Question

Show by means of equations how each of the following substances might be synthesized, starting from the indicated materials. Specify reagents and approximate reaction conditions. (a) methy1 2-methoxybenzoate from phenol. (b) \(2,6-\) dibromo-4-t-butylanisole from phenol. (c) 4-cyanophenoxyacetic acid from phenol. (d) cyanoquinone from hydroquinone.

Short answer

(a) Methy1 2-Methoxybenzoate synthesis from phenol: 1. O-methylation using dimethyl sulfate (or methyl iodide) and NaOH in DMF. 2. Friedel-Crafts Acylation using methacryloyl chloride (or chloroacetic acid) and AlCl3. (b) \(2,6-\)dibromo-4-t-butylanisole synthesis from phenol: 1. Bromination using Br2 and AlBr3. 2. O-methylation using dimethyl sulfate (or methyl iodide) and NaOH in DMF. 3. Friedel-Crafts Alkylation using tBuCl and AlCl3. (c) 4-cyanophenoxyacetic acid synthesis from phenol: 1. Nucleophilic aromatic substitution using NaCN in DMSO. 2. Hydrolysis of the nitrile using aqueous HCl (or H2SO4). 3. Esterification with chloroacetic acid in DMF under reflux. (d) Cyanoquinone synthesis from hydroquinone: 1. Oxidation using H2CrO4 in acetic acid. 2. Nucleophilic aromatic substitution using NaCN in DMSO at high temperature.

Step-by-step solution

O-methylation of Phenol

First, phenol needs to be converted to anisole (methoxybenzene) by reacting it with a methylating agent. The reagent commonly used is dimethyl sulfate (or other methylating agents such as methyl iodide) and a base like sodium hydroxide (NaOH). - Reagents: Dimethyl sulfate (or other methylating agents such as methyl iodide) and NaOH. - Reaction conditions: Room temperature and a polar aprotic solvent such as DMF.

Friedel-Crafts Acylation

Now, in order to add the methy1 benzoate group, we need to perform a Friedel-Crafts acylation reaction on anisole using acyl chloride. - Reagents: Methacryloyl chloride (or chloroacetic acid), aluminum chloride (AlCl3), or other Lewis acid catalyst. - Reaction conditions: Reactants are combined at 0°C, then the temperature is gradually raised to room temperature, stirring for several hours. (b) Synthesis of \(2,6-\) dibromo-4-t-butylanisole from Phenol

Bromination of Phenol

First, we need to introduce bromine in the ortho- and para-positions of phenol. For this, we can use elemental bromine (Br2) in the presence of a Lewis acid catalyst like AlBr3. - Reagents: Br2, AlBr3 (Lewis Acid Catalyst) - Reaction conditions: Reactants are combined at 0°C, then the temperature is gradually raised.

O-methylation of Brominated Phenol

Next, O-methylation of the dibromophenol is performed using a methylating agent like dimethyl sulfate and a base like NaOH. - Reagents: Dimethyl sulfate (or methyl iodide), NaOH - Reaction conditions: Room temperature and polar aprotic solvent such as DMF.

Introduce t-butyl group

Finally, perform a Friedel-Crafts alkylation reaction on the 2,6-dibromoanisole using tert-butyl chloride (tBuCl). - Reagents: tBuCl, AlCl3 (Lewis Acid Catalyst) - Reaction conditions: Reactants are combined at 0°C, then the temperature is raised to room temperature and stirred for a few hours. (c) Synthesis of 4-cyanophenoxyacetic acid from Phenol

Nucleophilic aromatic substitution

First, a nucleophilic aromatic substitution (S_NAr) reaction is performed on phenol with sodium cyanide (NaCN). - Reagents: NaCN - Reaction conditions: Mix reactants in a polar aprotic solvent like DMSO and heat the reaction at high temperature.

Hydrolysis of the nitrile

The nitrile is then hydrolyzed to a carboxylic acid using aqueous acid such as HCl. - Reagents: Aqueous HCl (or H2SO4) - Reaction conditions: Heating while stirring

Esterification to phenoxyacetic acid

Finally, perform an esterification reaction on the hydroxyl group of the 4-cyanophenol with chloroacetic acid: - Reagents: Chloroacetic acid - Reaction conditions: Stirring in a polar aprotic solvent like DMF under reflux. (d) Synthesis of Cyanoquinone from Hydroquinone

Oxidation of Hydroquinone to Quinone

First, hydroquinone is oxidized to quinone using an oxidizing agent like chromic acid (H2CrO4). - Reagents: H2CrO4 - Reaction conditions: Stirring in a polar solvent like acetic acid.

Nucleophilic aromatic substitution

Now, perform a nucleophilic aromatic substitution (S_NAr) reaction on quinone with sodium cyanide (NaCN). - Reagents: NaCN - Reaction conditions: Mix reactants in a polar aprotic solvent like DMSO and heat the reaction at high temperature.

Key concepts

Friedel-Crafts Acylation

Friedel-Crafts Acylation is a critical process in organic synthesis, especially when it comes to introducing acyl groups into aromatic rings. This powerful reaction involves the use of an acyl chloride and a Lewis acid catalyst, typically aluminum chloride (AlCl₃), to replace a hydrogen atom on an aromatic compound with an acyl group. The result is the formation of a ketone.

During the acylation, the aromatic ring acts as a nucleophile, attacking the acyl cation generated by the reaction of the acyl chloride with the Lewis acid catalyst. The reaction proceeds via the formation of a complex between the catalyst and the acyl chloride, followed by generation of the cation.

One key advantage of Friedel-Crafts Acylation is that it typically avoids polyalkylation, a common problem in the Friedel-Crafts alkylation. The newly formed acyl group is less reactive due to the electron-withdrawing effect of the carbonyl, preventing further reaction. Additionally, the reaction conditions usually involve cooling the reactants to 0°C and then warming gradually, ensuring that the reaction does not proceed too rapidly.

Nucleophilic Aromatic Substitution

Nucleophilic Aromatic Substitution (S_NAr) is a vital reaction mechanism in organic chemistry for modifying aromatic compounds. This type of substitution involves replacing a leaving group, typically a halide or a sulfonate, with a nucleophile. S_NAr reactions are often carried out under conditions that favor the stability of the intermediate complex, such as the use of polar aprotic solvents like dimethyl sulfoxide (DMSO).

The mechanism is facilitated by the presence of electron-withdrawing groups on the aromatic ring, which stabilize the negative charge of the intermediate Meisenheimer complex. The nucleophile attacks the carbon atom bearing the leaving group, and upon its departure, a new aromatic compound with the nucleophile attached is formed.

For example, when synthesizing cyano compounds from phenol, sodium cyanide serves as the nucleophile, targeting an activated aromatic ring. The use of high temperatures helps to overcome the activation energy barrier associated with the aromatic ring's stability.

O-methylation of Phenol

The O-methylation of phenol is a critical step toward modifying the properties of aromatic compounds by introducing a methoxy group (-OCH₃) at the hydroxyl position. This transformation enhances the electron-donating nature of the aromatic ring, directly influencing subsequent reactions.

Reagents such as dimethyl sulfate or methyl iodide are typically used as the methylating agents. In the presence of a base like sodium hydroxide (NaOH), these reagents effectively transfer a methyl group to the oxygen atom of the hydroxyl group in phenol, forming anisole.

This reaction is conducted at room temperature and utilizes polar aprotic solvents, such as dimethylformamide (DMF), which make the oxygen more nucleophilic and facilitate the methylation. The simplicity of this reaction allows for the efficient preparation of methoxy-substituted aromatic compounds essential to various synthetic routes.

Bromination of Phenol

Bromination of phenol involves the addition of bromine atoms to the aromatic ring of phenol, specifically at the ortho- and para-positions. This reaction is influenced by phenol's activating and ortho/para-directing nature due to the electron-donating effect of its hydroxyl group.

Elemental bromine (Br₂) is the brominating reagent, and reactions are typically carried out in the presence of a Lewis acid catalyst, such as aluminum tribromide (AlBr₃), to facilitate the formation of a bromonium ion, which acts as an electrophile. The reaction conditions generally involve starting at low temperatures, around 0°C, which helps control the reaction rate and prevents over-bromination, followed by a gradual increase in temperature.

As a result, the bromine atoms preferentially add to the positions next to (ortho) or opposite (para) to the hydroxyl group, yielding products that can undergo further synthetic transformations. This step is crucial in the buildup to more complex structures and functionalities in organic compounds.