Question

Following is a retrosynthetic analysis for an intermediate in the industrial synthesis of vitamin A. (a) Addition of one mole of \(\mathrm{HCl}\) to isoprene gives 4 -chloro-2-methyl-2-butene as the major product. Propose a mechanism for this addition and account its regioselectivity. (b) Propose a synthesis of the vitamin A precursor from this allylic chloride and ethyl acetoacetate.

Short answer

Question: Propose a mechanism for the addition of HCl to isoprene and explain its regioselectivity. Additionally, propose a synthesis of the vitamin A precursor using 4-chloro-2-methyl-2-butene and ethyl acetoacetate. Answer: The mechanism for the addition of HCl to isoprene involves protonation of the double bond, creating a carbocation, followed by a nucleophilic attack by chloride. The regioselectivity follows the Markovnikov rule, leading to 4-chloro-2-methyl-2-butene as the major product. The synthesis of the vitamin A precursor can be achieved through Claisen condensation, hydrolysis, and decarboxylation reactions using 4-chloro-2-methyl-2-butene and ethyl acetoacetate.

Step-by-step solution

Part (a): HCl Addition Mechanism

First, let's consider the addition of HCl to isoprene (\(\mathrm{C_5H_8}\)). The mechanism for this addition reaction proceeds through a two-step process: 1. Protonation of the double bond, creating a carbocation. 2. Nucleophilic attack by chloride, forming a new C-Cl bond. To draw the mechanism step-by-step: 1. Identify the double bond in isoprene and react it with HCl, resulting in the protonation of the double bond. \(\mathrm{C_5H_8 + HCl} \to \mathrm{C_5H_9^+ + Cl^-}\) 2. Nucleophilic attack of the chloride ion on the carbocation, forming the final product, 4-chloro-2-methyl-2-butene. \(\mathrm{C_5H_9^+ + Cl^-} \to \mathrm{C_5H_9Cl}\) Let's address the regioselectivity of this reaction. The regioselectivity is based on the Markovnikov rule, which states that the hydrogen atom will be added to the carbon with the greater number of hydrogen atoms, and the halogen will be added to the carbon with fewer hydrogen atoms. In the case of isoprene, the protonation results in the more stable carbocation, and the nucleophilic attack by chloride occurs at this carbon, following the Markovnikov rule. Hence, 4-chloro-2-methyl-2-butene is the major product.

Part (b): Synthesis of Vitamin A Precursor

Now let's propose a synthesis of the vitamin A precursor using the allylic chloride (4-chloro-2-methyl-2-butene) and ethyl acetoacetate. One potential approach is to use a Claisen condensation reaction, as it involves the ester and ketone components present in both molecules: 1. Deprotonate ethyl acetoacetate using a strong non-nucleophilic base, like \(\mathrm{NaH}\), to generate the enolate ion. \(\mathrm{C_6H_10O_3 + NaH} \to \mathrm{C_6H_9O_3^- + Na^+ + H_2}\) 2. Perform a nucleophilic attack by the enolate ion on the allylic chloride molecule at the carbocation position, creating a new C-C bond. \(\mathrm{C_5H_9Cl + C_6H_9O_3^-} \to \mathrm{C_{11}H_{17}O_3 + Cl^-}\) 3. Hydrolyse the ester group in the resulting product to create a carboxylic acid. \(\mathrm{C_{11}H_{17}O_3 + H_2O} \to \mathrm{C_{11}H_{18}O_4}\) 4. Perform a decarboxylation reaction to eliminate the carboxylic acid and form the vitamin A precursor. \(\mathrm{C_{11}H_{18}O_4} \to \mathrm{C_{10}H_{16}O_3 + CO_2}\) In summary, the synthesis of vitamin A precursor can be carried out through a series of reactions that involve Claisen condensation, hydrolysis, and decarboxylation.