Stereochemistry

Introduction to Stereochemistry

Stereochemistry is the branch of chemistry concerned with the three-dimensional aspects of molecules. The spatial arrangement of atoms in a molecule can significantly influence its physical, chemical, and biological properties. Many drugs, especially those derived from natural sources, are chiral and often exist as a single enantiomer rather than a racemic mixture.

• Chirality: A molecule is chiral if it is not superimposable on its mirror image. The central atom (usually carbon) bonded to four different groups is called a chirality centre.

• Enantiomers: Stereoisomers that are non-superimposable mirror images of each other. They often have identical physical properties but can have drastically different biological activities.

• Example: Penicillin V (2S, 5R, 6R) is active as an antibiotic, while its enantiomer is inactive.

• Racemic Mixtures: Laboratory-synthesized drugs are often sold as racemates (50:50 mixtures of enantiomers). For example, commercial ibuprofen contains both R and S isomers, but only the S enantiomer is pharmacologically active.

Importance in Pharmacy: Understanding stereochemistry is crucial for pharmacists and medicinal chemists because the wrong enantiomer can cause unintended effects or be pharmacologically inactive.

Stereochemistry of Open Chain Molecules

• Rotation around single (σ) bonds leads to different spatial arrangements called conformations.

• Conformational isomers (conformers): Molecules with the same formula but different spatial arrangements due to bond rotation. They interconvert rapidly and cannot be isolated.

• Representations:

  • Sawhorse representation: Oblique view showing all bonds.

  • Newman projection: End-on view of the C–C bond, useful for visualizing conformational differences.

• Staggered conformation: Lowest energy, most stable (all bonds as far apart as possible).

• Eclipsed conformation: Highest energy, least stable (bonds as close as possible), with torsional strain.

Conformations of Cyclohexane

• Chair conformation: Strain-free, all bonds staggered, most stable.

• Twist-boat conformation: Higher energy due to steric and torsional strain.

• Axial and Equatorial Positions: Each carbon in cyclohexane has one axial (perpendicular) and one equatorial (around the ring) hydrogen. Substituents prefer the equatorial position to minimize steric strain (1,3-diaxial interactions).

• Ring-flip: Interconverts axial and equatorial positions; rapid at room temperature.

Polycyclic Molecules

• Fused cycloalkane rings (e.g., decalin) have unique conformational properties. Cis-decalin has 1,3-diaxial interactions and is less stable than trans-decalin, which does not undergo ring-flip due to excessive strain.

Stereochemistry at Tetrahedral Centres

• Handedness (chirality): Arises from tetrahedral geometry of sp3-hybridized carbons bonded to four different groups.

• Enantiomers: Non-superimposable mirror images.

• Optical activity: Chiral molecules rotate plane-polarized light. Levorotatory (−) rotates left; Dextrorotatory (+) rotates right.

Assigning R/S Configuration

• Rank substituents by atomic number; lowest priority points away.

• Clockwise sequence = R; counterclockwise = S.

Diastereomers and Meso Compounds

• Diastereomers: Stereoisomers not related as mirror images; differ at one or more (but not all) chiral centres.

• Meso compounds: Achiral molecules with chiral centres due to an internal plane of symmetry.

Racemic Mixtures and Resolution

• Racemic mixture: 50:50 mix of enantiomers (±).

• Resolution: Separation of enantiomers, often via formation of diastereomeric salts and subsequent crystallization.

Structure-Activity Relationships (SAR)

Introduction to SAR

SAR studies the relationship between a drug's chemical structure and its biological activity. By systematically modifying functional groups, chemists identify which parts of a molecule are essential for activity and which can be altered to improve efficacy, selectivity, or pharmacokinetics.

• Key functional groups: Alcohols, phenols, aromatic rings, alkenes, ketones, aldehydes, amines, amides, quaternary ammonium salts, carboxylic acids, esters, alkyl/aryl halides.

• Pharmacophore: The essential features of a molecule required for biological activity.

Drug Optimization Strategies

• Variation of substituents: Changing alkyl or aromatic groups to probe binding site interactions.

• Extension of structure: Adding groups to explore additional binding interactions.

• Ring expansion/contraction: Adjusting ring size to optimize binding.

• Simplification: Removing non-essential parts to improve drug properties.

Optimizing Drug Properties

• Hydrophilic/hydrophobic balance: Adjusted by masking/unmasking polar groups, adding/removing hydrophobic groups, or varying N-alkyl substituents to tune pKa.

• Resistance to hydrolysis: Achieved by adding steric shields or using bioisosteres.

Quantitative Structure–Activity Relationship (QSAR)

QSAR Principles

• QSAR quantifies the relationship between physicochemical properties (hydrophobicity, electronic effects, steric factors) and biological activity.

• Common parameters: log P (partition coefficient), π (substituent hydrophobicity constant), σ (Hammett electronic constant), Es (Taft’s steric factor), MR (molar refractivity).

• QSAR equations can be linear or parabolic, depending on the range of values studied.

Hydrophobicity

• Partition coefficient (P): Measures hydrophobicity; higher P means more hydrophobic.

• Substituent hydrophobicity constant (π): Quantifies the effect of substituents on hydrophobicity.

Electronic Effects

• Hammett constant (σ): Measures electron-withdrawing/donating effects of substituents on aromatic rings.

Steric Factors

• Taft’s steric factor (Es): Quantifies the effect of substituent size on reaction rates.

• Molar refractivity (MR): Measures the volume and polarizability of substituents.

Hansch Equation

• Relates biological activity to multiple physicochemical properties:

or

Antibacterial Agents: Mechanisms and SAR

Mechanisms of Action

• Inhibition of cell metabolism (e.g., sulphonamides)

• Inhibition of bacterial cell wall synthesis (e.g., penicillins, cephalosporins)

• Interactions with the plasma membrane

• Disruption of protein synthesis (e.g., tetracyclines, aminoglycosides, chloramphenicol)

• Inhibition of nucleic acid transcription and replication (e.g., quinolones)

Sulphonamides: Structure-Activity Relationships

• Essential features: Para-amino group (unsubstituted), aromatic ring, sulphonamide group directly attached to the ring.

• R group: Only site for variation; affects pharmacokinetics.

• Mechanism: Competitive inhibition of dihydropteroate synthetase, blocking tetrahydrofolate synthesis in bacteria.

Applications of Sulphonamides

• Treatment of urinary tract infections, eye infections, mucous membrane infections, and gut infections.

Example Structures

The following image shows the structure of Streptomycin, an aminoglycoside antibiotic that disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit.

Additional info: Streptomycin is used to treat tuberculosis and other bacterial infections. Its structure contains multiple chiral centers and functional groups important for its activity.