Question

Diazepam, better known as Valium, is a central nervous system (CNS) sedative/ hypnotic. As a sedative, it diminishes activity and excitement and thereby has a calming effect. Back in 1976, based on the number of new and refilled prescriptions processed, diazepam was the most prescribed drug in the United States. Following is a retrosynthetic analysis for a synthesis of diazepam. Note that the formation of compound B involves a Friedel-Crafts acylation. In this reaction, it is necessary to protect the \(2^{\circ}\) amine by prior treatment with acetic anhydride. The acetyl-protecting group is then removed by treatment with aqueous \(\mathrm{NaOH}\) followed by careful acidification with \(\mathrm{HCl}\). (a) Given this retrosynthetic analysis, propose a synthesis for diazepam. (b) Is diazepam chiral? If so, how many of the possible stereoisomers are formed in this synthesis?

Short answer

(a) Synthesis of Diazepam: Step 1: Prepare the starting material (compound A) Prepare an appropriate starting material (compound A), which should be a suitable precursor for the Friedel-Crafts acylation reaction. Step 2: Protect the \(2^{\circ}\) amine Treat compound A with acetic anhydride to protect the \(2^{\circ}\) amine group in order to prevent unwanted reactions during the Friedel-Crafts acylation step. This results in the formation of compound A' with an acetyl-protecting group. Step 3: Friedel-Crafts acylation Perform a Friedel-Crafts acylation on compound A' to form compound B. This step introduces a new ketone group, which is an essential part of the diazepam structure. Step 4: Remove acetyl-protecting group (amine deprotection) Remove the acetyl-protecting group from compound B by treating it with aqueous \(\mathrm{NaOH}\), followed by careful acidification with \(\mathrm{HCl}\). This will reveal the \(2^{\circ}\) amine group, resulting in compound C. Step 5: Synthesis of Diazepam Continue the synthesis pathway from compound C by performing necessary chemical reactions to obtain the final product, diazepam. (b) Chirality and stereochemistry of Diazepam: Step 1: Assess the molecular structure and atom connectivity Examine the structure of diazepam and identify if it contains any stereogenic centers, which are defined as sp3 hybridized atoms bearing four different substituents. Step 2: Determine chirality If there are no stereogenic centers in diazepam, it is achiral. If it has one or more stereogenic centers, it is chiral. Step 3: Calculate the number of possible stereoisomers If diazepam is chiral and has stereogenic centers, calculate the number of possible stereoisomers using the formula \(2^n\), where n is the number of stereogenic centers. This will give the total number of stereoisomers that can be potentially formed during the synthesis. Answer: (a) The synthesis of diazepam involves 5 steps, including protection, Friedel-Crafts acylation, deprotection, and final reaction to obtain diazepam. (b) Diazepam is achiral as it does not have any stereogenic centers, and therefore, no stereoisomers can be formed during its synthesis.

Step-by-step solution

Prepare the starting material (compound A)

Prepare an appropriate starting material (compound A), which should be a suitable precursor for the Friedel-Crafts acylation reaction.

Protect the \(2^{\circ}\) amine

Treat compound A with acetic anhydride to protect the \(2^{\circ}\) amine group in order to prevent unwanted reactions during the Friedel-Crafts acylation step. This results in the formation of compound A' with an acetyl-protecting group.

Friedel-Crafts acylation

Perform a Friedel-Crafts acylation on compound A' to form compound B. This step introduces a new ketone group, which is an essential part of the diazepam structure.

Remove acetyl-protecting group (amine deprotection)

Remove the acetyl-protecting group from compound B by treating it with aqueous \(\mathrm{NaOH}\), followed by careful acidification with \(\mathrm{HCl}\). This will reveal the \(2^{\circ}\) amine group, resulting in compound C.

Synthesis of Diazepam

Continue the synthesis pathway from compound C by performing necessary chemical reactions to obtain the final product, diazepam. (b) Chirality and stereochemistry of Diazepam:

Assess the molecular structure and atom connectivity

Examine the structure of diazepam and identify if it contains any stereogenic centers, which are defined as sp3 hybridized atoms bearing four different substituents.

Determine chirality

If there are no stereogenic centers in diazepam, it is achiral. If it has one or more stereogenic centers, it is chiral.

Calculate the number of possible stereoisomers

If diazepam is chiral and has stereogenic centers, calculate the number of possible stereoisomers using the formula \(2^n\), where n is the number of stereogenic centers. This willl give the total number of stereoisomers that can be potentially formed during the synthesis.