Chapter 6: Stereochemistry Lecture Notes

Introduction to Stereoisomers

• Definition of Stereoisomers: These are molecules that possess the same atomic bonding (connectivity) but differ in their three-dimensional (3-D) arrangement of atoms.
• Contrast with Connectivity: Unlike constitutional isomers, which have different bonding patterns, stereoisomers have identical connectivity.
• Geometric Examples (Cis-Trans):
  • Cis-isomer: Groups (represented here as $me$ for methyl) are on the same side of a reference plane.
  • Trans-isomer: Groups (represented as $me$) are on opposite sides of a reference plane.

Chirality and Enantiomers

• Enantiomers: These are a specific type of stereoisomer. They are molecules that are mirror images of each other but are not identical—meaning they are non-superimposable.
• Chirality: A molecule is considered chiral if it lacks a plane of symmetry and is non-superimposable on its mirror image.
• Chiral Carbon (Chiral Center): A carbon atom is chiral if it is a tetrahedral carbon bonded to four different groups.
• Determining Mirror Images:
  • You can draw the enantiomer by reflecting the molecule across a mirror plane.
  • Switching the position of any two groups around a chiral center produces its enantiomer.
• Case Study: Naproxen (Aleve):
  • (S)-Naproxen: The active enantiomer marketed under the brand name Aleve.
  • (R)-Naproxen: The mirror image of the (S) form; it has a different 3-D arrangement despite having the same groups ($H_3C$, $H$, $OH$ group on the carboxylic acid, and the aromatic system).

Biological Significance and Diastereomers

• Importance in Biology: Chirality is crucial in biological systems including amino acids ($AA'S$), peptides, and proteins. Most naturally occurring amino acids exist solely as the (S)-enantiomer.
• Diastereomers:
  • Definition: Stereoisomers that are not mirror images of one another.
  • Requirements: Typically occurs in molecules with more than one chiral center.
• Analysis of 2-butanol:
  • Molecular formula: $CH_3CH(OH)CH_2CH_3$.
  • The second carbon ($C_2$) is a chiral carbon because it is bonded to four different groups: $H$, $OH$, $methyl\text{ (}CH_3\text{)}$, and $ethyl\text{ (}CH_2CH_3\text{)}$.
  • Drawing methods: You can represent these using wedges (coming toward you) and dashes (going away).
  • Proving enantiomers: If you draw two versions that appear to be mirror images, and attempting to superimpose them fails, they are enantiomers.

Relative Configuration and Optical Activity

• Optical Rotation: Chiral molecules will rotate the plane of polarized light. This is denoted as $\alpha$ (optical rotation).
• Direction of Rotation:
  • (+) Dextrorotatory: Rotates light to the right (clockwise). Examples use the prefix (d).
  • (-) Levorotatory: Rotates light to the left (counter-clockwise). Examples use the prefix (l).
• Case Study: Lactic Acid:
  • (+) Lactic acid: Known as (d)-lactic acid.
  • (-) Lactic acid: Known as (l)-lactic acid.
  • Relationship: These enantiomers rotate light in equal and opposite directions.

Chiral vs. Achiral Properties

• Chiral Properties:
  • Lacks a plane of symmetry.
  • Will rotate plane-polarized light.
  • Analogies: A right-handed desk or human hands.
  • Example: $H-C(Me)(Et)(OH)$ where the carbon is bonded to four distinct groups.
• Achiral Properties:
  • Has a plane of symmetry (you would have to break bonds to remove it).
  • Does not rotate light ($0$ optical rotation).
  • Example: Benzene ($C_6H_6$) and molecules like $Me-CH(OH)-Me$ (2-propanol) which has symmetry because two groups are identical ($Me$ and $Me$).
• Note on Identification: A molecule with no chiral carbons is generally achiral, but the presence of an internal plane of symmetry is the definitive test.

Absolute Configuration: The R and S System

• Definition: Absolute configuration refers to the actual 3-D spatial arrangement of the groups around a chiral center, denoted as (R) or (S).
• Cahn-Ingold-Prelog Priority Rules:
  1. Identify the Chiral Carbon: Locate the carbon atom with four different groups.
  2. Assign Priority by Atomic Number ($Z$): The atom with the highest atomic number gets the highest priority ($1$). The atom with the lowest atomic number (often Hydrogen, $Z=1$) gets the lowest priority ($4$).
  3. Orientation: Orient the molecule so that the lowest priority group ($4$) is pointing away from the viewer (represented by a dashed bond).
  4. Determine Rotation Path: Draw a path from priority $1 \rightarrow 2 \rightarrow 3$.
     • Clockwise = (R) (Rectus).
     • Counter-clockwise = (S) (Sinister).
• Special Rule (Reverse Trick): If the lowest priority group ($H$) is pointing toward you (wedge) instead of away (dash), determine the rotation and then reverse the answer (e.g., if it looks like S, it is actually R).

Complex Priority and Multiple Bonds

• Multiple Bond Rules: For assigning priority in the R/S system, multiple bonded atoms are treated as the equivalent number of single-bonded atoms.
  • A carbonyl group ($C=O$) is treated as a carbon bonded to two oxygens: $(O, O, H)$.
  • A carbon-carbon double bond ($C=C$) is treated as a carbon bonded to two carbons: $(C, C, H)$.
• The $2^n$ Rule:
  • Used to determine the maximum possible number of stereoisomers for a molecule.
  • Formula: $2^n$, where $n$ is the number of chiral carbons.
• Case Study: Threonine (Amino Acid):
  • Contains $2$ chiral carbons, so it has $2^2 = 4$ possible stereoisomers: $(2R, 3R)$, $(2S, 3S)$, $(2R, 3S)$, and $(2S, 3R)$.
  • Pairs like $(2R, 3R)$ and $(2S, 3S)$ are enantiomers.
  • Relationships between non-mirror pairs (e.g., $2R, 3R$ and $2R, 3S$) are diastereomers.
• Historical Context: The Murchison Meteorite found in Australia in the 1970s was significant because researchers found amino acids within it.

Meso Compounds

• The Exception to the $2^n$ Rule: A Meso compound occurs when a molecule has chiral carbons but also has an internal plane of symmetry.
• Characteristics:
  • Even though it has chiral centers, the molecule as a whole is achiral.
  • It does not rotate light (zero net optical rotation).
  • The mirror image of a meso compound is identical to the original molecule (superimposable).
• Example Analysis:
  • A molecule with $(2R, 3S)$ configuration where the two halves of the molecule are identical by symmetry.
  • If you rotate the axis $50\%$, you obtain the mirror image, proving they are identical.

Physical Properties and Racemic Mixtures

• Racemic Mixture (Racemate):
  • A $1:1$ ratio of (R) and (S) enantiomers.
  • Result: A net optical rotation of $0$ because the equal and opposite rotations cancel out.
• Comparing Physical Properties:
  • Enantiomers: Share identical physical properties such as boiling point ($bp$), melting point ($mp$), color, density, polarity, and solubility in achiral solvents.
  • Diastereomers: Possess different physical properties. They have different boiling points, melting points, and solubilities.
• Separation Techniques:
  • Enantiomers: Harder to separate. Requires a Chiral Auxiliary to turn the enantiomer pair ($R + S$) into a diastereomeric mixture ($RR + SR$). Once they are diastereomers, they can be separated by standard methods (like recrystallization), then the auxiliary is removed to recover the pure $R$ and $S$.
  • Diastereomers: Can be separated using standard laboratory techniques:
    • Recrystallization (based on solubility differences).
    • Distillation (based on boiling point differences).
    • Chromatography (based on polarity differences).

Big Picture: Isomer Classification

• Isomers: Entities with the same molecular formula.
  • Constitutional Isomers: Different bonding/connectivity.
  • Stereoisomers: Same bonding, different 3-D arrangement.
    • Enantiomers: Non-superimposable mirror images.
    • Diastereoisomers: Not mirror images.
      • Configurational: (R, S) arrangements.
      • Cis/Trans: Geometric arrangements around double bonds or rings.