Question

Propose a synthesis for 3,5 -dibromo-2-hydroxybenzoic acid (3,5-dibromosalicylic acid) from phenol.

Short answer

Question: Provide a proposed synthesis for 3,5-dibromo-2-hydroxybenzoic acid from phenol. Answer: The synthesis of 3,5-dibromo-2-hydroxybenzoic acid from phenol involves four main steps: 1. Protection of the phenol hydroxyl group using a MOM (methoxymethyl ether) protecting group. 2. Bromination of the aromatic ring to introduce bromine atoms at positions 3 and 5 using Br2 and a Lewis acid catalyst (AlBr3 or FeBr3). 3. Carboxylation of the aromatic ring at position 2 through the Kolbe-Schmitt reaction by treating with NaOH and then CO2 under high pressure and temperature. 4. Deprotection of the phenol hydroxyl group by treating with HCl or another suitable acidic environment to remove the MOM protecting group and obtain the final product, 3,5-dibromo-2-hydroxybenzoic acid.

Step-by-step solution

Protection of the phenol hydroxyl group

Phenol has an active hydroxyl group that can interfere with electrophilic aromatic substitutions. To avoid this interference, we will protect the hydroxyl group using a suitable protecting group. In this case, we can use a MOM (methoxymethyl ether) protecting group. To introduce the MOM group, react phenol with chloromethyl methyl ether (MOM-Cl) in the presence of a base (for example, NaH) to form MOM-protected phenol.

Bromination of the aromatic ring

The next step is to introduce bromine atoms to positions 3 and 5 of the aromatic ring. To achieve this, react the MOM-protected phenol with Br2 in the presence of a Lewis acid catalyst (such as AlBr3 or FeBr3) under electrophilic aromatic substitution conditions. The product will have bromine atoms at positions 3 and 5 of the aromatic ring to form 3,5-dibromo-MOM-protected phenol.

Carboxylation of the aromatic ring

Now, we need to introduce the carboxylic acid group at position 2 of the aromatic ring. This can be done by performing a reaction called the Kolbe-Schmitt reaction. First, treat the 3,5-dibromo-MOM-protected phenol with NaOH to form the phenoxide ion. Then, react the phenoxide ion with CO2 under high pressure (100 atm) and temperature (around 125°C) to form 3,5-dibromo-2-hydroxybenzoate. Finally, acidify the reaction mixture with HCl to obtain 3,5-dibromo-2-hydroxybenzoic acid with the MOM protecting group still attached.

Deprotection of the phenol hydroxyl group

The final step is to remove the MOM protecting group, revealing the hydroxyl group at position 2. To achieve this, treat the 3,5-dibromo-MOM-protected salicylic acid with HCl or another suitable acidic environment. The hydrolysis of the ether bond will cleave the MOM group, resulting in the final product, 3,5-dibromo-2-hydroxybenzoic acid (3,5-dibromosalicylic acid).

Key concepts

Electrophilic Aromatic Substitution

Electrophilic aromatic substitution (EAS) is a fundamental type of reaction that allows us to introduce substituents onto an aromatic ring. It is essential in synthetic chemistry when we want to modify aromatic compounds like phenol.

In an EAS, the aromatic ring acts as a nucleophile and interacts with an electrophile, which leads to the substitution of a hydrogen atom. The process involves the temporary disruption of the aromaticity when a carbocation (an intermediate) is formed, but the aromatic system is restored upon completion of the reaction.

For instance, when synthesizing 3,5-dibromo-2-hydroxybenzoic acid, bromination is a critical step that introduces bromine atoms to specific positions on the ring. This is done using Br₂ in the presence of a Lewis acid catalyst such as AlBr₃ or FeBr₃, which helps to stabilize the bromonium intermediate and facilitate the substitution.

MOM Protecting Group

Protecting groups are an ingenious way to temporarily mask the reactivity of certain functional groups during a multistep synthesis process. The MOM (methoxymethyl ether) protecting group is a popular choice for protecting hydroxyl groups of phenols.

The introduction of a MOM group can be achieved through the reaction of the phenol with chloromethyl methyl ether (MOM-Cl) in the presence of a base such as sodium hydride (NaH). The base serves to deprotonate the phenol, activating it for the subsequent attack on the MOM-Cl, leading to the formation of the ether.

The beauty of the MOM group lies in its stability under conditions that would normally affect hydroxyl groups, yet it can be removed selectively when desired. This is why we use it to protect the hydroxyl group of phenol during the bromination step in the synthesis of 3,5-dibromo-2-hydroxybenzoic acid.

Kolbe-Schmitt Reaction

The Kolbe-Schmitt reaction is an indispensable tool for introducing carboxyl groups into aromatic compounds. It is particularly useful when we need to place a carboxyl group in a position adjacent to an existing substituent on an aromatic ring.

To carry out the Kolbe-Schmitt reaction, initially, the phenol (or its protected form) is converted into a phenoxide ion by treatment with a strong base like sodium hydroxide (NaOH). The phenoxide ion then reacts with carbon dioxide (CO₂) under high pressure and temperature.

The reaction leads to the formation of a salicylate, which upon acidification gives the salicylic acid derivative. In our synthesis of 3,5-dibromo-2-hydroxybenzoic acid, the Kolbe-Schmitt reaction enables us to introduce a carboxyl group at the precise location needed on the aromatic ring, while other groups like MOM-protected hydroxyl remain unaffected.

Phenol Protection and Deprotection

Working with phenols requires strategic planning, especially when they're part of a molecule that's undergoing multiple reactions. To prevent unwanted reactions at the hydroxyl group, we protect it. The protection must be robust enough to withstand various conditions and then be removed without disturbing other parts of the molecule.

The final step in our synthetic process is the deprotection of the phenol hydroxyl group. After successfully completing reactions like the Kolbe-Schmitt, we expose the MOM-protected phenol to an acidic environment, which cleaves the MOM group off, liberating the hydroxyl group. For the synthesis of 3,5-dibromo-2-hydroxybenzoic acid, this deprotection step is critical as it reveals the desired functional group - the hydroxyl - restoring the original reactivity and completing the synthesis.