Chapter Overview
This chapter explores the fascinating world of stereoisomerism in organic chemistry, focusing on how molecules with the same molecular formula can have different spatial arrangements, leading to distinct properties and biological activities.
Learning Objective 1
Explain stereoisomerism and its division into geometric (cis/trans) and optical isomerism
Learning Objective 2
Describe geometrical isomerism in alkenes and explain its origin in terms of restricted rotation due to pi bonds
Learning Objective 3
Describe the shape of benzene and other aromatic molecules, including sp² hybridization
Learning Objective 4
Explain chiral centers and how they give rise to enantiomers
Learning Objective 5
Describe properties of enantiomers and their effects on polarized light
Learning Objective 6
Explain the significance of chirality in drug preparation using thalidomide as an example
In the early nineteenth century, Jakob Berzelius classified compounds as organic (from plants/animals) and inorganic (mineral origin). A key distinction was that organic compounds burn on heating while inorganic chemicals melt. This classification laid the foundation for understanding the unique properties of carbon-based molecules.
Organic Compounds Statistics
Stereoisomerism
Stereoisomers are molecules with identical molecular formulas and atomic connectivity but different spatial arrangements of atoms. This “handedness” in molecular structure has profound implications in biological systems where enzymes and receptors interact specifically with certain stereoisomers.
Key Concepts
- Constitutional Isomerism: Different connectivity of atoms
- Stereoisomerism: Same connectivity, different spatial arrangement
- Geometric Isomerism: Different arrangement around double bonds
- Optical Isomerism: Non-superimposable mirror images
Metabolic reactions are catalyzed by enzymes which have specific active sites that can only accommodate certain stereoisomers. This is why the “wrong” stereoisomer of a drug can cause side effects – it doesn’t fit properly into the enzyme’s active site.
Types of Isomerism
Geometric Isomerism
Geometric isomerism occurs in alkenes due to restricted rotation around the double bond. Each carbon in the double bond is sp² hybridized, forming one sigma (σ) bond and one pi (π) bond. The π bond’s electron cloud lies above and below the molecular plane, preventing free rotation.
Alkene Bonding
Visualization of sigma and pi bonds in ethene:
Sigma (σ) bond: Head-on overlap of sp² orbitals
Pi (π) bond: Sideways overlap of p orbitals
Rotation around the double bond requires breaking the π bond, which needs approximately 264 kJ/mol in ethene.
Cis-Trans Isomerism
This system is used for disubstituted alkenes:
Cis-but-2-ene
CH₃ groups on same side
Cis-isomer: Same substituents on the same side
Trans-but-2-ene
CH₃ groups on opposite sides
Trans-isomer: Same substituents on opposite sides
| Property | Cis-isomers | Trans-isomers |
|---|---|---|
| Polarity | Polar (has dipole moment) | Non-polar (zero dipole moment) |
| Stability | Less stable due to steric strain | More stable |
| Boiling Point | Higher | Lower |
| Melting Point | Lower | Higher |
| Reactivity | Generally more reactive | Less reactive |
The chemistry of vision involves cis-trans isomerization. Rhodopsin in the retina contains cis-retinal which converts to trans-retinal when light enters the eye. This transformation initiates nerve impulses to the brain, allowing us to see.
Optical Isomerism
Optical isomers are molecules that can rotate the plane of polarized light. They exist as pairs of enantiomers – non-superimposable mirror images, much like our left and right hands.
Chirality
Chiral molecules have a carbon atom bonded to four different groups. This asymmetric carbon (chiral center) creates handedness in the molecule.
- Chiral objects: Non-superimposable on their mirror images (like hands)
- Achiral objects: Superimposable on their mirror images
Lactic Acid
(S)-enantiomer
Levorotatory (-)
Rotates light counterclockwise
Lactic Acid
(R)-enantiomer
Dextrorotatory (+)
Rotates light clockwise
Racemic Mixtures
A racemic mixture contains equal amounts of both enantiomers and is optically inactive because the rotations cancel each other out.
Limonene has two enantiomers with different smells. (+)-limonene is found in lemons and oranges, while (-)-limonene is found in pine needles and peppermint. Our olfactory receptors can distinguish between these mirror-image molecules.
Chirality in Drug Preparation
The shape of biological systems and chiral drug molecules are deeply linked. Biological receptors are typically chiral, meaning they interact differently with each enantiomer of a drug.
Thalidomide Case Study
Thalidomide was prescribed for morning sickness in the 1950s-60s but caused severe birth defects. Research revealed:
(R)-thalidomide
Sedative
Therapeutic
Safe sedative effect
(S)-thalidomide
Teratogenic
Harmful
Causes birth defects
The two enantiomers of thalidomide interconvert in the body. Even if only the safe (R)-enantiomer is administered, it converts to the harmful (S)-enantiomer in vivo, making separation ineffective.
Separation Methods
| Method | Process | Advantages | Limitations |
|---|---|---|---|
| Optical Resolution | Separate racemic mixture using HPLC, crystallization, or enzymes | Well-established techniques | Time-consuming, expensive, maximum 50% yield |
| Asymmetric Synthesis | Use chiral catalysts to produce only desired enantiomer | High enantiomeric purity, more efficient | Requires specialized catalysts |
After the thalidomide tragedy, drug authorities like the FDA now require assessment of enantiomer activity for racemic drugs. This has led to increased development of single-enantiomer drugs (about 50% of new drugs are single enantiomers).
Key Points
- Organic chemistry studies hydrocarbons and their derivatives with carbon as the essential element
- Nearly 20 million organic compounds are known, with isomerism contributing to this diversity
- Isomerism results from same molecular formula but different structures
- Stereoisomers have same molecular and structural formulas but different spatial arrangements
- Geometric isomerism occurs in alkenes with different groups on double-bonded carbons
- Double bonds restrict rotation (264 kJ/mol to break π bond in ethene), enabling different configurations
- Cis-isomers have same groups on same side; trans-isomers have them on opposite sides
- E/Z designation is more precise than cis/trans for complex alkenes
- Optical isomerism occurs in chiral molecules with no plane of symmetry
- Chiral molecules have carbon atoms bonded to four different groups (chiral centers)
- Enantiomers are non-superimposable mirror images with identical physical properties except for optical activity
- Racemic mixtures contain equal enantiomers and are optically inactive
- Meso compounds have chiral centers but are optically inactive due to internal compensation
- Drug enantiomers can have different biological effects (e.g., thalidomide)
- Chiral catalysts in asymmetric synthesis can produce single enantiomers efficiently
Multiple Choice Questions
1. Which one of the following molecules will have the ability to rotate the plane of polarized light?
Answer: C) I, II and IV only
Explanation: Molecules I, II, and IV have chiral centers (carbon atoms bonded to four different groups), making them optically active. Molecule III does not have a chiral center as two of the groups attached to the potential chiral carbon are identical.
2. Which one of the following molecules shows optical isomerism?
Answer: C) CH₂=CHCH(Cl)CH₃
Explanation: This molecule has a chiral center at the carbon bonded to Cl, H, CH=CH₂, and CH₃ groups. All four groups are different, creating a chiral center that gives rise to optical isomerism.
Quiz Results
Short Answer Questions
1. Draw the cis-trans isomers of hex-3-ene and explain how they differ in physical properties.
Answer:
Cis-hex-3-ene
Both ethyl groups on same side
Properties: Higher boiling point, polar, less stable
Trans-hex-3-ene
Ethyl groups on opposite sides
Properties: Lower boiling point, non-polar, more stable
Explanation: In cis-hex-3-ene, the ethyl groups are on the same side of the double bond, creating a bent molecule with a net dipole moment. This leads to stronger intermolecular forces (higher boiling point) but also steric strain between the bulky ethyl groups (less stable). The trans isomer has a more linear structure with no net dipole, resulting in weaker intermolecular forces but less steric strain.
2. Highlight the importance of chirality in drugs. Why do we need to separate optical isomers in the preparation of drugs?
Answer: Chirality is crucial in drugs because biological systems are chiral. Enzymes, receptors, and other biological targets have specific three-dimensional structures that interact preferentially with one enantiomer over the other. This can lead to dramatically different pharmacological effects:
- One enantiomer may have the desired therapeutic effect
- The other enantiomer may be inactive, less effective, or even harmful
- In some cases, each enantiomer has different therapeutic effects
We separate optical isomers to ensure that only the therapeutically active enantiomer is administered. This:
- Reduces side effects from the inactive or harmful enantiomer
- Allows for lower dosages (increased potency)
- Improves safety profile of the drug
- May provide more predictable pharmacokinetics
The thalidomide tragedy is a prime example where one enantiomer was a safe sedative while the other caused severe birth defects.
Concept Assessment Exercises
Concept Assessment Exercise 7.1
Which of the following compounds can and cannot show cis-trans isomerism and why?
i. 1-chloroprop-1-ene
Explanation: 1-chloroprop-1-ene cannot show cis-trans isomerism because one carbon of the double bond (C1) has two identical hydrogen atoms. For geometric isomerism to occur, each carbon of the double bond must have two different substituents.
ii. 3-chloroprop-1-ene
Explanation: 3-chloroprop-1-ene cannot show cis-trans isomerism because the double bond is at the end of the chain (terminal alkene). The terminal carbon (C1) has two identical hydrogen atoms, preventing geometric isomerism.
iii. hex-2-ene
Explanation: Hex-2-ene can show cis-trans isomerism because both carbons of the double bond (C2 and C3) have two different substituents. C2 has H and CH₃, while C3 has H and CH₂CH₂CH₃.