Beta-Lactam Antibiotics Lecture Notes

Introduction to Lactams

• Lactams are technically amides but differ from typical amides.
• Typical amides have a lone pair of electrons on the nitrogen that is delocalized through resonance, making them less reactive.

Amide Structure

• Resonance Structure: Lone pair on nitrogen participates in resonance, making carbonyl carbon less electrophilic.
• Hybridization: Nitrogen in an ideal amide is Sp2 hybridized with planar geometry allowing best orbital overlap.

Beta-Lactam Structure

• Penicillin Structure: Contains a beta-lactam ring, an amide in a ring.
• Classification: The beta-lactam ring is named due to the positioning of its atoms (alpha, beta carbon, then nitrogen).

Historical Context

• During WWII, there was an effort to synthesize penicillin for its medicinal properties.
• Initial theories doubted the presence of a lactam ring due to expected low reactivity of amides.
• Chemists like R.B. Woodward supported and proved the beta-lactam structure.

Beta-Lactam Ring Characteristics

• Fused Ring System: Contains a four-membered beta-lactam ring and a five-membered ring.
• Non-planar Nitrogen: The fusion prevents nitrogen from being planar, reducing resonance stabilization.
• Increased Electrophilicity: Lack of resonance increases the partial positive charge on carbonyl carbon, making it more reactive.

Reactivity Factors

• Resonance Stabilization: Limited due to non-planar geometry prevents effective electron donation to carbonyl carbon.
• Ring Strain: The four-membered ring deviates from ideal Sp3 angles (109.5 degrees), increasing strain and reactivity.
  • Angle Strain: Deviation from ideal angles leads to increased strain.

Mechanism of Action

• Penicillin Mode of Action: Targets transpeptidase enzyme in bacterial cell walls.
• Nucleophilic Attack: The enzyme's OH group attacks the electrophilic carbonyl carbon in the beta-lactam ring.
• Breakage of Beta-Lactam Ring: Leads to the formation of a disabled enzyme that cannot build cell walls.

Implications of Beta-Lactam Antibiotics

• Prevents bacteria from building cell walls, allowing the immune system to combat bacterial infections effectively.

Conclusion

• Beta-lactam antibiotics like penicillin utilize the unique chemistry of the beta-lactam ring to inhibit bacterial cell wall synthesis.