Question

Starting with either benzene or toluene, how would you synthesize the following substances? Assume that ortho and para isomers can be separated. (a) 2 -Bromo-4-nitrotoluene (b) 1,3,5 -Trinitrobenzene (c) 2,4,6 -Tribromoaniline (d) \(m\) -Fluorobenzoic acid

Short answer

Use aromatic substitutions on toluene and benzene to achieve the desired products.

Step-by-step solution

Synthesize 2-bromo-4-nitrotoluene

Begin with toluene as the starting material. First, perform a bromination reaction using Br2/FeBr3. This will give a mixture of ortho and para isomers, but the para isomer is more favored. Next, carry out nitration using HNO3 and H2SO4. Under nitration of the brominated toluene, the ortho, para positions are favored, resulting in 2-bromo-4-nitrotoluene.

Synthesize 1,3,5-Trinitrobenzene

Start with benzene as the starting material. Perform stepwise nitration three times. Each nitration step involves using a nitrating mix of HNO3 and H2SO4. The first nitration gives nitrobenzene, the second addition is straightforward due to the activating nature of the nitro groups, and the final nitration yields 1,3,5-trinitrobenzene.

Synthesize 2,4,6-Tribromoaniline

Start with either benzene or aniline. If starting from benzene, perform a nitration to obtain nitrobenzene, and then reduce this to aniline using a reducing agent like Sn/HCl. Brominate the aniline in the presence of Br2 to obtain 2,4,6-tribromoaniline. Alternatively, starting with aniline, you can directly brominate with Br2.

Synthesize m-Fluorobenzoic acid

Start with benzoic acid, perform nitration to obtain m-nitrobenzoic acid by using HNO3/H2SO4. After nitration, reduce the nitro group to an amino group using catalytic hydrogenation (H2 over Pd/C). Convert the amino group to a fluorine using the Schiemann reaction (converting amino to diazonium salt, followed by replacement with fluoride ion).

Key concepts

Bromination

Bromination is a significant reaction for functionalizing aromatic compounds, particularly useful in synthesizing specific halogenated products. In this reaction, bromine (\(Br_2\)) is employed as the halogen source with a catalyst like iron(III) bromide (\(FeBr_3\)) to facilitate the substitution on an aromatic ring. This electrophilic aromatic substitution occurs because the catalyst generates a more reactive bromine species capable of attacking the electron-rich aromatic system.
When performing bromination on compounds like toluene, the reaction tends to favor para and ortho positions due to the electronic influence of the methyl group. The para position is often more favored over the ortho position due to steric hindrance. It’s essential for processes aiming to acquire specific isomers to carefully control the reaction conditions and utilize separation techniques to isolate the desired ortho or para isomers.

• Activation by catalyst (\(FeBr_3\)
• Favorable para substitution due to sterics
• Selective synthesis can require separation techniques

Nitration

Nitration is another critical process in organic synthesis, especially when modifying aromatic compounds. This reaction involves the substitution of a hydrogen atom on an aromatic ring with a nitro group (\(NO_2\)) and typically requires a nitrating mixture of concentrated nitric acid (\(HNO_3\)) and sulfuric acid (\(H_2SO_4\)).
In stepwise nitration, as seen in the synthesis of 1,3,5-trinitrobenzene, multiple nitro groups are introduced sequentially. Here, each additional nitro group enhances the ring's susceptibility to further nitration due to its electron-withdrawing and activating effect. This process requires precise control of reaction parameters like temperature and reactant ratios to ensure successful multiple substitutions without degrading the aromatic structure.
The nitration mechanism involves the formation of a nitronium ion (\(NO_2^+\)), which acts as the electrophile. It proceeds through an electrophilic substitution pathway, where the aromatic ring temporarily loses aromaticity during the addition before regaining stability through deprotonation.

• Nitrating mix: \(HNO_3\) and \(H_2SO_4\)
• Sequential nitration for multiple substitutions
• Careful control of conditions required

Fluorination

Fluorination of aromatic compounds is quite challenging due to the reactivity of fluorine. A well-known method to introduce fluorine into aromatic rings is the Schiemann reaction, which is valuable when synthesizing \(m\)-fluorobenzoic acid.
Typically, after creating a suitable precursor like \(m\)-nitrobenzoic acid, which is later reduced to an aromatic amine, the Schiemann reaction is employed. Here, the amino group is converted to a diazonium salt using nitrous acid, and then thermally decomposed in the presence of fluoroboric acid (\(HBF_4\)), resulting in the substitution of the amino group by a fluorine atom.
Fluorine’s incorporation enhances certain properties such as metabolic stability and polarity, making fluorinated compounds particularly useful in pharmaceuticals and agrochemicals.

• Use of Schiemann reaction for fluorination
• Formation of diazonium salts as an intermediate
• Enhancements in compound stability and functionality

Aromatic Compounds

Aromatic compounds, typified by benzene, are pivotal in organic chemistry due to their unique stability and versatility. The term "aromatic" refers to the presence of a cyclic, conjugated system with delocalized electrons, often following Hückel’s rule: \(4n + 2\) π electrons.
These compounds readily undergo substitutions, allowing the installation of various functional groups, exemplified by reactions like bromination and nitration. Aromatic compounds serve as vital starting materials for synthesizing more complex molecules, including pharmaceuticals, dyes, and plastics.
Besides their chemical reactivity, the ability of aromatic systems to stabilize charges makes them central in many reactions, including electrophilic aromatic substitutions. Understanding the behavior of aromatic compounds under different conditions assists chemists in selectively directing reactions to synthesize desired products efficiently.

• Defined by \(4n + 2\) π-electron system
• Undergo substitutions, maintaining aromaticity
• Foundation in synthesis of complex molecules