Question

Using your roadmaps as a guide, show how to convert ethanol, formaldehyde, and acetone into racemic ethyl 2-acetyl-5-oxohexanoate. You must use ethanol, formaldehyde, and acetone as the source of all carbon atoms in the target molecule. Show all reagents and all molecules synthesized along the way.

Short answer

Question: Outline the steps involved in synthesizing racemic ethyl 2-acetyl-5-oxohexanoate from ethanol, formaldehyde, and acetone. Answer: The process includes: 1. Formation of an ester from ethanol via esterification with ethanoic acid and catalytic sulfuric acid. 2. Formation of a carbon-carbon bond between the acetyl group and ester group obtained in step 1 using a Grignard reagent and acetone. 3. Extending the carbon chain by converting the tertiary alcohol obtained in step 2 to a primary amine, which then reacts with formaldehyde to form an imine. 4. Hydrolysis of the imine compound obtained in step 3 to yield racemic ethyl 2-acetyl-5-oxohexanoate.

Step-by-step solution

Formation of an ester from ethanol

To form an ester from ethanol, we will carry out an esterification reaction with ethanoic acid or its anhydride in the presence of catalytic sulfuric acid: CH3CH2OH + CH3COOH --(H2SO4)--> CH3CH2OOCCH3

Formation of a carbon-carbon bond

Now we will form a Grignard reagent from the ester obtained in step 1. The Grignard reagent will then react with acetone to form a tertiary alcohol: 1. CH3CH2OOCCH3 + Mg --(ether)--> CH3CH2OMgX, where X is halide (use dry ether to dissolve the Grignard reagent) 2. CH3CH2OMgX + CH3COCH3 --(ether)--> CH3CH2CH(OH)CH2COCH3

Extending the carbon chain - formation of imine with formaldehyde

First, we will prepare a primary amine (RNH2) from the tertiary alcohol obtained in step 2, and then react it with formaldehyde to form an imine. For this, we will carry out a two-step process: 1. CH3CH2CH(OH)CH2COCH3 --(SOCl2)--> CH3CH2CH(Cl)CH2COCH3 - convert alcohol to a chloro compound 2. CH3CH2CH(Cl)CH2COCH3 + 2NH3 --(Zn/Hg or Pd-C, reduction)--> CH3CH2CH(NH2)CH2COCH3 + HCl - convert chloro compound to amine 3. CH3CH2CH(NH2)CH2COCH3 + HCHO --(HCl)--> CH3CH2CH = NCH2CH2COCH3 - imine formation with formaldehyde

Hydrolysis of the imine to yield the final product

At this point, we will carry out a hydrolysis on the imine compound obtained in step 3 to yield the racemic ethyl 2-acetyl-5-oxohexanoate: CH3CH2CH = NCH2CH2COCH3 --(H3O+)--> CH3CH2CH(OH)CH2CH2COCH3 + NH3 - this reaction yields racemic ethyl 2-acetyl-5-oxohexanoate since hydrolysis of the imine creates a stereocenter that leads to the respective (R)- and (S)-enantiomers in a 1:1 ratio. The final product is racemic ethyl 2-acetyl-5-oxohexanoate, obtained from ethanol, formaldehyde, and acetone as sources of carbon atoms.

Key concepts

Esterification

Esterification is a chemical process responsible for forming an ester. This happens through the reaction of an alcohol and a carboxylic acid.
A catalyst, such as sulfuric acid (\( ext{H}_2 ext{SO}_4 \)), is typically used to speed up the reaction.
Here’s how it works: the hydroxyl group (OH) from the alcohol and the hydrogen (H) from the acid are removed to produce water,
leaving behind an ester linkage between the carbon of the acid and the oxygen of the alcohol.

• The general form of the reaction is: \( ext{R-OH} + ext{R'-COOH} ightarrow ext{R-COO-R'} + ext{H}_2 ext{O} \)
  
• In the exercise, ethanol reacts with ethanoic acid with the help of sulfuric acid to form an ester like ethyl acetate.
  

This is an essential step because it builds the initial structure needed for further reactions, such as forming a Grignard reagent.

Grignard Reagent

A Grignard reagent is an organic compound consisting of magnesium and a halogen, bonded to a carbon group.
It’s a powerful tool in organic synthesis for forming carbon-carbon bonds.
These reagents are created when an organohalide reacts with magnesium in dry ether. \( ext{R-X} + ext{Mg} ightarrow ext{R-Mg-X} \), where X is a halogen like Cl, Br, or I.

• They readily react with carbonyl compounds (such as ketones and aldehydes) to form alcohols after protonation.
  
• In the exercise, our ester-derived Grignard reagent reacts with acetone to produce a tertiary alcohol, which sets the stage for further transformations.
  

This process involves not only creating important intermediates but also demonstrates mastery in managing moisture since water disrupts Grignard formation.

Imine Formation

Imine formation is a key reaction in organic chemistry where a carbon-nitrogen double bond is produced.
This typically involves an aldehyde or ketone reacting with a primary amine.
The imine group is represented as \( \text{R-C=N-R'} \).
This reaction first involves nucleophilic attack by the amine on the carbonyl carbon, and subsequently, water is removed.

• Imines are often intermediate steps in the synthesis of complex molecules.
  
• During imine formation in the exercise, formaldehyde reacts with an amine to extend the carbon chain towards forming the target molecule.
  

This process showcases how ketones can be transformed into precursors for various compounds by creating these versatile imine linkages.

Amino Group Reduction

Amino group reduction is a transformation that reduces a compound to produce an amine from a precursor molecule.
Typical reducing agents include hydrogen gas with a palladium catalyst (Pd-C) or zinc amalgam (Zn/Hg) with an acid which facilitate the reduction.

• This process provides a means to convert functional groups, such as nitro or chloro, into useful amines.
  
• In this exercise, a tertiary alcohol is first converted into a chlorinated compound which is then reduced to a primary amine using Zn/Hg and hydrochloric acid.
  

The resulting amine is a key intermediate, allowing for further functional group transformations such as the aforementioned imine formation.

Racemization

Racemization refers to the process of converting an optically active compound into its racemic form.
This form contains equal amounts of two enantiomers, labeled (R) and (S), which are mirror images.
Racemization can occur through various methods such as acid or base catalysis during reaction.

• In synthesis, racemization is often undesired as it eradicates optical activity; however, it is crucial when producing a racemic mixture as the end goal.
  
• In the current exercise, the final product, racemic ethyl 2-acetyl-5-oxohexanoate, emerges from imine hydrolysis. This reaction's environment fosters the creation of a stereocenter, yielding a perfectly balanced racemic mixture.
  

This highlights the precision necessary during synthesis and how racemic mixtures offer distinct chemical properties useful across various applications.