Question

Paraldehyde, a sedative and hypnotic agent, is prepared by treatment of acetaldehyde with an acidic catalyst. Propose a mechanism for the reaction.

Short answer

Paraldehyde forms through the acidic-catalyzed trimerization of acetaldehyde involving protonation, nucleophilic attack, and cyclization steps.

Step-by-step solution

Protonation of Acetaldehyde

The mechanism begins with the protonation of the carbonyl oxygen of acetaldehyde by the acidic catalyst. This increases the electrophilicity of the carbonyl carbon, making it more susceptible to nucleophilic attack.

Nucleophilic Attack

A molecule of acetaldehyde, acting as a nucleophile, attacks the electrophilic carbonyl carbon of the protonated acetaldehyde. This step results in the formation of a hemiacetal intermediate.

Deprotonation

The hemiacetal intermediate undergoes deprotonation, losing a hydrogen ion (proton) which can be temporarily taken up by the acidic catalyst. This forms an alkoxide intermediate.

Formation of Oxocarbenium Ion

The alkoxide intermediate rearranges and, in the presence of the acidic environment, regenerates the carbonyl group by losing water to form an oxocarbenium ion.

Repetition and Cyclization

Steps 1-4 are repeated for two more molecules of acetaldehyde. Each cycle of nucleophilic attack and proton transfer brings another acetaldehyde into the chain, forming a linear structure which eventually cyclizes to form the six-membered ring structure of paraldehyde.

Stabilization of Paraldehyde

Finally, the newly formed paraldehyde can undergo additional tautomerization or stabilization steps, involving shifts of protons or resonance structures, but the main carbon framework of the trimolecular cycle remains intact.

Key concepts

Protonation of Acetaldehyde

In the initial step of the reaction mechanism, acetaldehyde reacts with an acidic catalyst, which adds a proton to the acetaldehyde molecule. This protonation specifically targets the oxygen atom within the carbonyl group of acetaldehyde.

• Acetaldehyde, also known as ethanal, has a highly polar carbonyl group, meaning one atom (oxygen) is far more electronegative than the other (carbon).
• By protonating the oxygen atom, the molecule's overall electronegativity increases, making the carbonyl carbon highly susceptible to nucleophilic attacks.

Through this enhancement in electrophilicity, subsequent steps in the reaction mechanism are facilitated, leading to complex transformations.

Hemiacetal Intermediate

Once the acetaldehyde molecule is accessible for reaction, a nucleophilic acetaldehyde molecule attacks the electrophilic carbon atom of the protonated molecule. This specific nucleophilic reaction forms a particular compound called a hemiacetal intermediate.

• The term "hemiacetal" refers to a molecule featuring an alcohol (OH) group and an alkoxide group attached to the same carbon atom.
• This intermediate is a transient structural arrangement occurring during the formation of larger complex molecules.

The hemiacetal intermediate is not a permanent part of the final product but is a crucial step leading towards the construction of more stabilized structures, such as the oxocarbenium ion.

Nucleophilic Attack

Nucleophilic attack is a common reaction step wherein an electron-rich nucleophile targets and attacks an electron-poor electrophile, usually a positively charged ion or a polar molecule. In the acetaldehyde reaction mechanism, these nucleophilic attacks occur multiple times.

• The electron-rich acetaldehyde acts as a nucleophile, first attacking the protonated acetaldehyde's carbonyl carbon.
• This continuous attack continues through several steps to create and extend the molecular chain.

Each nucleophilic interaction helps elongate the sequence of acetaldehyde units, fostering the development of larger molecular assemblies that eventually transition into cyclic structures. These steps are critical for building complex molecules like paraldehyde.

Oxocarbenium Ion Formation

The rearrangement of the hemiacetal intermediate into an oxocarbenium ion is a complex process characterized by both the reformation of a carbonyl group and the expulsion of a water molecule. This transformation aids in stabilizing and setting the groundwork for cyclization.

• Oxocarbenium ions feature a positively charged carbon, typically formed by losing a bonded water molecule.
• The acidic environment provides the necessary conditions for this rearrangement to proceed smoothly and without disruption.

This oxocarbenium ion formation is a pivotal reaction step, essentially restructuring the molecular framework. It precedes the actual bonding of additional acetaldehyde molecules, culminating in the cyclic formation of paraldehyde.