Question

Following is a retrosynthetic analysis for an intermediate in the industrial synthesis of vitamin \(\mathrm{A}\). (a) Addition of one mole of 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

Provide a short summary of the HCl addition to isoprene and its regioselectivity explanation. The HCl addition to isoprene occurs in two steps, with the initial protonation of the double bond leading to the formation of a carbocation, followed by the attack of the chloride ion to form the major product, 4-chloro-2-methyl-2-butene. The regioselectivity of this reaction can be explained by the stability of the carbocations. The tertiary carbocation is more stable than its alternatives due to hyperconjugation and the electron-donating inductive effect of surrounding alkyl groups, which leads to the formation of a more stable 2-methyl-2-butene structure.

Step-by-step solution

Part (a): Mechanism for HCl addition to isoprene

1. Protonation of the double bond: When HCl reacts with isoprene, the double bond acts as a nucleophile and attacks the proton (H+) from the HCl, forming a carbocation and leaving a negatively charged chloride ion (Cl-). The most stable carbocation is formed at the tertiary carbon, which is the 2-methyl-2-butene structure due to hyperconjugation and induction. \[ \text{Isoprene} + \mathrm{HCl} \rightarrow \text{Carbocation} + \mathrm{Cl}^{\mathrm{-}} \] 2. Attacking by chloride ion: The negatively charged chloride ion (Cl-) then attacks the carbocation at the tertiary carbon, forming the final product 4-chloro-2-methyl-2-butene. \[ \text{Carbocation} + \mathrm{Cl}^{\mathrm{-}} \rightarrow \text{4-chloro-2-methyl-2-butene} \]

Part (a): Regioselectivity explanation

The regioselectivity in this reaction can be explained by considering the stability of the carbocations. In general, carbocations that have more substituted carbons (higher degree) are more stable due to the effects of hyperconjugation and the electron-donating inductive effect of the surrounding alkyl groups. In this case, the carbocation forms at the tertiary carbon which leads to a more stable 2-methyl-2-butene structure.

Part (b): Synthesis of vitamin A precursor from allylic chloride and ethyl acetoacetate

1. Claisen condensation: Perform a Claisen condensation between ethyl acetoacetate and the allylic chloride (4-chloro-2-methyl-2-butene). This would involve the deprotonation of ethyl acetoacetate, followed by the nucleophilic attack of its enolate ion on the allylic chloride (the leaving group will be chloride ion). This results in the formation of a β-ketoester. \[ \text{Ethyl acetoacetate} + \text{4-chloro-2-methyl-2-butene} \rightarrow \text{β-ketoester} + \mathrm{Cl}^{\mathrm{-}} \] 2. Formation of enol: Tautomerize the resulting β-ketoester to its enol form. This involves the proton transfer from the keto group's α-carbon to the carbonyl oxygen. The product will be an enol. 3. Cyclization: The enol product will undergo an intramolecular aldol reaction, which allows the formation of the ring structure that is found in the vitamin A precursor. 4. Dehydration: Remove the hydroxyl group, resulting in the formation of a double bond that leads to the final vitamin A precursor compound. By following these steps, you can successfully synthesize the vitamin A precursor from the allylic chloride and ethyl acetoacetate.

Key concepts

Carbocation Stability

When understanding reactions in organic chemistry, especially those involving carbocations, it's essential to recognize the significance of carbocation stability. Carbocations are positively charged carbon species that play a crucial role as intermediates in many chemical reactions. The stability of a carbocation is primarily influenced by:

• **Substitution Level:** More substituted carbocations, such as tertiary carbocations, are more stable than secondary and primary ones. This is due to the greater electron-donating capability of additional carbon groups.
• **Hyperconjugation:** This involves the stabilization of the carbocation through the overlap of \( ext{C-H}\) sigma bonds with the empty p-orbital of the carbocation, allowing delocalization of charge.
• **Inductive Effect:** The presence of electron-donating groups via sigma-bonds helps disperse the positive charge, providing greater stability.

In the specific case of isoprene reacting with HCl, the formed carbocation at a tertiary position—2-methyl-2-butene—is stabilized through both hyperconjugation and induction, leading to a more stable structure and dictating the course of the reaction.

Claisen Condensation

The Claisen condensation is an essential reaction in organic synthesis, forming carbon-carbon bonds through the interaction of esters and carbonyl compounds. This reaction mainly involves the following steps:

• **Deprotonation:** A strong base, often an alkoxide ion, deprotonates the \(\alpha\)-position of an ester to form an enolate ion.
• **Nucleophilic Attack:** The enolate ion acts as a nucleophile, attacking the carbonyl carbon of another ester molecule, forming a \(\beta\)-keto ester.

In the synthesis of a vitamin A precursor, the allylic chloride (formed from isoprene) is mixed with ethyl acetoacetate. Here, the chloro group acts as a leaving group, allowing the enolate (from ethyl acetoacetate) to form a carbon-carbon bond, leading to a \(\beta\)-keto ester. This type of Claisen condensation efficiently stitches together two molecular fragments, making it a go-to strategy for constructing complex organic structures.

Regioselectivity

Regioselectivity refers to the preference for a chemical reaction to occur at one direction or position over others, especially in situations where multiple outcomes are possible. It is often driven by factors like:

• **Stability of Intermediates:** Often, the formation of the most stable intermediate (such as a carbocation) guides the regioselective outcome of a reaction.
• **Electronic Effects:** Variations in electron density across a molecule can favor reaction sites that stabilize developing charges.
• **Steric Factors:** Bulky groups can limit access to certain sites on a molecule, directing reactions to less hindered areas.

When isoprene undergoes addition with HCl, the preference is for the formation of 4-chloro-2-methyl-2-butene. Here, regioselectivity is influenced by the stability of the tertiary carbocation intermediate, where hyperconjugation and inductive effects play significant roles in channeling the reaction pathway towards this major product.

Aldol Reaction

The aldol reaction is a fundamental carbon-carbon bond-forming reaction in organic chemistry, often involved in the construction of complex molecules. This reaction involves:

• **Enolate Formation:** Initiated by the deprotonation of an aldehyde or ketone's \(\alpha\)-carbon using a base, producing an enolate ion.
• **Nucleophilic Addition:** The enolate ion then acts as a nucleophile, attacking the carbonyl carbon of another aldehyde or ketone, leading to the formation of a \(\beta\)-hydroxy carbonyl compound.
• **Dehydration:** Often, further elimination reactions (release of a water molecule) occur, forming an \(\alpha,\beta\)-unsaturated carbonyl compound.

In the synthesis steps for vitamin A precursor, the enol form of the \(\beta\)-keto ester undergoes intramolecular aldol condensation. This forms a ring structure, crucial for the intricate architecture of vitamin A. The final stages involve dehydration, setting up the crisp double bonds necessary for the desired vitamin A precursor.