Question

2-Ethyl-1-hexanol was needed for the synthesis of the sunscreen octyl \(p\)-methylcinnamate. Show how this alcohol could be synthesized (a) by an aldol condensation of butanal and (b) by a malonic ester synthesis starting with diethyl malonate.

Short answer

Question: Describe two synthesis pathways for 2-ethyl-1-hexanol using aldol condensation of butanal and malonic ester synthesis with diethyl malonate. Answer: The two synthesis pathways for 2-ethyl-1-hexanol are: 1. Aldol condensation of Butanal - This pathway involves the reaction of butanal with itself to form a β-hydroxyaldehyde through aldol condensation, followed by the reduction of the carbonyl group of the aldol product to form the alcohol using a reducing agent like NaBH4. 2. Malonic Ester Synthesis with Diethyl Malonate - This pathway starts with the deprotonation of diethyl malonate to form an enolate ion, followed by the reaction of this enolate ion with an alkyl halide through an SN2 mechanism. The resulting product is then hydrolyzed and decarboxylated to form a carboxylic acid, which is reduced to the desired alcohol, 2-ethyl-1-hexanol, using a reducing agent like LiAlH4.

Step-by-step solution

Identify reactants and product

First, we need to identify the reactants needed for the aldol condensation. In this case, our starting material is butanal (C4H8O) and the product is 2-ethyl-1-hexanol (C8H18O).

Determine aldol product

For an aldol condensation, the carbonyl compound (aldehyde or ketone) reacts with itself (or another carbonyl compound) to form a β-hydroxyaldehyde or β-hydroxyketone. In this case, the reaction of butanal with itself will form a β-hydroxyaldehyde.

Perform aldol condensation

To perform the aldol condensation, we need to deprotonate the α-carbon of butanal and have it attack the carbonyl carbon of another butanal molecule. This will generate the aldol product (a β-hydroxyaldehyde). During this reaction, a water molecule is eliminated.

Reduction of the aldol product to form the alcohol

The final step in the synthesis of 2-ethyl-1-hexanol is the reduction of the carbonyl group of the aldol product to form the alcohol. This can be done using a reducing agent such as NaBH4. b) Malonic Ester Synthesis with Diethyl Malonate To start the synthesis process using the malonic ester synthesis method, we need to identify the starting materials and the product. In this case, our starting material is diethyl malonate.

Identify reactants and product

First, we need to identify the reactants needed for the malonic ester synthesis. In this case, our starting material is diethyl malonate (C9H16O2) and the product is 2-ethyl-1-hexanol (C8H18O).

Determination of ester enolate

For the malonic ester synthesis, the ester is first deprotonated to form an enolate ion, which is a nucleophile. This enolate ion is then ready to react with an electrophile (e.g., alkyl halide) to form a new bond.

Alkylation of enolate ion

The enolate ion of the malonic ester then reacts with the alkyl halide using an SN2 mechanism to form a new bond, replacing one of the ethyl groups on the ester.

Hydrolysis and decarboxylation

The resulting product of the malonic ester synthesis is then hydrolyzed under acidic conditions to form the corresponding dicarboxylic acid. This dicarboxylic acid subsequently undergoes decarboxylation upon heating to remove one of the carboxyl groups and form a monofunctional carboxylic acid.

Reduction of carboxylic acid to alcohol

Finally, the carboxylic acid is reduced to form the desired alcohol, 2-ethyl-1-hexanol. This can be done using a reducing agent such as LiAlH4, followed by the addition of an aqueous solution to quench the reaction. In conclusion, we have shown two possible synthesis pathways for the synthesis of 2-ethyl-1-hexanol using aldol condensation of butanal and malonic ester synthesis with diethyl malonate.

Key concepts

Aldol Condensation

Aldol condensation is a fundamental reaction in organic chemistry that enables the formation of carbon-carbon bonds, thereby constructing complex molecules from simpler ones. This reaction involves the condensation of an aldehyde or ketone with a carbon nucleophile that has at least one α-hydrogen atom.

The process is initiated by the deprotonation of the α-carbon to generate an enolate ion, which is highly nucleophilic. This enolate attacks the carbonyl carbon of another molecule, leading to the creation of a new carbon-carbon bond. When starting with butanal, aldol condensation can yield a β-hydroxyaldehyde product.

Subsequent steps often involve dehydration to create an α,β-unsaturated carbonyl compound. In the context of the exercise, the target alcohol, 2-ethyl-1-hexanol, requires the reduction of the β-hydroxyaldehyde product to an alcohol. This is achieved using a reducing agent such as sodium borohydride (NaBH₄).

Malonic Ester Synthesis

Malonic ester synthesis is a powerful multi-step method for producing carboxylic acids with substituents at the α-position. The process begins with the esterification of malonic acid, followed by deprotonation to create an enolate ion. The highly reactive enolate is then alkylated via an SN2 mechanism in which it displaces a leaving group in an alkyl halide, leading to the formation of a substituted malonic ester.

Further steps include hydrolysis and decarboxylation to produce the corresponding carboxylic acid. The reaction with diethyl malonate in the exercise results in an alkylated malonic acid which, after decarboxylation, is converted to the target compound, 2-ethyl-1-hexanol, by a reduction step. Lithium aluminium hydride (LiAlH₄) is commonly used in this final reduction step, transforming the carboxylic acid into the desired alcohol.

Reduction Reactions

Reduction reactions are vital in organic synthesis for converting various functional groups to alcohols, a process essential in the formation of 2-ethyl-1-hexanol. These reactions typically involve the addition of hydrogen or the removal of oxygen from a molecule.

In the aldol condensation pathway, the intermediate β-hydroxyaldehyde is reduced to an alcohol using sodium borohydride (NaBH₄), which is a mild reducing agent suitable for selective reductions. On the other hand, in the malonic ester synthesis, the carboxylic acid group is reduced to an alcohol by using the stronger reducing agent lithium aluminium hydride (LiAlH₄). This reduction step is vital to transform the synthesized carboxylic acid into the target alcohol.

SN2 Mechanism

The SN2 mechanism is a type of nucleophilic substitution reaction pivotal in many organic transformations, including in the synthesis path using diethyl malonate. This bimolecular reaction involves the displacement of a leaving group by a nucleophile with an inversion of configuration at the reactive carbon center.

In the malonic ester synthesis mentioned in the exercise, the nucleophile is the enolate ion formed from diethyl malonate. This enolate attacks an electrophilic carbon (usually indicated by the presence of a good leaving group, like a halide), pushing out the leaving group in a single concerted step. Factors like steric hindrance and the quality of the leaving group can profoundly affect the rate and outcome of an SN2 reaction. The resulting carbon chain after the SN2 step undergoes further transformations before finally being reduced to the target alcohol, 2-ethyl-1-hexanol.