Acyl Halides
Acyl halides (R-CO-X, usually X = Cl) are the most reactive of the carboxylic acid derivatives. They react with water, alcohols, amines, carboxylates, and even Friedel-Crafts electrophiles with minimal catalysis. Their high reactivity makes them the “workhorse” intermediates for installing acyl groups on any nucleophile.
Why Acyl Halides Are So Reactive
Two reasons:
- Excellent leaving group. Chloride (Cl⁻) is the conjugate base of HCl (pKa −7). Very weak base, very stable anion, leaves effortlessly after nucleophile attack.
- Minimal resonance donation. Chlorine’s lone pairs are in 3p orbitals, which have poor overlap with the carbonyl’s 2p system. So Cl donates only weakly into the C=O by resonance, keeping the carbonyl electrophilic.
Compare with esters: the OR’s oxygen lone pair is in a 2p orbital, well-matched to the carbonyl, so it donates strongly. This reduces the carbonyl’s electrophilicity. Acid chlorides have no such reduction.
Formation from Carboxylic Acids
Standard preparation (from Ch 8.9):
- SOCl₂ is the primary reagent. RCOOH + SOCl₂ → RCOCl + SO₂↑ + HCl↑. Both byproducts escape as gases.
- PCl₃ or PCl₅ also work but produce phosphorus byproducts.
- Oxalyl chloride (ClCOCOCl) is a milder alternative.
Typical Reactions
Acyl chlorides react with almost any nucleophile at room temperature, usually in the presence of a tertiary amine (like pyridine or triethylamine) to neutralize the HCl byproduct.
| Nucleophile | Product | Notes |
|---|---|---|
| Water (H₂O) | Carboxylic acid + HCl | Usually fast - avoid contact if not wanted |
| Alcohol (R’-OH) | Ester + HCl | Requires pyridine to neutralize acid |
| Amine (R’₂NH) | Amide + HCl | Very fast, must control stoichiometry |
| Carboxylate (R’COO⁻) | Anhydride | Standard anhydride synthesis |
| Grignard (R’MgX) | Ketone (if 1 eq) or 3° alcohol (if 2 eq) | Control stoichiometry |
| Gilman reagent (R’₂CuLi) | Ketone (stops there; organocuprates are selective) | Useful for clean ketone synthesis |
| Hydride (R’NaBH₄ or LiAlH(OR’)₃) | Aldehyde (partial) or alcohol (full) | Mild hydride sources are selective |
Friedel-Crafts Acylation (Briefly)
Acyl halides + Lewis acid (AlCl₃) + benzene → aryl ketone. The AlCl₃ coordinates to Cl, generating an acylium ion (RCO⁺) that acts as a super-electrophile in electrophilic aromatic substitution.
Net: C₆H₆ + RCOCl + AlCl₃ → C₆H₅COR + HCl + AlCl₃.
Friedel-Crafts acylation is useful for installing alkyl groups on aromatic rings (followed by Clemmensen or Wolff-Kishner reduction to remove the carbonyl, giving the alkyl-substituted benzene). This workaround avoids the rearrangement and over-alkylation problems of direct Friedel-Crafts alkylation.
Note: AAMC content outline does not cover Friedel-Crafts in detail, so this is Passage Peek territory.