replaced by a different group, would generate enantiomers
• Diastereotopic ligands are identical ligands on a carbon that, if replaced by a different group, would generate diastereomers
• Enzymes often exhibit stereospecificity, reacting selectively with one enantiomer or one face of a prochiral molecule