Chirality and Isomerism Overview

Chirality (Abridged)

• This presentation provides an overview of chirality, a key concept in understanding the structure and function of pharmaceutical molecules.
• It covers constitutional isomerism, geometric isomerism (cis and trans), IUPAC nomenclature (Z and E), stereoisomerism, and an introduction to chiral carbons.
• The information is presented in an abridged format, providing a condensed summary of the topic.
• It emphasizes the importance of chirality in determining the function and efficacy of drugs.

Constitutional Isomerism

• Constitutional isomers, also called structural isomers, are molecules with the same chemical formula but different connectivity of carbon atoms.
• They have different physical and chemical properties, including melting point, boiling point, solubility, and density.
• Different connectivity leads to varying functional groups within the molecules.
• Constitutional isomers cannot interconvert.

Example of C₉H₈O₄ Isomers

• Aspirin (plant/synthetic origin), a non-steroidal anti-inflammatory drug (NSAID), has analgesic, antipyretic, and antiplatelet properties.
• Caffeic acid, a plant-derived compound, is a key intermediate in lignin biosynthesis with anti-cancer and antioxidant properties.
• 4-Hydroxyphenyl-pyruvic acid is found in animals and is an intermediate in the metabolism of tyrosine. If not processed efficiently excess can become toxic.

Geometric Isomerism (Cis and Trans)

• Geometric isomers have the same chemical formula and connectivity, but differ in the spatial arrangement of their substituents around a double bond (alkene).
• Two geometric isomers are cis and trans isomers. Cis isomers have substituents on the same side of the double bond; trans isomers have substituents on opposite sides of the double bond.
• Isomers are not interconvertible between cis and trans forms at ambient or body temperatures.

Examples of C₄H₄O₄ Isomers (Maleic and Fumaric Acid)

• Maleic acid (cis-form) is commonly used as a salt base for medicines in the pharmaceutical industry. Its melting point is 139-140°C.
• Fumaric acid (trans-form) is also used as a salt base for medicines in the pharmaceutical industry. Its melting point is 287°C.

IUPAC Nomenclature for Alkenes (Cahn-Ingold-Prelog, CIP Rules)

• The CIP rules provide a systematic way to name alkenes.
• The prefix 'Z' is used when the two highest priority groups are on the same side of the double bond.
• The prefix 'E' is used when the two highest priority groups are on opposite sides of the double bond.

Worked Example: Fumaric Acid

• Fumaric acid is an alkene with the molecular formula C₄H₄O₄.
• When using the CIP rules, the groups on both sides of the double bond, that have the highest priority dictate whether a molecule is Z or E.
• The groups are on opposite sides so it's an E isomer.

Why is Geometry Important?:

• The correct Z (trans) geometry of tamoxifen is crucial for tight binding to the estrogen receptor.
• This leads to inhibition of cell signals, which prevents breast cancer cell growth.

Stereoisomerism

• Stereoisomers are molecules with the same atomic connectivity, but different spatial arrangements.
• Stereoisomers are categorized as either enantiomers or diastereomers.
• Enantiomers are non-superimposable mirror images, while diastereomers are non-superimposable non-mirror images.
• Stereoisomerism is important for the pharmaceutical industry. Incorrect stereochemistry can lead adverse effects in patients.

Terminology

• Stereoisomerism is synonymous with chirality.
• A chiral carbon atom has four different atoms or groups attached.
• A racemic mixture (racemate) is a 1:1 mixture of enantiomers.
• Optically inactive implies achirality.
• Enantiomers are non-superimposable mirror images, while diastereomers are non-superimposable non-mirror images.

What is a Chiral Carbon?

• A chiral carbon atom is sp³ hybridised and has four different atoms or groups attached to it.
• Chirality can be determined by whether the molecule is superimposable on its mirror image.
• Non-superimposable mirror images are called enantiomers.

Practice: Identify the Chiral Carbons

• A series of chemical structures and examples of chiral molecules are presented. Students are encouraged to identify chiral carbons within the molecules.

Nomenclature

• The IUPAC system uses CIP rules, assigning R or S configurations to chiral centers.
• R configuration is assigned when groups have a clockwise order of decreasing priority, and S when there's an anti-clockwise order.

Steps to Classify Chirality

• Steps for determining chiral center configurations (R/S) are detailed.

Worked Example: Acebutolol

• A worked example demonstrates the process of identifying the chiral carbon and determining its R or S configuration in acebutolol.

What do we do if Priority 4 Atom not at Back?

• Addressing cases where the priority 4 atom is not at the back involves rotating the structure.

Key Messages: Alkene Geometry

• Z and E designations are crucial for describing alkene geometry.
• The priority of substituents is essential for accurate nomenclature.
• Alkene geometry is vital for proper binding to target molecules. Correct geometry contributes to better drug potency.

Interactions with Other Enantiomers

• Chiral species (receptors and enzymes) often interact differently with different enantiomers.
• The correct enantiomer is crucial, since incorrectly matched shapes lead to poor binding or no binding at all.

Vigabatrin (Sabril®)

• Vigabatrin is used in epilepsy treatment.
• The (S)-enantiomer is active as an anti-convulsant.
• Increases GABA levels to reduce seizures.

Fluoxetine (Prozac®)

• Fluoxetine is used in depression treatment.
• The (S)-enantiomer is the pharmacologically active form.
• Eliminates rapidly to a lower volume from the bloodstream.

Warfarin

• Warfarin (a blood thinner) is administered as a racemate.
• The (S)-enantiomer is more effective and longer-lasting than the (R) form.

Why are Amines Rarely Chiral?

• Amines can undergo inversion and lose their chirality.

Key Messages

• Pharmaceuticals often have chiral carbons, creating stereoisomerism.
• Enantiomers have opposite rotations of polarized light but the same chemical and physical properties.

This quiz provides an overview of chirality, focusing on its significance in pharmaceuticals. It covers various types of isomerism, including constitutional and geometric isomerism, along with IUPAC nomenclature. Gain insights into how these concepts impact drug function and efficacy in a concise format.