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Substitution Reactions of Carboxylic Acid Derivatives

Substitution Reactions of Carboxylic Acid Derivatives. Mechanism. LINK. Substitution at the sp 2 hybridized carbonyl group employs a two-step addition-elimination sequence as shown above.

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Substitution Reactions of Carboxylic Acid Derivatives

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  1. Substitution Reactions of Carboxylic Acid Derivatives

  2. Mechanism LINK Substitution at the sp2 hybridized carbonyl group employs a two-step addition-elimination sequence as shown above.

  3. Relative to substitution at an sp3 hybridized carbon, the two-step addition-elimination scheme of the carboxylic acid derivatives is more facile…. i.e. it has a lower energy barrier, due to the placement of the negative charge in the intermediate on an atom of higher electronegativity (oxygen).

  4. Nature frequently employs carboxylic acid derivatives, since these bonds are relatively easy to form and to cleave. Enzymes can catalyze both processes.

  5. Mechanistic Features of Peptide Bond Formation in the Ribosome LINK LINK

  6. Mechanistic Features of Peptide Bond Hydrolysis (in the active site of a peptidase enzyme)

  7. Triglyceride Acetyl CoA

  8. Carboxylic Acid Derivatives

  9. Acid Chloride + Amine → Amide Notice the inclusion of the tertiary amine (Et3N) to neutralize the HCl side product.

  10. Mechanism of Acid Chloride + Amine → Amide

  11. Notice that the amine nitrogen is functioning as a nucleophile, while the amide nitrogen is not (due to the resonance stabilization of the amide bond).

  12. Notice that the amine nitrogen is a stronger nucleophile than is the hydroxy group (due to higher basicity and nucleophilicity of nitrogen).

  13. Notice that the azide functionality (N3) is not nucleophilic.

  14. Notice greater reactivity of acylchloride (RCOCl) than that of alkyl halide (RCH2X).

  15. Notice the use of pyridine in the example below as both a mild nucleophile, but also as a catalyst for the acylation process.

  16. Notice that the secondary amine is the nucleophile, while the tertiary nitrogen remains unreacted.

  17. 4-Dimethylaminopyridine (DMAP), used in the example below, is a particularly effective catalyst of the acylation process.

  18. Acid Chloride + Alcohol → Ester

  19. Acid Chloride + Hydride Source → Primary Alcohol Recall that nucleophilic hydride sources are boron or aluminum-based, while NaH is used almost exclusively as a base (not as a nucleophile)

  20. Notice the preferential reduction of the (more reactive) acid chloride over the (unreactive, under these conditions) ester functionalities.

  21. Acid Chloride + (2 eq) Carbanion → Tertiary Alcohol

  22. Anhydride + Amine → Amide

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