Lecture 26- Carboxylic Acid Derivatives

Carboxylic Acid Derivatives

Overview

• This unit covers carboxylic acid derivatives, including:

  • Acid chlorides

    • Most reactive derivatives

  • Anhydrides

  • Esters

  • Amides

  • Salts

    • Least reactive derivatives

Nucleophilic Acyl Substitution

• Key process involving a nucleophile (nuc) and a leaving group (LG).

  • The leaving group is often also a electron withdrawing group(electronegative atom).

Forms intermediate

Leaving Groups

• Leaving group: A group of charged or uncharged atoms that departs during a substitution or displacement reaction.

  • The lower the $pK_a$ of the conjugate acid, the better the leaving group.

    or

  • Good leaving groups are weak bases (e.g., $I^-$, $Br^-$).

    • You want it to have low reactivity so that it dosen’t reattack the carbonyl.

  • Poor leaving groups are strong bases (e.g., $F^-$, $HO^-$, $RO^-$).

    • They often won’t leave.

Reactivity of Carboxylic Acid Derivatives

• Reactivity decreases as the leaving group becomes more basic.

  

• More reactive derivatives can be converted into less reactive ones.

• Can go from least reactive derivative(carboxylate salt) ,using SoCl2, to the most reactive(Acid Chloride)

Acid Chlorides

• An activated form of a carboxylic acid.

• Chloride is a good leaving group, facilitating acyl substitution.

• Synthesized using thionyl chloride $(SOCl2$), phosphorus pentachloride ($PCl5),$ or oxalyl chloride.

• Example reaction using oxalyl chloride:

  $C(O)OH + ClC(O)C(O)Cl \rightarrow C(O)Cl + HCl + CO + CO_2$

Acyl Chlorides and Amines

• Reaction mechanism for acyl chloride and amine.

• Protonation step in the Intermediate.

Formation of Amides from Anhydrides

• Amides can be formed from anhydrides.

Esters: Fischer Esterification

• Esters are produced by heating a carboxylic acid in an alcohol solvent with a small amount of strong acid.

Mechanism of the Fischer Esterification

• Acid-catalyzed nucleophilic acyl substitution of a carboxylic acid.

  • Requires the H⁺ catalyst.

• When ${}^{18}O$-labeled methanol reacts with benzoic acid, the methyl benzoate produced is ${}^{18}O$-labeled, while the water is unlabeled.

  • It is the alcohol that carboxyl that ends up on the ester.

    • This is because OH minus is a bad leaving group but water is.

• Involves the formation of a tetrahedral intermediate.

  

• Creation of a leaving group and product formation.

• Note: The reaction is reversible.

• Note: $H^+$ is a catalyst (essential for the reaction but not consumed).

Ester Formation and Hydrolysis

• Le Chatelier’s principle can be used to force the reaction in the forward or reverse direction.

Carboxylic Acid into Amides

• Carboxylic acids can be converted to amides.

• Forms intermediary salt.

Amides

• Least reactive derivatives of carboxylic acids; they are poor electrophiles due to delocalization of the nitrogen lone pair.

• Nitrogen in amides is less electronegative, making it a poor leaving group.

Amide Hydrolysis in Acid ($H^+$)

• Formation of a tetrahedral intermediate.

• Collapse of the tetrahedral intermediate and product formation.

• Nitrogen has been protonated and is no longer a good nucleophile.

Base-Catalyzed Amide Hydrolysis

• Amide hydrolysis can also occur under basic conditions.

Use OH^- to attack the carbonyl

Amides: Chemical Synthesis

• Chemists use protecting groups to temporarily stop unwanted reactivity and use specialized reagents.

• Creates many different types of products.

  • Protecting groups can be used to make functional groups unreactive, creating the selected products.

Amides: Synthesis in Nature

• Amides are synthesized in nature through various biological processes.

  • Example in nature for the synthesis of a protein.

Interconversion of Derivatives

• More reactive derivatives can be converted to less reactive derivatives.