Fluoxetine, an antidepressant, is better known as Prozac®. Suggest reagents that could be used to make the indicated C–O bond of fluoxetine. [Note that CF₃, an electron-withdrawing group, is para to where the new bond will be formed.]

Verified step by step guidance

1. Identify the type of reaction needed to form the C–O bond in fluoxetine. This is typically an ether formation reaction.
2. Consider the electronic effects of the CF3 group, which is an electron-withdrawing group. This will influence the reactivity of the aromatic ring.
3. Select a suitable phenol or alcohol that can react with the aromatic ring to form the ether linkage. The presence of the CF3 group suggests that the reaction may require activation.
4. Choose a reagent that can facilitate the formation of the C–O bond. Common reagents for ether formation include strong bases or catalysts that can activate the alcohol or phenol.
5. Consider using a method such as the Williamson ether synthesis, which involves the deprotonation of an alcohol to form an alkoxide ion, followed by a nucleophilic substitution reaction with an aryl halide.

Key Concepts

Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution (NAS) is a reaction where a nucleophile replaces a leaving group on an aromatic ring. This process is facilitated by electron-withdrawing groups, such as CF3, which stabilize the negative charge in the intermediate. In fluoxetine, the CF3 group is para to the site of substitution, enhancing the reactivity of the aromatic ring towards nucleophiles.

Role of Electron-Withdrawing Groups

Electron-withdrawing groups (EWGs) like CF3 increase the electrophilicity of the aromatic ring by pulling electron density away from it. This makes the ring more susceptible to attack by nucleophiles. In the context of fluoxetine, the CF3 group enhances the likelihood of forming the C–O bond by stabilizing the transition state during the reaction.

Formation of Ether Bonds

The formation of ether bonds typically involves the reaction of an alcohol with an alkyl halide or through the Williamson ether synthesis. In the case of fluoxetine, the formation of the C–O bond can be achieved by using a suitable nucleophile, such as an alkoxide ion, which attacks the electrophilic carbon on the aromatic ring, facilitated by the presence of the CF3 group.