Carboxylic Acid Derivatives (Chapter 20)

• The halide atom (bonded to the carbonyl Carbon) withdraws electron density from the carbonyl Carbon, which increases the electrophilicity of the Carbon. • The halide atom is a stable leaving group, which causes nucleophilic attack at the carbonyl Carbon to be a favorable process.

Acyl Halide Hydrolysis Irreversible The acyl halide hydrolysis reaction is occurs very fast and is highly exothermic.

Acyl Halide Esterification Irreversible The acyl halide esterification reaction requires a weak base (i.e. Triethylamine).

Acyl Halide Amidification Irreversible

H2O A halide ion and acid (i.e. HX) are produced as byproducts of acyl halide hydrolysis.

• Option #1: 2 Amine • Option #2: Amine, N(Et)3 • Option #3: Amine, Pyridine • Acyl Halide Amidification can occur only with 0°/1°/2° Amines. (Reactions of acyl halides with 3° Amines form acyl ammonium salts rather than amides.) • The second reagent (Amine or N(Et)3 or Pyridine) is used to neutralize the HX byproduct to prevent amide hydrolysis.

R—OH, N(Et)3 The N(Et)3 (triethylamine) catalyst is added to neutralize the HX byproduct of acyl halide esterification.

The carbonyl Carbon (of the acyl halide) is highly electrophilic due to the electron-withdrawing effect of the halide atom, so the nucleophile is readily able to attack the Carbon without catalyst activation.

• Nucleophilic Attack at the Carbonyl Carbon • Intramolecular Proton Transfer to Neutralize Charges • π-Electron Rearragement to Eliminate the Halide • Depronotation to Yield Nonionic Carbonyl Group Nucleophilic attack at the carbonyl Carbon forms a sp3-hybridized tetrahedral intermediate.

• Acyl Halide Hydrolysis • Acyl Halide Esterification • Acyl Halide Amidification

The carbonyl Oxygen (of acyl halides) is weakly basic due to the poor positive-charge compatibility of the halide atom, so protonation results in a highly unstable conjugate acid compound. Protonation of the carbonyl Carbon forms a resonance structure that places a positive charge on the halide atom. Since the halide is highly electronegative, it is highly unfavorable for it to possess a positive charge.

• N(Et)3 neutralizes the HX byproduct to prevent the ester hydrolysis side reaction from occurring. (Esters are stable only under neutral conditions or mildly basic conditions.) • N(Et)3 is a weak base, so it cannot deprotonate the alcohol reagent’s hydroxyl Hydrogen. • N(Et)3 does not react with acyl halides (to form amides) due to the steric hindrance about the Nitrogen atom.

• Heated Acid-Catalyzed Alcohol Addition • Two-Step Substitution-Esterification The two-step substitution-esterification mechanism is a more efficient means to synthesize esters (from carboxylic acids) than acid-catalyzed alcohol addition.

• Heated Amine Addition • Two-Step Substitution-Amidification The two-step substitution-amidification mechanism is a more efficient means to synthesize amides (from carboxylic acids) than acid-catalyzed alcohol addition.

Amine, Δ High heat is required for heated amide addition to occur.

R—OH + H2SO4, Δ A strong acid catalyst (e.g. H2SO4) and high heat are required for acid-catalyzed alcohol addition to occur.

• SOCl2 / PBr3 • Alcohol, N(Et)3

• SOCl2 / PBr3 • Amine, N(Et)3 The N(Et)3 is added during the second step to neutralize the HX byproduct.

• Substitution-Esterification can occur under standard reaction conditions, whereas Amide Addition requires high temperatures. • Substitution-Esterification is irreversible, whereas Alcohol Addition is reversible. Two-Step Substitution-Amidification is a more favorable reaction than Heated Amine Addition.

• Substitution-Esterification does not require a strong acid catalyst to occur, whereas Alcohol Addition does require a strong acid. • Substitution-Esterification can occur under mild reaction conditions, whereas Alcohol Addition requires high temperatures. • Substitution-Esterification is irreversible, whereas Alcohol Addition is reversible. Two-Step Substitution-Esterification is a more favorable reaction than Acid-Catalyzed Alcohol Addition.

• The mechanism requires highly unstable reaction conditions (i.e. strong acids + high temperatures). • The mechanism is reversible (via excess reagents or H2O removal).

• The mechanism requires highly unstable reaction conditions (i.e. high temperatures). • The mechanism is reversible (via excess reagents or H2O removal).

Acyl Halide Anhydride Synthesis

R—O—OH, Δ R—O—OH = Carboxylic Acid The acyl halide anyhydride synthesis reaction produces acid (i.e. HX) as byproduct.