Question

Suggest a synthesis for each of the following, using nitrobenzene and any other necessary reagents. (a) \(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{~N}=\mathrm{NC}_{6} \mathrm{H}_{5}\) (c) \(\mathrm{p}-\mathrm{CH}_{3} \mathrm{C}_{6} \mathrm{H}_{4} \mathrm{NH}_{2}\) (b) \(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NHOH}\) (d) \(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{ND}_{2}\)

Short answer

(a) To synthesize Azobenzene (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{~N}=\mathrm{NC}_{6} \mathrm{H}_{5}\)), follow these steps: 1. Reduce nitrobenzene to aniline (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NH}_{2}\)) using \(\mathrm{Sn}/\mathrm{HCl}\). 2. Form diazonium salt (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{N}_{2}^{+} \mathrm{Cl}^{-}\)) with nitrous acid (\(\mathrm{HNO}_2\)) using sodium nitrite (\(\mathrm{NaNO}_2\)) and hydrochloric acid (\(\mathrm{HCl}\)). 3. Perform coupling reaction with another equivalent of aniline to produce azobenzene. (c) To synthesize p-Toluidine (\(\mathrm{p}-\mathrm{CH}_{3} \mathrm{C}_{6} \mathrm{H}_{4} \mathrm{NH}_{2}\)): 1. Nitrate nitrobenzene to obtain 1,3-dinitrobenzene using a mixture of \(\mathrm{HNO}_3\) and \(\mathrm{H}_{2} \mathrm{SO}_{4}\). 2. Reduce 1,3-dinitrobenzene to 3-nitroaniline using \(\mathrm{Fe}/\mathrm{HCl}\). 3. Alkylate 3-nitroaniline using methyl chloride (\(\mathrm{CH}_{3} \mathrm{Cl}\)) and \(\mathrm{AlCl}_3\) (Friedel-Crafts Alkylation) to obtain p-toluidine. (b) To synthesize Phenylhydroxylamine (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NHOH}\)): 1. Partially reduce nitrobenzene to nitrosobenzene (\(\mathrm{C}_6\mathrm{H}_5\mathrm{NO}\)) using \(\mathrm{Zn}/\mathrm{HCl}\). 2. Reduce nitrosobenzene with lithium aluminum hydride (\(\mathrm{LiAlH}_4\)) in THF to obtain phenylhydroxylamine. (d) To synthesize Benzene-d2-amine (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{ND}_{2}\)): 1. Reduce nitrobenzene to aniline (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NH}_{2}\)) using \(\mathrm{Sn}/\mathrm{HCl}\). 2. Replace N-H with N-D using deuterium and a transition metal catalyst, such as palladium/carbon (\(\mathrm{Pd/C}\)), to yield benzene-d2-amine.

Step-by-step solution

- Reduction of nitrobenzene to aniline

Start with the reduction of nitrobenzene to aniline using a reducing agent such as \(\mathrm{Sn}/\mathrm{HCl}\). This will give \(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NH}_{2}\).

- Formation of diazonium salt

Next, react aniline with nitrous acid (\(\mathrm{HNO}_2\)) in cold conditions to form a diazonium salt (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{N}_{2}^{+} \mathrm{Cl}^{-}\)). This reaction is facilitated using sodium nitrite (\(\mathrm{NaNO}_2\)) and hydrochloric acid (\(\mathrm{HCl}\)) as reagents.

- Coupling reaction

Lastly, react the diazonium salt with another equivalent of aniline to perform a coupling reaction. This will produce the target compound azobenzene (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{~N}=\mathrm{NC}_{6} \mathrm{H}_{5}\)). (c) Synthesis of p-Toluidine (\(\mathrm{p}-\mathrm{CH}_{3} \mathrm{C}_{6} \mathrm{H}_{4} \mathrm{NH}_{2}\)):

- Nitration of nitrobenzene

Start by nitrating nitrobenzene using a mixture of nitric acid (\(\mathrm{HNO}_3\)) and sulfuric acid (\(\mathrm{H}_{2} \mathrm{SO}_{4}\)) as the nitrating agent to obtain the 1,3-dinitrobenzene intermediate.

- Reduction of 1,3-dinitrobenzene

Next, reduce 1,3-dinitrobenzene using a reducing agent such as \(\mathrm{Fe}/\mathrm{HCl}\) to produce 3-nitroaniline.

- Friedel-Crafts Alkylation

Finally, alkylate 3-nitroaniline using methyl chloride (\(\mathrm{CH}_{3} \mathrm{Cl}\)) and \(\mathrm{AlCl}_3\) (Friedel-Crafts Alkylation) to obtain p-toluidine (\(\mathrm{p}-\mathrm{CH}_{3} \mathrm{C}_{6} \mathrm{H}_{4} \mathrm{NH}_{2}\)). (b) Synthesis of Phenylhydroxylamine (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NHOH}\)):

- Reduction of nitrobenzene to nitrosobenzene

Start by reducing nitrobenzene using \(\mathrm{Zn}/\mathrm{HCl}\) in a partial reduction to obtain nitrosobenzene (\(\mathrm{C}_6\mathrm{H}_5\mathrm{NO}\)).

- Reduction of nitrosobenzene

Next, reduce nitrosobenzene using lithium aluminum hydride (\(\mathrm{LiAlH}_4\)) in THF (tetrahydrofuran) to obtain phenylhydroxylamine (\(\mathrm{C}_6\mathrm{H}_5\mathrm{NHOH}\)). (d) Synthesis of Benzene-d2-amine (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{ND}_{2}\):

- Reduction of nitrobenzene to aniline

Start by reducing nitrobenzene to aniline using a reducing agent such as \(\mathrm{Sn}/\mathrm{HCl}\), giving \(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{NH}_{2}\).

- Replacement of N-H with N-D

Lastly, replace the N-H group with N-D by adding deuterium in the presence of a transition metal catalyst, such as palladium/carbon (\(\mathrm{Pd/C}\)). This will yield benzene-d2-amine (\(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{ND}_{2}\)).

Key concepts

Reduction of Nitrobenzene

Nitrobenzene reduction is the critical first step in many synthetic transformations. The process involves the conversion of nitrobenzene (\(\text{C}_6\text{H}_5\text{NO}_2\)) into aniline (\(\text{C}_6\text{H}_5\text{NH}_2\)). Typically, a reducing agent such as tin in hydrochloric acid (\(\text{Sn}/\text{HCl}\)) is used. This reaction effectively breaks the N=O bonds of the nitro group, introducing hydrogen into the molecule.

This reduction is crucial because it produces aniline, an amino compound that serves as a pivotal intermediate for further chemical reactions.

• The reducing conditions are harsh enough to ensure complete conversion.
• It's important to control the temperature to avoid over-reduction.

Once converted to aniline, the compound can undergo a variety of further transformations, expanding the potential for chemical synthesis.

Diazonium Salt Formation

Once aniline (\(\text{C}_6\text{H}_5\text{NH}_2\)) is prepared, the formation of a diazonium salt is the next logical step for several synthetic routes. This involves the reaction of aniline with nitrous acid (\(\text{HNO}_2\)), which is generated in situ from sodium nitrite (\(\text{NaNO}_2\)) and hydrochloric acid (\(\text{HCl}\)) under cold conditions.

This process transforms aniline into a diazonium ion (\(\text{C}_6\text{H}_5\text{N}_2^+\text{Cl}^-\)), a versatile intermediate. Due to its reactive nature, the diazonium ion can easily participate in further reactions such as coupling reactions.

• Keep the solution cold to stabilize the diazonium salt.
• Diazonium salts can decompose if overheated, releasing nitrogen gas.

In synthetic chemistry, diazonium salts are often employed to introduce various functional groups or to facilitate complex transformations.

Friedel-Crafts Alkylation

Friedel-Crafts alkylation is an essential method for the alkylation of aromatic rings. This technique allows the introduction of alkyl groups onto an aromatic ring, enhancing the molecular diversity.

Typically, this process requires the presence of a Lewis acid catalyst, like \(\text{AlCl}_3\), and an alkyl halide, such as methyl chloride (\(\text{CH}_3\text{Cl}\)). During the reaction, the electrophilic alkyl group from the alkyl halide is transferred to the aromatic ring. This specific reaction can convert 3-nitroaniline to p-toluidine.

• Watch out for side reactions, such as polyalkylation.
• Lewis acids are crucial to activating the alkyl halide for the reaction.

This method allows chemists to enhance and modify the aromatic rings, thus expanding the scope of synthetic applications.

Coupling Reaction

In organic synthesis, coupling reactions are pivotal for creating complex structures from simple molecules. One of the most known applications is the formation of azo compounds, like azobenzene, from diazonium salts.

This process involves the reaction of a diazonium compound with another aromatic compound under alkaline conditions, often using a second equivalent of aniline. The end product, azobenzene (\(\text{C}_6\text{H}_5\text{N} = \text{N}\text{C}_6\text{H}_5\)), showcases the versatility of coupling reactions in creating colored and functional compounds.

• Azo compounds are typically used as dyes due to their vibrant colors.
• Control over reaction conditions can influence the formation of different azo derivatives.

These reactions widen the repertoire of organic transformations, opening doors to innovative compound designs.

Nitration and Reduction Steps

Nitration followed by reduction is a two-step process often employed in the synthesis of amino-aromatic compounds. Initially, the aromatic ring of nitrobenzene is nitrated using a nitrating mixture of concentrated sulfuric acid (\(\text{H}_2\text{SO}_4\)) and nitric acid (\(\text{HNO}_3\)). This results in the introduction of nitro groups, such as in the formation of dinitrobenzene.

Subsequent reduction of these nitro groups, for instance using iron in the presence of hydrochloric acid (\(\text{Fe}/\text{HCl}\)), results in the formation of multi-amino products, such as 3-nitroaniline.

• Nitration is highly exothermic; careful temperature control is necessary.
• Reduction converts nitro groups to amino groups, which are highly reactive.

This sequence of reactions allows chemists to redesign aromatic substrates into valuable amino compounds with applications in dyes, drugs, and organic materials.