Stereochemistry and Isomerism

Stereochemistry and Isomerism — Spatial Arrangement of Atoms

Stereochemistry is the study of the three-dimensional arrangement of atoms in molecules and how this affects chemical behavior. In pharmacy, stereochemistry is critically important — different stereoisomers of the same drug can have dramatically different biological activities, potencies, and side effect profiles. Thalidomide is the classic tragic example: one enantiomer treated morning sickness while the other caused severe birth defects.

Classification of Isomerism

Structural Isomers (Constitutional Isomers)

Atoms are connected in a different order:

• Chain isomers: Different carbon skeleton (e.g., n-pentane vs. isopentane)
• Position isomers: Different position of functional group (e.g., 1-propanol vs. 2-propanol)
• Functional group isomers: Different functional groups (e.g., ethanol vs. dimethyl ether)

Stereoisomers

Same connectivity, different spatial arrangement:

• Conformational isomers — rotate about single bonds, interconvert rapidly at room temperature
• Configurational isomers — require bond breaking to interconvert:
  • Geometric (cis-trans / E-Z) isomers
  • Optical (enantiomers and diastereomers)

Geometric Isomerism (Cis-Trans / E-Z)

Occurs in alkenes and cyclic compounds when rotation around a double bond or ring is restricted.

Alkenes — E/Z System:

The E/Z system (IUPAC) assigns priority to substituents on each carbon of the double bond:

• Z (zusammen, German for “together”) = higher priority groups on the same side
• E (entgegen, German for “opposite”) = higher priority groups on opposite sides

To assign E or Z:

1. Assign CIP priority (atomic number) to substituents on each double-bond carbon
2. Compare priorities on each carbon
3. If both high priorities are on same side → Z; opposite sides → E

Cyclic Compounds:

Cis-trans in cycloalkanes: substituents on the same side of the ring plane (both up or both down) = cis; opposite sides = trans.

Chirality and Optical Isomerism

Chiral Centre (Stereocentre): A carbon atom bonded to four different substituents — it cannot be superimposed on its mirror image.

Key Terms:

• Enantiomers: Non-superimposable mirror-image pairs of chiral molecules. They rotate plane-polarized light in equal but opposite directions.
• Dextrorotatory (d or +): Rotates light clockwise (right)
• Laevorotatory (l or –): Rotates light anticlockwise (left)
• Racemic mixture (dl or ±): 50:50 mixture of enantiomers — optically inactive

The R/S System (Cahn-Ingold-Prelog):

1. Assign priorities 1→4 to substituents (highest atomic number = priority 1)
2. Orient molecule so lowest priority (4) points away from you
3. Trace 1→2→3: clockwise = R (rectus), anticlockwise = S (sinister)

Diastereomers

Diastereomers are stereoisomers that are NOT mirror images of each other. They have different physical properties (melting points, boiling points, solubilities) and different chemical reactivity.

Important case: Molecules with two or more chiral centres — each centre can be R or S, giving 2ⁿ stereoisomers. Pairs that are not mirror images = diastereomers.

Conformational Analysis

Alkanes — Newman Projections:

Viewing along a carbon-carbon bond:

• Staggered conformation: Substituents 60° apart — most stable for ethane and substituted ethane
• Eclipsed conformation: Substituents aligned — highest energy, least stable
• Anti (staggered): Substituents 180° apart — most stable for butane
• Gauche: Substituents 60° apart — higher energy than anti

Cycloalkanes:

• Chair conformation of cyclohexane: Most stable; alternating axial and equatorial positions
• Axial positions: Perpendicular to ring plane; alternating up/down around ring
• Equatorial positions: Roughly in the plane of the ring; larger, less steric hindrance
• Substituents prefer equatorial positions to minimize 1,3-diaxial interactions

Pharmaceutical Significance of Stereochemistry

• Drug-receptor binding requires precise 3D fit — enantiomers may have very different activities
• S-ibuprofen is the active analgesic; R-ibuprofen is inactive but slowly converts in vivo
• S-citalopram is the active antidepressant; R-citalopram is a by-product of synthesis
• Many drugs are marketed as single enantiomers due to better safety/efficacy profiles
• Prochirality: Some molecules have prochiral centres that become chiral during metabolic activation (e.g., ethanol metabolism via acetaldehyde)

SAPC Examination Tips

1. Draw R/S on 2D paper: Practice the “swivel” method — when the lowest priority is on a wedge/dash, determine R/S directly; if it’s not, swap it with the group pointing away and reverse the answer.
2. E/Z vs. R/S are different systems — E/Z describes alkene geometry; R/S describes tetrahedral chirality.
3. Thalidomide reminder — know this example and be able to explain why chiral switch policies are complex.
4. For cyclic conformations — always draw the chair clearly with axial/equatorial positions labelled; marks are often lost on poorly drawn cyclohexane chairs.
5. Tartaric acid is a common exam molecule: it has two identical chiral centres → meso form (optically inactive) + enantiomeric pair (R,R and S,S).