Lecture Notes: Reactivity of Carbonyl Compounds

Overview

• Focus on the reactivity of carbonyl compounds, specifically the addition of nucleophiles to carbonyls.
• Discussion on electrophilic and nucleophilic spots in carbonyls.

Key Concepts

HOMO and LUMO

• HOMO (Highest Occupied Molecular Orbital): Typically the carbonyl oxygen; holds the most reactive electrons.
• LUMO (Lowest Unoccupied Molecular Orbital): The pi star orbital; site for electron addition.

Reaction Mechanism

• Addition Step: Nucleophile attacks the carbonyl carbon, forming a new bond and breaking the C=O pi bond.
• Intermediate Formation: Forms a tetrahedral intermediate with a negatively charged oxygen.
  • Must compare the reactivity of the nucleophile to the negatively charged oxygen.

Nucleophile Reactivity

• Nucleophiles reactive at least as the negatively charged oxygen are suitable for direct attack.
• Example: OH- is reactive enough to attack a carbonyl carbon directly.
• Non-reactive Nucleophiles: Water is stable and needs catalysis to attack carbonyls.

Catalysis

• Acid Catalysis: Protonate the carbonyl to form a more reactive oxonium ion, allowing nucleophilic attack.
• Nucleophiles like Amines: More nucleophilic than water, can attack aldehydes with acid catalysis in one concerted step.

Specific vs. General Acid Catalysis

• Specific Acid Catalysis: Protonation occurs first, then the addition step.
• General Acid Catalysis: Protonation and attack can happen simultaneously, notable with amines.

Substitution Reactions

• Follow an addition step with an elimination step.
• Leaving Groups: Reaction outcome depends on the ability of groups to leave compared to the negatively charged oxygen.

Reversible Reactions

• Reactions can be reversible; equilibrium is critical.
• Example: The elimination of an OH group after nucleophilic attack.

Reduction Reactions

• Nucleophilic acyl substitution leads to substitution and reduction.
• Acyl Substitution: Swapping out leaving groups to form new compounds.

Carbonyl Reactivity

• Ranking reactivity: Acid chlorides > Esters > Aldehydes > Ketones.
• Reduction Agents:
  • Sodium Borohydride: Reacts with aldehydes and ketones but not esters.
  • Lithium Aluminum Hydride: Stronger, reacts with esters and leads to full reduction to alcohols.

Practical Reagents

• Aqueous Workup: Used to neutralize reactions, often final step in reactions to isolate product.
• Hydride Delivery Reagents: Used for delivering hydrides to carbonyls without carrying excess charge.

Advanced Topics

• Dibal-H: An alternative to lithium aluminum hydride for controlled reductions to aldehydes.
  • Allows reduction of esters to aldehydes without going further to alcohols.

Conclusion

• Understanding nucleophile and electrophile interactions with carbonyls is crucial.
• Many reactions pivot around the balance of reactivity and stability of intermediates and products.
• Future topics include detailed mechanisms and examples in the following chapters.