Question

One problem with reductive amination as a method of amine synthesis is that by-products are sometimes obtained. For example, reductive amination of benzaldehyde with methylamine leads to a mixture of \(N\) -methylbenzylamine and \(N\) -methyldibenzylamine. How do you suppose the tertiary amine by-product is formed? Propose a mechanism.

Short answer

The tertiary amine forms when N-methylbenzylamine reacts again with benzaldehyde and is subsequently reduced.

Step-by-step solution

Mechanism Initiation with Imine Formation

Start by reacting benzaldehyde with methylamine to form an imine. Benzaldehyde, which has a carbonyl group, reacts with the nucleophilic lone pair on the nitrogen of methylamine. This reaction leads to the formation of an imine (a compound with a nitrogen double-bonded to a carbon) following the loss of water.

Reduction of the Imine

The imine formed in Step 1 is then reduced to form a secondary amine, in this case, N-methylbenzylamine. A reducing agent, such as sodium cyanoborohydride (NaBH3CN), is typically used to perform this reduction by donating electrons to the imine, breaking the carbon-nitrogen double bond and forming a secondary amine.

Formation of Tertiary Amine

The secondary amine (N-methylbenzylamine) can react with another molecule of benzaldehyde to undergo a second reductive amination. This reaction repeats the steps of imine formation and reduction, leading to the creation of a tertiary amine, N-methyldibenzylamine. Here, the secondary amine acts as the nucleophile attacking the carbonyl carbon of benzaldehyde again.

Completion of the Mechanism

After the formation of the imine with the secondary amine, the imine is reduced again by the reducing agent to form the tertiary amine. This secondary reaction competes with the initial primary reaction, leading to the by-product formation.

Key concepts

Amine Synthesis

Amine synthesis through reductive amination is an important technique in organic chemistry. It allows for the creation of primary, secondary, and tertiary amines by following a specific pathway of transformation. The process begins with the reaction of an aldehyde or ketone with a primary amine. This key step enables subsequent reduction through a reducing agent.

• Primary amines are formed by reducing an initially formed imine.
• Secondary amines are created when secondary imines undergo reduction.
• Tertiary amines are formed when secondary amines react further in a similar reductive manner.

Understanding the context and role of each component in amine synthesis makes it easier to predict and control the products obtained in a laboratory setting. Clear understanding helps chemists optimize reaction conditions to favor desired products.

Imine Formation

Imine formation is a key step in reductive amination. It occurs when a carbonyl compound such as an aldehyde or ketone interacts with an amine. Here, the nitrogen in the amine attacks the carbonyl carbon, forming a nitrogen-carbon double bond. This results in the creation of an imine, characterized by a double bond between carbon and nitrogen, after the release of a water molecule.
The reaction is generally facilitated by acidic conditions, helping to protonate the carbonyl oxygen, making the carbon more electrophilic. The loss of water is essential as it drives the reaction toward imine formation. Being an unstable intermediate, imines require further reduction to make stable amine products capable of significant chemical utility. This initial transformation is pivotal in the formation of various amine configurations.

By-product Mechanism

By-product formation in reductive amination can often complicate synthesis outcomes. Specifically, tertiary amines can appear as by-products due to secondary reactions of intermediates. During the reaction sequence:

• A secondary amine, like N-methylbenzylamine, may react with additional aldehyde molecules.
• This secondary amine can undergo another cycle of imine formation and reduction.

The tertiary amine by-product, such as N-methyldibenzylamine, is generated through this subsequent interaction. This occurs when there is an excess of aldehyde or inadequate control over reaction conditions. Therefore, by-products often arise from competitive pathways that essentially repeat primary reaction steps, utilizing newly formed secondary amines.

Tertiary Amine Formation

Tertiary amine formation happens in the additional pathways of reductive amination where secondary amines are present. It involves taking a secondary amine, like N-methylbenzylamine, and reacting it with an aldehyde to form a new imine, which then gets reduced to give a tertiary amine.

• The secondary amine acts once more as a nucleophile, targeting the carbonyl group of the aldehyde.
• An imine forms and is reduced a second time to yield the final tertiary amine product.

This transformation emphasizes why controlling reaction parameters—like the amount of aldehyde and reaction time—and understanding the properties of intermediate molecules is crucial. Achieving selective formation of tertiary amines without by-products depends on managing these reactions at every step.