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Chapter 22: Problem 46

Starting with benzenamine, propose a synthesis of aklomide, an agent used to treat certain exotic fungal and protozoal infections in veterinary medicine. Several intermediates are shown to give you the general route. Fill in the blanks that remain; each requires as many as three sequential reactions. (Hint: Review the oxidation of amino- to nitroarenes in Section \(16-5 .\) )

Short Answer

Expert verified
Nitrate aniline to nitrobenzene, reduce to aniline, acetylate to acetanilide, chlorinate, and then hydrolyze to aklomide.

Step by step solution

01

- Nitration

To oxidize the amino group to a nitro group, first convert benzenamine (aniline) to nitrobenzene. This can be done by nitration using a mixture of concentrated nitric acid (HNO3) and sulfuric acid (H2SO4). The reaction proceeds as follows: \[ \text{C6H5NH2 + HNO3 + H2SO4} \rightarrow \text{C6H5NO2} + H2O + H2SO4 \]
02

- Reduction of Nitro Group

Next, the nitro group of nitrobenzene is reduced to give the corresponding amino group. This can be done using catalytic hydrogenation (H2/Pd) or by using reducing agents like iron (Fe) and hydrochloric acid (HCl). The equation is: \[ \text{C6H5NO2 + 3H2} \rightarrow \text{C6H5NH2 + 2H2O} \]
03

- Formation of Acetanilide

Protect the amino group by acetylation to form acetanilide. This is done by reacting aniline with acetic anhydride: \[ \text{C6H5NH2 + (CH3CO)2O} \rightarrow \text{C6H5NHCOCH3 + CH3COOH} \]
04

- Chlorination

Next, introduce a chlorine atom to the aromatic ring. This can be achieved by treating acetanilide with chlorine gas in the presence of a catalyst, like iron (Fe): \[ \text{C6H5NHCOCH3 + Cl2/Fe} \rightarrow \text{2-Chloroacetanilide + HCl} \]
05

- Hydrolysis

Finally, hydrolyze the acetanilide to yield aklomide. This is done by treating 2-chloroacetanilide with aqueous acid or base to remove the acetyl protecting group: \[ \text{2-Chloroacetanilide + H2O} \rightarrow \text{Aklomide (2-chloroaniline)} \]

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Key Concepts

These are the key concepts you need to understand to accurately answer the question.

Nitration Reaction
Nitration is a critical step in synthesizing various aromatic compounds. It involves introducing a nitro group (鈥揘O鈧�) into an aromatic ring. Starting with benzenamine, which is also known as aniline, we can perform nitration to obtain nitrobenzene. This reaction uses a mixture of concentrated nitric acid (HNO鈧�) and sulfuric acid (H鈧係O鈧�). The sulfuric acid acts as a catalyst and helps generate the nitronium ion (NO鈧傗伜) necessary for the reaction:
  • C鈧咹鈧匩H鈧� + HNO鈧� + H鈧係O鈧� 鈫� C鈧咹鈧匩O鈧� + H鈧侽 + H鈧係O鈧�
Converting the amino group (-NH鈧�) to a nitro group (-NO鈧�) is essential because it allows further functionalization in subsequent steps. The use of both acids must be handled with care due to their corrosive nature.
Reduction of Nitro Group
Once we have nitrobenzene, the nitro group can be reduced back to an amino group. This is the reverse of the initial nitration and can be done using various reducing agents such as catalytic hydrogenation (H鈧�/Pd), or more traditionally, iron filings and hydrochloric acid (Fe/HCl). The general reaction for this reduction process is:
  • C鈧咹鈧匩O鈧� + 3H鈧� 鈫� C鈧咹鈧匩H鈧� + 2H鈧侽
The reduction restores the amino group, allowing for new functional groups to be added in subsequent steps. This reaction is an example of a reduction, where the nitro group (鈥揘O鈧�) is converted back into an amino group (鈥揘H鈧�), underscoring the idea that functional group interconversion is vital for complex molecule synthesis.
Acetylation
To protect the newly formed amino group on aniline, we perform acetylation, forming acetanilide. Acetylation uses acetic anhydride as the acetyl donor, reacting with aniline to form acetanilide and acetic acid:
  • C鈧咹鈧匩H鈧� + (CH鈧僀O)鈧侽 鈫� C鈧咹鈧匩HCOCH鈧� + CH鈧僀OOH
This reaction protects the amino group by forming a less reactive amide. Protecting groups like acyl groups are crucial in multi-step syntheses, as they prevent unwanted reactions at the amino group, ensuring selective reactions can occur at other parts of the molecule.
Chlorination of Aromatic Compounds
With the amino group protected, we can now introduce a chlorine atom onto the aromatic ring. Chlorination of acetanilide can be achieved by treating the compound with chlorine gas (Cl鈧�) in the presence of an iron (Fe) catalyst:
  • C鈧咹鈧匩HCOCH鈧� + Cl鈧�/Fe 鈫� 2-Chloroacetanilide + HCl
The iron acts as a catalyst to facilitate the generation of the chlorine radical essential for the halogenation reaction. This reaction places a chlorine atom ortho to the acetanilide, considering the directing effects of the acyl group.
Hydrolysis of Acetanilide
The final step is hydrolysis, which involves removing the acetyl protecting group to yield the active compound, aklomide. Hydrolysis of 2-chloroacetanilide can be performed using aqueous acid or base to convert the amide back into an amine:
  • 2-Chloroacetanilide + H鈧侽 鈫� Aklomide (2-chloroaniline)

Under acidic or basic conditions, the amide bond is cleaved, regenerating the amine structure. This step is crucial to obtain the final bioactive molecule. Hydrolysis accomplishes the goal of selectively removing the protecting group to unmask the desired functional group, necessary for the final therapeutic activity of the compound.

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Most popular questions from this chapter

Which one of the two chlorides will solvolyze more rapidly: (1-chloroethyl)benzene, or chloro(diphenyl)methane, \(\left(\mathrm{C}_{6} \mathrm{H}_{5}\right)_{2} \mathrm{CHCl}\) ? Explain your answer.

1-Chloro-4-methylbenzene ( \(p\) -chlorotoluene) is not a good starting material for the preparation of 4-methylphenol ( \(p\) -cresol) by direct reaction with hot \(\mathrm{NaOH}\), because it forms a mixture of two products. Why does it do so, and what are the two products?

Phenylmethanol (benzyl alcohol) is converted into (chloromethyl)benzene in the presence of hydrogen chloride much more rapidly than ethanol is converted into chloroethane. Explain.

Triphenylmethyl radical, \(\left(\mathrm{C}_{6} \mathrm{H}_{5}\right)_{3} \mathrm{C} \cdot\), is stable at room temperature in dilute solution in an inert solvent, and salts of triphenylmethyl cation, \(\left(\mathrm{C}_{6} \mathrm{H}_{5}\right)_{3} \mathrm{C}^{+}\), can be isolated as stable crystalline solids. Propose explanations for the unusual stabilities of these species.

Hexachlorophene (margin) is a skin germicide formerly used in soaps. It is prepared in one step from \(2,4,5\) -trichlorophenol and formaldehyde in the presence of sulfuric acid. How does this reaction proceed? (Hint: Formulate an acid-catalyzed hydroxymethylation for the first step.)
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