Question

Propose steps for the following conversions using a reaction of a diazonium salt in at least one step of each conversion. (a) Toluene to 4 -methylphenol ( \(p\)-cresol) (b) Nitrobenzene to 3 -bromophenol (c) Toluene to \(p\)-cyanobenzoic acid (d) Phenol to \(p\)-iodoanisole (e) Acetanilide to \(p\)-aminobenzylamine (f) Toluene to 4-fluorobenzoic acid (g) 3-Methylaniline ( \(m\)-toluidine) to \(2,4,6\)-tribromobenzoic acid

Short answer

(a) To convert Toluene to 4-methylphenol (p-cresol), first nitrate Toluene to form 4-Nitrotoluene, reduce it to 4-Methylaniline (p-Toluidine), form diazonium salt with NaNO2 and HCl, and finally hydrolyze the diazonium salt to get p-cresol. (b) To convert Nitrobenzene to 3-bromophenol, first reduce Nitrobenzene to Aniline, brominate Aniline to form 2,4-dibromoaniline, form diazonium salt, and hydrolyze the diazonium salt to get 3-bromophenol. (c) To convert Toluene to p-cyanobenzoic acid, first nitrate Toluene to form 4-Nitrotoluene, reduce it to 4-Methylaniline (p-Toluidine), form a diazonium salt, undergo Sandmeyer reaction to form p-cyanotoluene, and then oxidize the resulting molecule to obtain p-cyanobenzoic acid. (d) To convert Phenol to p-iodoanisole, first nitrate Phenol to form 4-Nitrophenol, reduce it to Aniline, form diazonium salt, react with potassium iodide to form p-Iodobenzene, and finally perform Friedel-Crafts alkylation to get p-iodoanisole. (e) To convert Acetanilide to p-aminobenzylamine, first hydrolyze Acetanilide to form Aniline, brominate Aniline to form 4-Bromoaniline, form a diazonium salt, and finally replace the diazonium ion with benzylamine to get the product, p-aminobenzylamine. (f) To convert Toluene to 4-fluorobenzoic acid, first nitrate Toluene to form 4-Nitrotoluene, reduce it to 4-Methylaniline (p-Toluidine), form a diazonium salt with NaNO2 and HCl, react it with potassium fluoride and antimony trifluoride to form 4-fluorotoluene, and finally oxidize it to 4-fluorobenzoic acid. (g) To convert 3-Methylaniline (m-toluidine) to 2,4,6-tribromobenzoic acid, first form a diazonium salt, undergo Sandmeyer reaction to form 3-bromotoluene, brominate it twice to form 2,4,6-tribromotoluene, and finally oxidize it to 2,4,6-tribromobenzoic acid.

Step-by-step solution

(a) Conversion of Toluene to 4-methylphenol (p-cresol)

Step 1: Nitration - Treat Toluene with a mixture of concentrated nitric and sulfuric acids to form 4-Nitrotoluene. Step 2: Reduction - Reduce 4-Nitrotoluene to 4-Methylaniline (p-Toluidine) using a reducing agent such as tin chloride and hydrochloric acid. Step 3: Formation of diazonium salt - Treat 4-Methylaniline with NaNO2 and HCl to form 4-Methylbenzenediazonium chloride. Step 4: Hydrolysis - Treat the diazonium salt with water to convert it into 4-methylphenol (p-cresol).

(b) Conversion of Nitrobenzene to 3-bromophenol

Step 1: Reduction - Reduce Nitrobenzene to Aniline using a reducing agent such as tin chloride and hydrochloric acid. Step 2: Bromination - Treat Aniline with Bromine in presence of a polar solvent such as water to form 2,4-dibromoaniline. Step 3: Formation of diazonium salt - Treat 2,4-dibromoaniline with NaNO2 and HCl to form 2,4-dibromobenzenediazonium chloride. Step 4: Hydrolysis - Treat the diazonium salt with water to convert it into 3-bromophenol.

(c) Conversion of Toluene to p-cyanobenzoic acid

Step 1: Nitration - Treat Toluene with a mixture of concentrated nitric and sulfuric acids to form 4-Nitrotoluene. Step 2: Reduction - Reduce 4-Nitrotoluene to 4-Methylaniline (p-Toluidine) using a reducing agent such as tin chloride and hydrochloric acid. Step 3: Formation of diazonium salt - Treat 4-Methylaniline with NaNO2 and HCl to form 4-Methylbenzenediazonium chloride. Step 4: Sandmeyer reaction - Treat the diazonium salt with copper cyanide to form p-cyanotoluene. Step 5: Oxidation - Oxidize the methyl group to carboxyl group using a strong oxidizing agent like potassium permanganate to form p-cyanobenzoic acid.

(d) Conversion of Phenol to p-iodoanisole

Step 1: Nitration - Treat Phenol with a mixture of concentrated nitric and sulfuric acids to form 4-Nitrophenol. Step 2: Reduction - Reduce 4-Nitrophenol to Aniline using a reducing agent such as tin chloride and hydrochloric acid. Step 3: Formation of diazonium salt - Treat Aniline with NaNO2 and HCl to form benzenediazonium chloride. Step 4: Sandmeyer reaction - Treat the diazonium salt with potassium iodide to form p-Iodobenzene. Step 5: Friedel-Crafts alkylation - Use methyl chloride and aluminum chloride as a catalyst to form p-iodoanisole.

(e) Conversion of Acetanilide to p-aminobenzylamine

Step 1: Hydrolysis - Treat acetanilide with a strong base such as sodium hydroxide and water to form aniline. Step 2: Bromination - Treat Aniline with Bromine in presence of a polar solvent such as water to form 4-Bromoaniline. Step 3: Formation of diazonium salt - Treat 4-Bromoaniline with NaNO2 and HCl to form 4-bromobenzenediazonium chloride. Step 4: Replacement - Treat the diazonium salt with benzylamine and potassium iodide to form p-aminobenzylamine.

(f) Conversion of Toluene to 4-fluorobenzoic acid

Step 1: Nitration - Treat Toluene with a mixture of concentrated nitric and sulfuric acids to form 4-Nitrotoluene. Step 2: Reduction - Reduce 4-Nitrotoluene to 4-Methylaniline (p-Toluidine) using a reducing agent such as tin chloride and hydrochloric acid. Step 3: Formation of diazonium salt - Treat 4-Methylaniline with NaNO2 and HCl to form 4-Methylbenzenediazonium chloride. Step 4: Balz-Schiemann Reaction - Treat the diazonium salt with potassium fluoride and antimony trifluoride to form 4-fluorotoluene. Step 5: Oxidation - Oxidize the methyl group to carboxyl group using a strong oxidizing agent like potassium permanganate to form 4-fluorobenzoic acid.

(g) Conversion of 3-Methylaniline (m-toluidine) to 2,4,6-tribromobenzoic acid

Step 1: Formation of diazonium salt - Treat 3-Methylaniline with NaNO2 and HCl to form 2-Methylbenzenediazonium chloride. Step 2: Sandmeyer reaction - Treat the diazonium salt with copper bromide to form 3-bromotoluene. Step 3: Bromination - Treat 3-bromotoluene with Br2/FeBr3 to form 2,4-dibromotoluene. Step 4: Bromination - Perform another bromination with Br2/FeBr3 to form 2,4,6-tribromotoluene. Step 5: Oxidation - Oxidize the methyl group to carboxyl group using a strong oxidizing agent like potassium permanganate to form 2,4,6-tribromobenzoic acid.

Key concepts

Organic Synthesis

Organic synthesis is essential in the realm of chemistry and revolves around constructing organic molecules through a series of chemical reactions. Complex molecules are typically built up step by step from simpler substances, using a toolkit of reactions that form or cleave bonds between carbon atoms, add or remove functional groups, and manipulate the molecular framework of compounds. In the context of the exercise provided, organic synthesis is demonstrated through the several transformations, each involving a series of steps and reactions tailored for constructing a specific chemical structure from a basic starting material such as toluene.

For instance, to synthesize 4-methylphenol from toluene, one would undertake nitration, reduction, diazonium salt formation, and hydrolysis. This sequence illustrates how different chemical reactions are interwoven to achieve a target molecule, showcasing the vast potential and systematic nature of organic synthesis in forming complex and diverse organic structures.

Sandmeyer Reaction

The Sandmeyer reaction is a cornerstone of organic chemistry for substituting aromatic amines. This classic reaction involves converting an aromatic amine to a diazonium salt, which is then reacted with copper salts like copper chloride, copper bromide, or copper cyanide to introduce a new functional group, such as a halogen or cyano group. The reaction is particularly useful because it allows for the attachment of groups to an aromatic ring that are otherwise difficult to attach through direct methods.

In one of the examples from the exercise, 4-Methylbenzenediazonium chloride is transformed using the Sandmeyer reaction with copper cyanide to yield p-cyanotoluene. This reaction showcases the specificity and versatility of the Sandmeyer reaction in the toolkit of aromatic substitutions, facilitating the creation of complex molecules in medicinal chemistry, dye manufacturing, and materials science.

Aromatic Substitution

Aromatic substitution is a type of reaction where an atom, typically hydrogen, attached to an aromatic system, is replaced by another atom or group of atoms. This reaction is fundamental to the field of organic chemistry, as it allows the modification of aromatic compounds by introducing a wide range of functional groups into their structure.

Examples of aromatic substitution reactions include nitration, sulfonation, halogenation, and Friedel-Crafts alkylation or acylation. For example, during the conversion of nitrobenzene to 3-bromophenol, an aromatic substitution reaction is employed to brominate aniline, followed by the transformation of a diazonium salt to the final product. Each aromatic substitution reaction comes with its own set of electronic and steric requirements, dictating where the new group will be placed on the aromatic ring, which is crucial for the design of molecular architectures in pharmaceuticals and agrochemicals.

Oxidation Reactions

Oxidation reactions are chemical processes that involve the increase of the oxidation state of a molecule through the loss of electrons. In organic chemistry, oxidation reactions are used to modify the structure of organic molecules by adding oxygen or removing hydrogen to create new functional groups like carbonyls, carboxylic acids, or alcohols.

Throughout the exercises, several instances of oxidation are present, such as the transformation of a methyl group to a carboxyl group using strong oxidizing agents like potassium permanganate in the synthesis of p-cyanobenzoic acid and 4-fluorobenzoic acid from toluene derivatives. Oxidative processes play a pivotal role in the synthesis and functionalization of organic compounds, reinforcing the ability to tailor the chemical properties of molecules for applications ranging from drug development to materials science.