Question

The compound 3,5,5-trimethyl-2-cyclohexenone can be synthesized using acetone and ethyl acetoacetate as sources of carbon atoms. New carbon-carbon bonds in this synthesis are formed by a combination of aldol reactions and Michael reactions. Show reagents and conditions by which this synthesis might be accomplished.

Short answer

Answer: The two key steps are: 1. A Michael addition reaction between acetone and ethyl acetoacetate using sodium ethoxide as the base. 2. An intramolecular aldol condensation of the Michael addition product to form the cyclohexenone ring, using sodium ethoxide as the base.

Step-by-step solution

Michael Addition

Firstly, we need to carry out the Michael addition reaction between acetone and ethyl acetoacetate. This reaction forms a new carbon-carbon bond. For this reaction, a strong base such as sodium ethoxide (NaOEt) is required. $$ acetone\ +\: ethyl\: acetoacetate\overset{NaOEt}{\longrightarrow} Michael\: addition\: product\tag{i} $$

Intramolecular Aldol Condensation

Next, we need to perform an intramolecular aldol condensation on the Michael addition product to form the cyclohexenone ring. This reaction also requires a strong base. Sodium ethoxide (NaOEt) can be used again to carry out this step. $$ Michael\: addition\: product\overset{NaOEt}{\longrightarrow} 3,5,5-trimethyl-2-cyclohexenone\tag{ii} $$

Overview

In summary, the synthesis of 3,5,5-trimethyl-2-cyclohexenone from acetone and ethyl acetoacetate is accomplished through two key steps: 1. A Michael addition reaction between acetone and ethyl acetoacetate using sodium ethoxide as the base (Reaction i). 2. An intramolecular aldol condensation of the Michael addition product to form the cyclohexenone ring, using sodium ethoxide as the base (Reaction ii). By following these two steps, you can successfully synthesize 3,5,5-trimethyl-2-cyclohexenone using acetone and ethyl acetoacetate as the starting materials.

Key concepts

Michael Addition

The Michael addition is a notable reaction in organic chemistry, named after the American chemist Arthur Michael. It's a method for forming carbon-carbon bonds by adding a nucleophile to an α,β-unsaturated carbonyl compound. In simpler terms, it involves the coupling of a compound with a double bond next to a carbonyl group (the Michael acceptor) with another molecule that has an active hydrogen atom (the Michael donor) using a base.

For example, in the exercise provided, ethyl acetoacetate, which contains an activated methylene group, acts as the Michael donor, whereas acetone, with its double bond adjacent to the ketone, acts as the Michael acceptor. The strong base, sodium ethoxide, deprotonates the ethyl acetoacetate, leading to the formation of a nucleophilic enolate ion that attacks the α,β-unsaturated carbonyl of acetone, forging a new carbon-carbon bond. This kind of reaction is pivotal for assembling complex molecules in organic synthesis as it allows the rapid construction of carbon frameworks.

Aldol Condensation

Aldol condensation is a fundamental reaction in organic chemistry, where two carbonyl compounds (usually aldehydes or ketones) combine to form a larger β-hydroxy carbonyl compound, known as an 'aldol'. This reaction sequence typically consists of an addition followed by a dehydration. The product, which features a new carbon-carbon bond at the α-position of one of the carbonyl groups, can often undergo subsequent elimination of water to yield an α,β-unsaturated carbonyl compound.

In the context of the textbook exercise, an intramolecular aldol condensation occurs after the initial Michael addition. The base, again sodium ethoxide, generates an enolate from the michael addition product, which then attacks the carbonyl within the same molecule, resulting in the formation of a new carbon-carbon bond and the subsequent closure of a cyclohexenone ring. Mastery of this reaction is crucial for students as it enables the synthesis and modification of complex organic compounds, including natural products and pharmaceuticals.

Carbon-Carbon Bond Formation

Carbon-carbon (C-C) bond formation is the cornerstone of organic chemistry, as it allows chemists to create a vast array of complex structures from simpler compounds. Both the Michael addition and the aldol condensation highlighted in the exercise are examples of reactions that facilitate C-C bond formation.

The significance of C-C bond forming reactions lies in their ability to extend carbon chains and introduce functionality, enabling the synthesis of everything from medicines to materials. Ensuring a precise mechanism and proper conditions for these reactions are essential, as is the understanding of the nature of the reagents involved. A deep comprehension of these reactions not only aids in synthetic strategy but also enriches a student's overall grasp of organic chemistry's core principles.

Cyclohexenone Synthesis

Cyclohexenones are a group of compounds featuring a six-membered ring with a double bond and a ketone, and are important intermediates in organic synthesis. In the Educational platform's example, the synthesis of 3,5,5-trimethyl-2-cyclohexenone showcases the transformation of linear precursors into a cyclic structure through the strategic use of Michael addition followed by an intramolecular aldol reaction.

Creating cyclohexenones typically involves building up the ring system through the establishment of new carbon bonds and the careful selection of reaction conditions to ensure the ring is properly formed. By adding basic conditions and manipulating temperature and solvent conditions, students can achieve cyclization, a high-yield conversion often seen in the synthesis of natural products and pharmaceuticals.