Question

Following is a synthesis for the antifungal agent tolciclate. (a) Propose a mechanism for formation of (A). (b) Show how (A) can be converted to tolciclate. Use 3 -methyl- \(N\)-methylaniline as the source of the amine nitrogen and thiophosgene, \(\mathrm{Cl}_{2} \mathrm{C}=\mathrm{S}\), as the source of the \(\mathrm{C}=\mathrm{S}\) group.

Short answer

Question: Propose a mechanism for the formation of (A) and describe how it can be converted to tolciclate using 3-methyl-N-methylaniline and thiophosgene. Answer: The formation of (A) involves a nucleophilic attack of the oxygen atom of an alcohol on the carbonyl carbon of an acyl chloride, followed by proton transfer from hydrochloric acid to the oxygen atom. To convert (A) to tolciclate, 3-methyl-N-methylaniline is first activated by deprotonating its amine group and then reacts with thiophosgene to form an isothiocyanate intermediate. This intermediate undergoes nucleophilic attack on (A), followed by bond rearrangement, elimination of the chloride ion, and proton transfer to yield tolciclate.

Step-by-step solution

Formation of (A)

To propose a mechanism for the formation of (A), we need to consider the possible reaction pathways for the given starting materials. We will analyze the reaction mechanism step by step. 1. Nucleophilic attack of the oxygen atom on the carbonyl carbon: The oxygen atom of the alcohol attacks the electrophilic carbonyl carbon from the acyl chloride, breaking the pi bond between carbon and oxygen and forming a new alkyl-oxygen bond. 2. Proton transfer: The negatively charged oxygen atom (after the nucleophilic attack) will take a proton from the hydrochloric acid, formed in the reaction, to neutralize its charge and form a stable product, an ester. The overall reaction mechanism for the formation of (A) can be summarized as: Alcohol + Acyl Chloride -> Ester + HCl

Conversion of (A) to Tolciclate

To convert (A) to tolciclate, we will use 3-methyl-N-methylaniline and thiophosgene as the sources of the amine nitrogen and C=S group, respectively. We will go through the process step by step. 1. Activation of thiophosgene: Thiophosgene can be activated by reacting with a base such as triethylamine (Et3N), which deprotonates the amine group in 3-methyl-N-methylaniline. This generates a negatively charged nitrogen atom that acts as a nucleophile. 2. Nucleophilic attack on thiophosgene: The activated nitrogen atom in 3-methyl-N-methylaniline attacks the thiophosgene at the carbon atom, forming a new C-N bond and breaking one of the carbon-chlorine bonds. This results in the formation of an isothiocyanate intermediate. 3. Nucleophilic attack on (A): The isothiocyanate intermediate further reacts with the ester (A) by nucleophilic attack on the carbonyl carbon, followed by a rearrangement of the bonds and elimination of the leaving group (chloride ion). 4. Proton transfer: The negatively charged oxygen atom (after the nucleophilic attack) will again take a proton from the hydrochloric acid, formed in the previous reaction, to neutralize its charge and form a stable product, tolciclate. Hence, the synthesis of tolciclate from (A) can be summarized as: (A) + 3-methyl-N-methylaniline + Thiophosgene -> Tolciclate

Key concepts

Nucleophilic Attack

Nucleophilic attack is a fundamental concept in organic chemistry that involves a nucleophile, which is a chemical species rich in electrons, attacking an electron-deficient or positively charged atom, known as an electrophile. During the synthesis of tolciclate, the first key step involves a nucleophilic attack, where an oxygen atom from an alcohol group attacks a carbonyl carbon atom. The alcohol's oxygen atom acts as the nucleophile because it has lone pairs of electrons readily available. The carbonyl carbon atom, being part of an acyl chloride, is highly electrophilic due to the presence of the highly electronegative chlorine atoms pulling electron density away from the carbon. This leaves the carbon atom electron-deficient and susceptible to attack.

When the nucleophilic attack occurs, it breaks the double bond between the carbonyl carbon and its oxygen, which also leads to the formation of a new bond between the nucleophile and the carbon atom. This type of reaction is central to many processes in organic synthesis, as it allows for the formation of new bonds and the construction of complex molecules from simpler ones.

Ester Formation

Ester formation is another critical reaction in organic chemistry, particularly in the synthesis of various compounds like pharmaceuticals, including tolciclate. Esters are formed via a reaction between an alcohol and a carboxylic acid or its derivatives, such as acyl chlorides or anhydrides. During the formation of compound (A) in the tolciclate synthesis, an ester is produced by reacting an alcohol with an acyl chloride. The mechanism initiates with a nucleophilic attack of the alcohol on the electrophilic carbonyl carbon of the acyl chloride, followed by a proton transfer to the oxygen atom, which finalizes the ester formation.

The reaction results in the release of hydrochloric acid (HCl) as a by-product, which is typical for esterifications involving acyl chlorides. The process is catalyzed by acidic or basic conditions that speed up the proton transfer. Ester formation is a reversible reaction; however, in the case of acyl chlorides, the reaction proceeds almost to completion due to the good leaving group properties of chloride ions.

Amine Nitrogen Source

In organic synthesis, amines are valuable compounds that often serve as nitrogen sources. Amines are derivatives of ammonia, where one or more hydrogen atoms have been replaced by alkyl or aryl groups. During the synthesis of tolciclate, 3-methyl-N-methylaniline functions as the amine nitrogen source. The nitrogen atom in the amine is nucleophilic due to its lone pair of electrons, which allows it to attack electrophilic centers in other molecules.

The amine reacts with thiophosgene, and the process begins with the activation of the amine through the deprotonation by a base such as triethylamine. This activation increases the nucleophilicity of the nitrogen atom, which then attacks the carbon atom in thiophosgene, leading to the formation of a new carbon-nitrogen bond. The roles of nitrogen sources in such reactions are pivotal as they help build the molecular framework of many organic compounds, including drugs, dyes, and polymers.

Mechanism of Organic Reactions

The mechanism of organic reactions provides an in-depth understanding of how reactions proceed at the molecular level. It describes the sequence of bond-making and bond-breaking steps that lead to the final product. Understanding the mechanism is essential for predicting the outcomes of reactions and for designing new synthetic routes in chemistry. In the context of synthesizing tolciclate, the mechanism involves several steps, including the nucleophilic attacks we've discussed, bond rearrangements, and proton transfers.

A reaction mechanism helps chemists to visualize and explain why certain products are formed, how intermediates contribute to the overall reaction, and the influence of various conditions on the reaction rate and product distribution. In many cases, mechanisms can be quite complex, involving a series of consecutive or competing steps. The key to manipulating chemical reactions lies in understanding these intricate details of reaction mechanisms.