Chapter 6: Stereoisomers – Stereochemistry and Isomerism in Organic Molecules

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Stereochemistry

Introduction to Stereochemistry

Stereochemistry is the study of the three-dimensional (3D) arrangement of atoms within molecules. It is crucial in organic chemistry because the spatial orientation of atoms can dramatically affect the properties and biological activity of compounds. For example, the drug thalidomide exists as two stereoisomers: one is an effective sedative, while the other is highly teratogenic (causes birth defects).

Isomers are compounds with the same molecular formula but different structures.
Stereochemistry focuses on isomers with the same connectivity but different spatial arrangements.

Importance of Stereochemistry

Stereochemistry affects drug safety and efficacy (e.g., thalidomide).
Many biological molecules are stereospecific, meaning only one isomer is biologically active.

Examples of Stereoisomer Effects

Property of Isomer A	Isomer A	Isomer B	Property of Isomer B
Commercially available anti-inflammatory (AleveTM)	naproxen sodium	isomer B structure	Inactive as anti-inflammatory, severe liver toxicity
160 times sweeter than sugar; common artificial sweetener	aspartame	isomer B structure	Bitter tasting
Antimycobacterial drug used in tuberculosis treatment	ethambutol	isomer B structure	Causes blindness

Isomers

Classification of Isomers

Isomers are divided into two main categories:

Constitutional isomers (structural isomers): Same molecular formula, different connectivity of atoms.
Stereoisomers: Same molecular formula and connectivity, but different spatial arrangement of atoms.

Types of Stereoisomers

Conformational isomers (conformers): Interconvert rapidly by rotation about single bonds; cannot be separated.
Configurational isomers: Can only interconvert by breaking covalent bonds; can be separated.

Constitutional vs. Stereoisomers

Definitions and Examples

Constitutional isomers: Atoms are connected in different ways, leading to different functional groups or structures. Example: ethanol (CH3CH2OH) vs. dimethyl ether (CH3OCH3).
Stereoisomers: Atoms are connected in the same way but arranged differently in space. Example: cis-4-methylcyclohexanol vs. trans-4-methylcyclohexanol.

Stereoisomers

Types of Stereoisomers

Conformational isomers (conformers): Rapidly interconvert at room temperature; cannot be separated. Stability varies among conformers.
Configurational isomers: Cannot interconvert unless covalent bonds are broken; can be separated due to different physical properties.

Conformers

Conformational Isomerism

Conformers arise from rotation about C–C single bonds and amine inversion.
Examples include eclipsed, staggered, anti, gauche, and ring flip conformations.
Conformers are not isolable but are important for understanding molecular flexibility.

Configurational Isomers

Properties and Separation

Configurational isomers require breaking covalent bonds to interconvert.
They have distinct physical properties (e.g., boiling point, dipole moment) and can be separated.

Chirality

Concept of Chirality

Chirality refers to objects (or molecules) that are not superimposable on their mirror images.
Achiral objects are superimposable on their mirror images.
Chirality in molecules is often due to the presence of an asymmetric center (usually a carbon atom bonded to four different groups).

Identifying Chiral Centers

An asymmetric center has four different groups attached and lacks a plane of symmetry.
Chiral centers can be identified by examining molecular structure for such atoms.

Chirality Table

Molecule	Four different groups on any atom?	Mirror image	Superimposable?	Symmetry?
cyclohexane	No	Yes	Yes	Yes, multiple planes of symmetry
methylcyclopentane	No	Yes	Yes	Yes, one plane of symmetry
3-chlorocyclohexane	Yes, C3 is an asymmetric center	No	No	No plane of symmetry
5-methyl-5-ethylcyclohexane	Yes, C5 is an asymmetric center	No	No	No plane of symmetry

Enantiomers

Definition and Properties

Enantiomers are pairs of molecules that are nonsuperimposable mirror images of each other.
They have identical chemical and physical properties except for their interaction with plane-polarized light and chiral environments.
Enantiomers can be separated and may have different biological activities (e.g., (R)-carvone smells like spearmint, (S)-carvone smells like caraway).

Naming Enantiomers: The R/S System

The Cahn-Ingold-Prelog (CIP) system is used to assign absolute configuration (R or S) to chiral centers.
Assign priorities to substituents based on atomic number; if atomic numbers are equal, move outward to the next atom.
For double/triple bonds, treat as if the atom is bonded to equivalent "phantom" atoms.
Draw a cyclic arrow from priority 1 to 2 to 3; if the lowest priority group is pointing away, clockwise is R, counterclockwise is S.

R/S Assignment Table

Molecule	Priority assigned	Explanation	Model snapshot
Example 1	2 has a second carbon attached, whereas 4 only has hydrogens	Assign priorities and determine R/S	Model image
Example 2	4 is attached to a carbon, whereas 2 only has hydrogens	Assign priorities and determine R/S	Model image

Optical Activity

Optically active molecules rotate plane-polarized light.
Measured using a polarimeter.
Dextrorotatory (+): rotates light clockwise; Levorotatory (−): rotates light counterclockwise.
A racemic mixture contains equal amounts of both enantiomers and shows no net rotation.

Specific Rotation Equation

The specific rotation () is calculated as:

Where is the observed rotation (degrees), is the path length (dm), and is the concentration (g/mL).

Optical Purity and Enantiomeric Excess

Optical purity is the ratio of observed rotation to the rotation of the pure enantiomer:

Enantiomeric excess is the percentage of one enantiomer over the other.

Multiple Chiral Centers

Number of Stereoisomers

The maximum number of stereoisomers for a molecule is , where is the number of chiral centers.
Molecules with multiple chiral centers can have enantiomers and diastereomers.

Diastereomers

Definition and Properties

Diastereomers are stereoisomers with more than one chiral center that are not mirror images of each other and are nonsuperimposable.
Diastereomers have different physical and chemical properties and can be separated by standard laboratory techniques (e.g., recrystallization, distillation).

Diastereomer Properties Table

Compound	Solubility (H2O, 20°C) (g/100 mL)	Melting point (°C)	Refractive index	Density (g/mL)
(R,R)-tartaric acid	139	171–174	1.436	1.7598
meso-tartaric acid	125	165–166	1.355	1.6460

Meso Compounds

Definition and Characteristics

Meso compounds have two or more chiral centers, a plane of symmetry, and are superimposable on their mirror image.
Despite having chiral centers, meso compounds are achiral due to internal symmetry.
Example: meso-tartaric acid.

Additional Info

Chiral centers can exist on atoms other than carbon (e.g., nitrogen in amines), but rapid inversion often prevents isolation of enantiomers.
Fischer projections are a way to represent stereochemistry in molecules, especially carbohydrates and amino acids.