Chapter 3: Molecular Relationships, Stereochemistry, and Chirality

Molecular Relationships

  • Hexane and Isomers

    • Molecules to consider:

      • Hexane: C6H14

      • 2-Methylpentane

      • 3-Methylpentane

      • 2,3-Dimethylbutane

      • 2,2-Dimethylbutane

  • Types of Isomers

    • Constitutional Isomers: Isomers that have the same molecular formula but different connectivity (different arrangements of atoms). e.g.,

      • Butane and 2-Methylpropane (C4H10)

      • 1-Chloropropane vs. 2-Chloropropane (C3H7Cl)

    • Conformational Isomers: Different arrangements of atoms that arise from the rotation around a single bond.

    • Example of Eclipsed and Staggered Conformations:

      • Fully eclipsed: Methyl groups at 0º apart

      • Staggered (Gauche): Methyl groups at 60º apart

      • Eclipsed: Methyl groups at 120º apart

      • Anti: Methyl groups at 180º apart

Thalidomide Case Study

  • Background: Thalidomide was first marketed in 1957, intended for use in relieving anxiety, sleep disturbances, and morning sickness.

  • Impact: Public health issues arose regarding teratogenicity (ability to cause birth defects) leading to its withdrawal by 1961.

    • Affected Infants: Estimated 10,000 infants conceived while mothers took thalidomide, with a mortality rate of approx. 40% around birth.

    • Symptoms in Survivors: Limb, eye, urinary tract, and heart abnormalities

Stereoisomerism and Chirality

  • Definitions to Cover:

    • Stereochemistry: Study of the 3D structure of molecules and their isomers due to spatial orientation of atoms.

    • Chirality: Property of a molecule that is not superimposable on its mirror image. A chiral object has "handedness".

    • Asymmetry: Refers to the lack of symmetry; a molecule with a chiral center shows asymmetry.

Chiral Carbons (Asymmetric Carbons)

  • Chiral Carbon (C*): A carbon atom bonded to four different groups, making it non-identical to its mirror image

  • Identical Mirror Images: Carbons with bonds to four identical groups do NOT create a chiral center.

  • Non-Superimposable Mirrors: Carbons that have three identical groups and one different group lead to identical mirror images.

  • KeyPoint: Carbons with four distinct groups are chiral.

Visualising Chirality with Chirality Centers

  • Mirror Images: Chiral objects cannot be superposed on their mirror images, such as left vs. right hands, certain snail shells, and the twist in a gazelle's horns.

  • Non-superimposable examples: Plants, hurricanes, and other helical structures with handedness.

Optical Activity and Interaction with Chiral Light

  • Chiral molecules interact with plane-polarized light differently:

    • Chiral substances rotate light in opposite directions.

    • Optical Activity: The rotation of polarized light by chiral substances.

Identification of Chirality

  • Steps to Determine Chirality of Carbons:

    1. Identify the chiral center(s).

    2. Assign configuration (using R/S or clockwise/counterclockwise) based on priority of attached groups.

    3. Use CIP system to rank groups based on Atomic Number.

    4. You can determine if two stereocenters are identical, enantiomers, or diastereomers.

Cahn-Ingold-Prelog (CIP) Priority Rules

  • Assigning configuration:

    • Highest Atomic Number (AN) = Highest Priority

    • In cases of identical atoms, evaluate the next set of atoms

    • Configuration determined as either R (clockwise) or S (counterclockwise).

Importance of Chirality in Medicine

  • Approximately 66% of drugs in development are chiral; 51% studied as single enantiomers.

  • Statistical Data: In 2008, $205 billion was attributed to single enantiomer drugs out of total worldwide sales of $475 billion for formulated products.

Isomers in Detail

  • Classification of Isomers:

    • Constitutional Isomers: Compounds with the same formula but different connection arrangements.

    • Stereoisomers: Molecules with same connection sequences but differing spatial arrangements.

      • Enantiomers: Non-superposable mirror images

      • Diastereomers: Non-mirror image stereoisomers

Meso Compounds

  • Meso Compounds: Achiral despite multiple stereocenters due to the presence of a plane of symmetry, reducing total distinct stereoisomers.

Fischer Projections

  • Fischer Projections: Simplified representation of chiral centers using horizontal and vertical lines to eliminate wedges and dashes.

  • Basic Rules:

    • Cross represents C* (chiral carbon)

    • Horizontal lines signify bonds coming forward (wedges)

    • Vertical lines indicate bonds going back (dashes)

Optical Purity and Enantiomeric Excess

  • Definition: The degree to which one enantiomer dominates in a mixture.

  • Optical Activity: Racemic mixtures (equal amounts of both enantiomers) display no optical activity.

  • Enantiomerically Pure: Describes a sample containing only one enantiomer.

Conclusion

  • Crucial Aspects:

    • Identification of chiral centers is key to understanding chirality in molecules

    • Chirality significantly impacts the properties of compounds, especially in pharmacology.

    • The concept of optical activity provides practical analysis for distinguishing between chiral molecules.