Question

Among the newer-generation diuretics is bumetanide, prescribed under several trade names, including Bumex and Fordiuran. Following is an outline of a synthesis of this (a) Propose a synthesis of 4 -chloro-3-nitrobenzoic acid from toluene. (b) Propose reagents for Step (1). Hint: It requires more than one reagent. (c) Propose a mechanism for reaction (2). (d) Propose reagents for Step (3). Hint: It too requires more than one reagent. (e) Is bumetanide chiral? If so, which of the possible stereoisomers are formed in this synthesis?

Short answer

Question: Propose a synthesis of 4-chloro-3-nitrobenzoic acid from toluene and determine if bumetanide is chiral. Answer: The synthesis of 4-chloro-3-nitrobenzoic acid from toluene can be achieved through the following steps: 1. Nitrate the toluene to form 4-nitrotoluene, using concentrated sulfuric acid (H2SO4) and nitric acid (HNO3) at low temperature. 2. Convert the nitro group in the 4-nitrotoluene to an amine group to form 4-amino-3-chlorotoluene, using the Sandmeyer reaction with CuCl. 3. Perform an oxidation step using potassium permanganate (KMnO4) to convert the methyl group of the 4-amino-3-chlorotoluene to a carboxylic acid group. Bumetanide is chiral, as it possesses at least one chiral center. In this synthesis, a racemic mixture of stereoisomers is obtained, including both possible enantiomers (R and S) in equal quantities.

Step-by-step solution

Propose a synthesis of 4-chloro-3-nitrobenzoic acid from toluene

First, we need to nitrate the toluene to form 4-nitrotoluene. This can be done using a mixture of concentrated sulfuric acid (H2SO4) and nitric acid (HNO3) at low temperature. Next, we need to convert the nitro group in the 4-nitrotoluene to an amine group to form 4-amino-3-chlorotoluene. This can be done using the Sandmeyer reaction with CuCl. Finally, to obtain the desired product, 4-chloro-3-nitrobenzoic acid, we need to perform an oxidation step using potassium permanganate (KMnO4) to convert the methyl group of the 4-amino-3-chlorotoluene to a carboxylic acid group.

Propose reagents for Step (1)

For the nitration of toluene to form 4-nitrotoluene, the required reagents are concentrated sulfuric acid (H2SO4) and nitric acid (HNO3). The reaction will proceed at low temperature, usually around 0-5 °C.

Propose a mechanism for reaction (2)

The mechanism for the Sandmeyer reaction is as follows: 1. Formation of diazonium salt: The nitro group on the aromatic ring is first reduced to amine using a reducing agent like tin (Sn) and hydrochloric acid (HCl). Next, the amine reacts with sodium nitrite (NaNO2) in the presence of hydrochloric acid (HCl) to generate the diazonium salt. 2. Formation of 4-amino-3-chlorotoluene: The diazonium salt reacts with copper(I) chloride (CuCl) to replace the diazonium group with a chlorine atom, forming 4-amino-3-chlorotoluene.

Propose reagents for Step (3)

To perform the oxidation step and convert the methyl group of 4-amino-3-chlorotoluene to a carboxylic acid group, we can use potassium permanganate (KMnO4) in the presence of an aqueous solution of sodium hydroxide (NaOH).

Is bumetanide chiral? If so, which of the possible stereoisomers are formed in this synthesis?

We can determine if a molecule has a chiral center by examining whether it possesses an atom (usually carbon) with four different substituents attached. Looking at the structure of bumetanide, it is evident that there is at least one chiral center. So, yes, bumetanide is chiral. In this synthesis, we can expect to obtain a racemic mixture of stereoisomers. In other words, we will obtain both possible enantiomers (R and S) in equal quantities. This is a consequence of using achiral reagents and reaction conditions in the synthesis, which does not allow for any control of stereochemistry at the chiral center, resulting in the formation of both stereoisomers.

Key concepts

Sandmeyer Reaction

When it comes to constructing complex molecules in organic chemistry, one pivotal transformation is the Sandmeyer reaction. This versatile reaction is primarily used to replace an amine group on an aromatic ring with a variety of other substituents, such as halogens.

The process starts with the conversion of an aromatic amine into a diazonium salt, usually involving a reaction with sodium nitrite (NaNO2) and a strong acid like HCl. The diazonium salt is an unstable intermediate which can then be reacted with copper(I) chloride (CuCl) or other copper(I) salts to introduce the desired substituent, such as a chlorine atom in the case of making 4-amino-3-chlorotoluene from 4-nitrotoluene.

The Importance of Temperature Control

Managing the temperature is a key factor for a successful Sandmeyer reaction; it is typically carried out at cold temperatures to stabilize the diazonium salt. By controlling the reaction conditions, chemists can manipulate which substituents will replace the diazonium group, expanding the versatility of the aromatic compounds that can be synthesized.

Nitration of Toluene

Nitration is a fundamental reaction in organic chemistry, used to add a nitro group to an aromatic ring, such as benzene or toluene. Nitration of toluene is a crucial step when preparing various derivatives needed for complex syntheses.

This reaction is traditionally performed using mixed acid, a combination of concentrated sulfuric acid (H2SO4) and nitric acid (HNO3). The role of sulfuric acid is to generate the nitronium ion, a powerful electrophile, which attacks the aromatic ring of toluene. Toluene is more open to electrophilic aromatic substitution than benzene due to the methyl group's electron-donating effect, making the ring more reactive toward the nitronium ion.

Positional Selectivity

The methyl group of toluene directs the incoming nitro group to the ortho and para positions. However, specific reaction conditions, such as temperature, can influence the proportion of ortho to para substitution. Low temperatures typically favour the para product, which is more relevant in synthesizing bumetanide.

Oxidation with Potassium Permanganate

Oxidation in organic chemistry is the process of increasing the oxygen content or decreasing the hydrogen content of a molecule. Potassium permanganate (KMnO4) is a powerful oxidizing agent often used to convert primary alcohols into carboxylic acids and alkenes into diols or ketones, depending on the conditions.

In the synthesis of bumetanide, oxidation is crucial for transforming the methyl group of 4-amino-3-chlorotoluene into a carboxylic group, ultimately giving 4-chloro-3-nitrobenzoic acid. This is achieved by treating the compound with KMnO4 in an alkaline medium. The reaction is exothermic and must be controlled to avoid overoxidation.

Selectivity and Yield

The choice of solvent and temperature is essential to ensure high selectivity and yield of the desired product. The oxidation step can be sensitive to the presence of other functional groups in the molecule, requiring careful consideration of reaction conditions.

Chirality and Stereoisomers

Chirality is a geometric property where an object is not superimposable on its mirror image, much like our hands. In organic chemistry, chirality often arises when a carbon atom is bonded to four different groups. Molecules with this feature are called chiral and can exist in two forms that are non-superimposable mirror images of each other; these forms are known as enantiomers.

Each enantiomer of a chiral compound can have drastically different chemical behaviours, especially when interacting with other chiral environments—which is common in biological systems. This makes understanding and controlling chirality vital in the synthesis of pharmaceuticals.

In the case of bumetanide synthesis, since no steps in the reaction selectively produce one enantiomer over the other (stereoselectivity), the final product is often a racemic mixture. This mixture contains equal parts of both the 'R' and 'S' stereoisomers. Depending on the application, separation of these enantiomers might be necessary, as they can have different effects on biological systems.