Question

The Ritter reaction is especially valuable for the synthesis of \(3^{\circ}\) alkanamines. In fact, there are few alternative routes to them. This reaction is illustrated by the first step in the following sequence. In the second step, the Ritter product is hydrolyzed to the amine. (a) Propose a mechanism for the Ritter reaction. (b) What is the product of a Ritter reaction using acetonitrile, \(\mathrm{CH}_{3} \mathrm{CN}\), instead of \(\mathrm{HCN}\), followed by reduction of the Ritter product with lithium aluminum hydride?

Short answer

Answer: The final product would be a tertiary amine in which the nitrogen atom has an additional methyl group compared to the amine formed from the Ritter reaction with HCN.

Step-by-step solution

Activation of the nitrile by Lewis acid

The Lewis acid, such as AlCl3, coordinates to the lone pair of electrons on the nitrogen atom of the nitrile, making the carbon of the nitrile more electrophilic.

Nucleophilic attack of the haloalkane

The haloalkane attacks the electrophilic carbon of the activated nitrile, forming a new carbon-carbon bond and displacing the nitrogen atom as a leaving group (still coordinated to the Lewis acid).

Rearrangement and loss of halide ion

The nitrogen atom regains the electron pair from the Lewis acid, resulting in a carbocation intermediate. The carbocation then undergoes a rearrangement, with the neighboring group (R) migrating to the carbocation center and the halide ion leaving.

Formation of stable imine and regeneration of Lewis acid

The nitrogen atom attacks the new carbocation center, displacing the halide ion and forming a stable iminium ion, and the Lewis acid is regenerated.

Hydrolysis of imine to amine

Lastly, hydrolysis of the iminium ion with water occurs under acidic conditions, forming the final amine product. (b) Identifying the product of a Ritter reaction using acetonitrile instead of HCN, followed by the reduction of the Ritter product with lithium aluminum hydride:

The Ritter reaction with acetonitrile

With acetonitrile (CH3CN) instead of HCN, the iminium ion formed after the rearrangement step will have a methyl group attached to the nitrogen instead of a hydrogen. This iminium ion is the Ritter product.

Reduction of the Ritter product with lithium aluminum hydride

Treating the iminium ion (formed in step 1) with lithium aluminum hydride (LiAlH4) will reduce the iminium ion to the corresponding amine, which has an additional methyl group compared to the amine formed from the Ritter reaction with HCN. The final product would be an amine where a methyl group is added to the nitrogen atom, compared to the original amine formed from the Ritter reaction with HCN.

Key concepts

Synthesis of Alkanamines via Ritter Reaction

The Ritter reaction stands out as a versatile method for synthesizing tertiary alkanamines, particularly when there are limited alternative pathways. The process commences with the activation of a nitrile, which is typically a molecule like acetonitrile, by a Lewis acid such as aluminum chloride. This step is crucial because it makes the nitrile's carbon atom highly electrophilic, meaning it has a strong affinity for electrons and can readily react with nucleophiles, such as haloalkanes.

During the reaction, a haloalkane undergoes a nucleophilic attack, bonding to the carbon of the nitrile and displacing the nitrogen group. Following this, a rearrangement takes place resulting in the formation of an iminium ion. Finally, this iminium ion undergoes hydrolysis, liberating the desired tertiary amine. This approach offers a direct path to alkanamines, often with high efficiency.

Mechanism of Nucleophilic Attack in Ritter Reaction

In the Ritter reaction, the concept of nucleophilic attack is pivotal. It occurs when a haloalkane, which contains a halogen atom, acts as the nucleophile and seeks an electrophilic carbon to bond with. The activated nitrile, with its electron-deficient carbon, becomes the perfect target.

In step-by-step terms, after the addition of a Lewis acid, the haloalkane approaches and forms a bond with the nitrile's carbon, successfully displacing the nitrogen which remains loosely associated with the Lewis acid. This not only creates a new molecule but also sets the stage for further transformations that lead to the creation of an iminium ion, a crucial intermediate for synthesizing alkanamines.

Iminium Ion Hydrolysis in Ritter Reaction

The culmination of the Ritter reaction is the hydrolysis of the iminium ion, which results in the formation of an alkanamine. This step is vital as it transforms the intermediate, an iminium ion, into the final functional product, the tertiary amine. Hydrolysis takes place under acidic conditions where water reacts with the iminium ion, leading to the cleavage of the carbon-nitrogen double bond.

The addition of water introduces an -OH group to the iminium ion, which then further reacts to release a proton and form the final tertiary amine. The hydrolysis is facilitated by the acidic environment, which helps in proton transfer and stabilizes the reactants and products. This transformation underscores the importance of controlling reaction conditions to achieve the desired outcome in organic synthesis.