Overview
This lecture covers the acidity and reactivity of alpha hydrogens in carbonyl compounds, focusing on keto-enol tautomerization, alpha substitution reactions, and the mechanisms underlying these transformations.
Alpha Carbon Acidity
- Alpha hydrogens are those on the carbon adjacent to a carbonyl group (C=O).
- Alpha hydrogens in carbonyl compounds are more acidic (pKa 16-20 for aldehydes/ketones, ~25 for esters) compared to typical sp³ C-H bonds (pKa >60).
- Increased acidity is due to resonance stabilization of the conjugate base (enolate), delocalizing electrons onto the carbonyl oxygen.
- Esters are less acidic than aldehydes/ketones due to competition for electron delocalization with their own substituents.
- Compounds with multiple electron-withdrawing groups (e.g., beta-diketones) are even more acidic due to enhanced resonance stabilization.
Carbon Acids and Stability
- A carbon acid is any compound with an acidic hydrogen on an sp³ carbon, especially those adjacent to a carbonyl.
- Delocalization of negative charge onto electronegative atoms (like oxygen) increases acid strength.
- Beta-diketones or beta-keto esters have especially low pKa values due to resonance with two carbonyls.
Keto-Enol Tautomerization
- Tautomers are isomers differing in the position of a hydrogen and a double bond (keto vs. enol forms).
- In most cases, the keto form is more stable than the enol.
- Hydrogen bonding can stabilize the enol form in some cases, shifting the equilibrium toward the enol (e.g., beta-diketones).
- For phenol, the enol tautomer predominates due to aromatic stability.
Tautomerization Mechanisms
- Can be catalyzed by acid or base.
- Base-catalyzed: base removes an alpha hydrogen to form an enolate, which is protonated to yield the enol.
- Acid-catalyzed: carbonyl oxygen is protonated, water removes the alpha hydrogen, yielding an enol.
Alpha Substitution Reactions
- Alpha halogenation replaces an alpha hydrogen with a halogen (Br, Cl, I) via enol/enolate intermediate.
- Acid-catalyzed substitution replaces only one alpha hydrogen.
- Base-promoted substitution can replace all alpha hydrogens due to increased acidity after each halogenation.
Special Case: Carboxylic Acids and HVZ Reaction
- Direct alpha substitution in carboxylic acids is difficult due to competing acidity at the carboxyl hydrogen.
- Hell-Volhard-Zelinsky (HVZ) reaction (reagents: PBr₃, Br₂, water) replaces one alpha hydrogen with bromine.
- The reaction proceeds via conversion of carboxylic acid to acyl bromide, then tautomerization and bromination.
Synthetic Utility
- Alpha-halo carbonyl compounds can be used to introduce other substituents at the alpha position using weak bases.
- Strong bases can cause elimination reactions instead of substitution.
Key Terms & Definitions
- Alpha Carbon — the carbon adjacent to a carbonyl group.
- Enolate Ion — resonance-stabilized anion formed by deprotonating an alpha hydrogen.
- Tautomerization — process where tautomers (keto and enol forms) interconvert.
- Keto Form — structure with a C=O double bond; generally more stable.
- Enol Form — structure with a C=C double bond and an OH group.
- Carbon Acid — compound with an acidic hydrogen on an sp³-hybridized carbon.
- HVZ Reaction — named reaction for alpha bromination of carboxylic acids using PBr₃/Br₂.
Action Items / Next Steps
- Review Table 17.1 on carbon acids and their pKa values.
- Summarize the mechanisms for acid- and base-catalyzed alpha substitution.
- Prepare for discussion of enolate ion formation and its reactions in the next lecture.