Exhaustive Study Notes on Stereochemistry and Bioorganic Isomerism

Stereochemistry: Overview and Basic Concepts

• Course Details:

  • Topic: Stereochemistry (BB-112: Bioorganic Chemistry I)
  • Lecturer: Tayab Moin, Lecturer, Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong.

• Definition of Isomerism:

  • Isomers are defined as compounds that possess the same molecular formula but differ in their physical and chemical properties.
  • The term for this phenomenon is Isomerism.

• Major Classifications of Isomerism:

  • Structural Isomerism: Also referred to as 2D isomerism. It involves differences in the arrangement of atoms within a structure.
  • Stereoisomerism: Also referred to as 3D isomerism. It involves the different spatial arrangements of atoms.
    • Some stereoisomers are chiral and optically active.
    • All chiral molecules are optically active.

Structural Isomerism

• Definition: Two or more compounds sharing the same molecular formula but having different structures (the specific arrangement of atoms). Due to the structural change, both physical and chemical properties change.

• Example (Butane, $C_4H_{10}$):

  • n-Butane: A straight chain arrangement ($CH_3-CH_2-CH_2-CH_3$).
  • Isobutane: A branched chain arrangement ($CH_3-CH(CH_3)-CH_3$).

• Sub-types of Structural Isomerism:

  1. Chain Isomerism: Compounds sharing the same molecular formula but differing in the carbon chain or carbon skeleton.
  2. Functional Group Isomerism: Compounds sharing the same molecular formula but differing in the type of functional group present in the molecule.
  3. Position Isomerism: Compounds sharing the same molecular formula but differing in the position of the same functional group, substituent, or unsaturation within the carbon chain.
  4. Metamerism: Compounds sharing the same molecular formula but differing in the carbon chain distribution on either side of a specific functional group.
  5. Tautomerism: A specialized form of isomerism where one compound can transform into another form via the movement of:
     • A hydrogen atom ($H$).
     • A double bond.
     • Both forms exist in a state of equilibrium and interconvert easily.

Tautomerism and Equilibrium

• Example: Keto-Enol Tautomerism:
  • Keto form: $CH_3-CO-CH_2-CH_3$. This form is generally more stable (approx. $99.9\%$).
  • Enol form: $CH_3-C(OH)=CH-CH_3$. This form is generally less stable (approx. $0.001\%$).
  • Mechanism: The $H$ atom moves from a carbon atom to an oxygen atom, while the double bond shifts from $C=O$ to $C=C$.

Stereoisomerism

• Definition: Compounds that have the same molecular formula and the same structural sequence (constituents connected in the same order) but differ in their configuration or conformation (spatial arrangement in 3D space).

• Classifications of Stereoisomerism:

  1. Optical Isomerism.
  2. Geometric Isomerism.
  3. Conformational or Rotational Isomerism.

Optical Isomerism and Enantiomers

• Definition: A type of stereoisomerism where molecules share the same formula and structure but differ in how they rotate plane-polarized light.

• Enantiomers:

  • These are non-superimposable mirror images of each other (analogous to left and right hands).
  • Causal Factor: Presence of an asymmetric carbon atom (chiral center), which is a carbon attached to four distinct groups.
  • Rotation of Light:
    • Dextrorotatory ($d$ or $+$): Rotates light clockwise.
    • Levorotatory ($l$ or $-$): Rotates light anticlockwise.
  • Properties: Enantiomers possess identical physical and chemical properties in ordinary conditions, with two exceptions:
    1. Direction of light rotation.
    2. Reactions with other chiral compounds.

• Named Examples:

  • $d$-Lactic acid and $l$-Lactic acid.
  • $d$-Tartaric acid and $l$-Tartaric acid.

Enantiomers vs. Diastereomers

• Relationship to Chiral Centers:

  • If you change all chiral centers in a molecule, you produce an enantiomer.
  • If you change some but not all chiral centers, you produce a diastereomer.

• Key Differences:

  • Enantiomers:
    • Non-superimposable mirror images.
    • Identical physical properties (melting point, boiling point, density, etc.).
    • Different behavior in chiral environments (e.g., enzymes).
  • Diastereomers:
    • Stereoisomers that are not mirror images of each other.
    • Example: $D$-glucose and $D$-galactose.
    • They are distinct compounds with different physical and chemical properties (solubility, stability, etc.).

Meso Compounds

• Definition: A meso isomer is a single, pure compound that has two or more chiral centers but is achiral overall.
• Criteria:
  • Possesses an internal plane of symmetry.
  • Is superimposable on its mirror image.
  • Optical Activity: Optically inactive. This is because one half of the molecule rotates light in one direction while the other half rotates it equally in the opposite direction, canceling out the effect (internal compensation).
• Example: $i$-Tartaric acid (meso-tartaric acid).

Nomenclature Quiz Results

• Compound 1: 4-ethyl-2-methyl hexane.
• Compound 2: 4-ethyl-3,3-dimethyl heptane.
• Compound 3: 2,3,5-trimethyl-4-propyl heptane.

Geometric Isomerism

• Definition: Stereoisomers resulting from different spatial arrangements around a restricted bond (usually a carbon-carbon double bond, $C=C$).

• Types:

  1. Cis Isomer: Similar atoms or groups are on the same side of the restricted bond.
  2. Trans Isomer: Similar atoms or groups are on diagonally opposite sides of the restricted bond.

• Comparison (Cis vs. Trans):

  • Polarity: Cis is usually more polar (dipoles add up); Trans is usually less polar (dipoles cancel).
  • Stability: Cis is usually less stable due to steric hindrance (bulky groups pushing against each other); Trans is usually more stable.
  • Occurrence: Trans isomers are often more common in nature.
  • Examples: Cis-but-2-ene vs. Trans-but-2-ene.

• Mechanism: The pi-bond ($\pi$-bond) is formed by sidewise overlapping of parallel p-orbitals. To convert between isomers, rotation of $180^{\circ}$ must occur, which breaks and then reforms the $\pi$-bond.

Conformational or Rotational Isomerism

• Definition: Stereoisomers differing by rotation about a carbon-carbon ($C-C$) single bond. These are easily interconvertible and non-isolable.
• Conformers/Rotamers: The stable conformations with minimum potential energy.
• Ethane Conformations (Newman Projections):
  1. Eclipsed: Full overlap of atoms; highest energy.
  2. Skew: Intermediate positioning.
  3. Staggered: Full apart; maximum distance between atoms; most stable/minimum potential energy.

Chirality of Molecules

• Requirements for Chirality:
  1. The molecule must contain at least one asymmetric carbon atom ($C^*$).
  2. The molecule must lack any element of symmetry (plane of symmetry, center of symmetry, or alternating axis of symmetry).
  3. The molecule must be non-superimposable on its mirror image.
• Chiral Centers: Denoted by an asterisk ($C^*$). A carbon attached to four different groups.

Relative Configuration (D and L System)

• Definition: Correlating the configuration of an asymmetric carbon to a known standard (Glyceraldehyde).
• System by Dee and Ell:
  • D-isomer: $OH$ group is on the right-hand side in a Fischer projection.
  • L-isomer: $OH$ group is on the left-hand side in a Fischer projection.
• Rule for Sugars: The configuration is determined by the $OH$ group on the bottom chiral center when the most oxidized carbon (aldehyde) is at the top.
• Important Distinction: There is no direct relationship between the structural prefix ($D/L$) and the direction of optical rotation ($+/-, d/l$).
  • Example: $L$-($+$)-lactic acid exists (L-configuration, but dextrorotatory).

Racemisation

• Definition: The process of converting an optically active compound (pure enantiomer) into a racemic mixture ($50:50$ mixture of enantiomers).
• Properties of Racemic Mixture: It is optically inactive due to external compensation.
• Catalysts for Racemisation:
  • Heat (vibrates and breaks bonds).
  • Acid or Base (removal and reattachment of $\alpha$-hydrogen).
  • Light (photochemical energy to break bonds).
  • Enzymes.

Resolution of Racemic Mixtures

• Definition: The separation of a racemic mixture ($\pm$) into its pure optical constituents ($+$) and ($-$).
• Methods of Resolution:
  1. Physical Methods: Manual separation of crystals (conglomerates). Rare and difficult. Example: Sodium ammonium tartrate.
  2. Chemical Resolution: Reacting the racemic mixture with a pure chiral resolving agent (e.g., tartaric acid, brucine, quinine).
     • Forms a mixture of diastereomers (salts).
     • Diastereomers have different solubilities and can be separated by fractional crystallization.
     • Separated salts are then hydrolyzed to retrieve pure enantiomers.
  3. Enzymatic Resolution: Using enzymes (like lipase) that selectively react with only one enantiomer.
  4. Chiral Chromatography: Using HPLC columns with chiral stationary phases that interact differently with each enantiomer.
  5. Biochemical/Biological Separation: Using microorganisms (Asymmetric Destruction). Example: Penicillium glaucum destroys $d$-ammonium tartrate, leaving only the $l$-form.

Questions & Discussion

• Probable Exam Questions:

  1. Define racemization with example ($2$ marks).
  2. Differentiate between diastereomers and enantiomers ($3$ marks).
  3. What is racemic resolution? ($1$ mark).
  4. List the methods of racemic resolution ($3$ marks).
  5. Explain the chemical resolution of racemates ($4$ marks).

• Presentation Topics:

  • Ionic, Covalent, Coordinate covalent, H-bond, Metallic bond.
  • VSEPR theory.
  • Structural isomers.
  • Configurational (geometric and optical) isomers.
  • Chirality & conformational isomers.
  • Relative configuration and Racemisation.
  • Resolution of Racemic mixtures.

• Presentation Instructions:

  • Groups of $5$ members; $10$ minutes total ($2$ minutes per person).
  • Marking based on dedication ($most weight$), slide preparation, and clarity.