Question

Amantadine is effective in preventing infections caused by the influenza A virus and in treating established illnesses. It is thought to block a late stage in the assembly of the virus. Amantadine is synthesized by treating 1-bromoadamantane with acetonitrile in sulfuric acid to give \(N\)-adamantylacetamide, which is then converted to amantadine. (a) Propose a mechanism for the transformation in Step \(1 .\) (b) Describe experimental conditions to bring about Step 2 .

Short answer

Answer: The proposed mechanism for the synthesis of Amantadine from 1-bromoadamantane includes protonation of acetonitrile by sulfuric acid and a nucleophilic substitution (SN2) reaction between protonated acetonitrile and 1-bromoadamantane, resulting in N-adamantylacetamide. To convert N-adamantylacetamide to Amantadine, experimental conditions include using a reducing agent like LiAlH4 or NaBH4 in a suitable solvent such as dry ether or THF under an inert atmosphere, followed by an acid/base work-up to isolate Amantadine from the reaction mixture.

Step-by-step solution

Propose a mechanism for Step 1

To propose the mechanism, we start by identifying the substrates, which are 1-bromoadamantane and acetonitrile, and the product, N-adamantylacetamide. The reaction proceeds as follows: 1. Protonation of acetonitrile by sulfuric acid, generating a more electrophilic species. 2. Nucleophilic substitution (SN2) reaction between the protonated acetonitrile and 1-bromoadamantane, resulting in the formation of N-adamantylacetamide and the release of a bromide ion. The overall mechanism can be summarized in the following equation: 1-bromoadamantane + Acetonitrile + H2SO4 -> N-adamantylacetamide + HBr

Experimental conditions for Step 2

To convert N-adamantylacetamide to Amantadine, a reduction reaction is needed. Experimental conditions for this reaction are as follows: 1. Use a reducing agent, such as Lithium Aluminum Hydride (LiAlH4) or Sodium Borohydride (NaBH4), to reduce the amide to amine. This step will generate Amantadine and a byproduct, depending on the reducing agent used. 2. Perform this reaction in a suitable solvent, such as dry ether or tetrahydrofuran (THF), under an inert atmosphere (e.g., nitrogen or argon) to avoid side reactions caused by the presence of oxygen. 3. After the completion of the reaction, perform an acid/base work-up to isolate Amantadine from the reaction mixture. Typically, this involves quenching the reaction with an aqueous acidic solution, followed by extraction with an organic solvent and subsequent purification steps (e.g., column chromatography or crystallization) to obtain Amantadine in its pure form. With this step-by-step procedure, you can synthesize Amantadine from 1-bromoadamantane through the intermediate N-adamantylacetamide.

Key concepts

Amantadine Synthesis

Amantadine, a medication effective against the influenza A virus, is intricately synthesized through a multi-step chemical process. To create Amantadine, chemists commence by treating 1-bromoadamantane with acetonitrile in the presence of sulfuric acid. This reaction leads to the formation of N-adamantylacetamide as an intermediate product.

The synthesis' success hinges on precise conditions and an understanding of reaction mechanisms, notably the SN2 reaction for the initial step. Converting the subsequent N-adamantylacetamide into Amantadine necessitates a reduction process. Chemists often employ strong reducing agents such as Lithium Aluminum Hydride (LiAlH₄) or Sodium Borohydride (NaBH₄) for this transformation. To complete the synthesis, the reaction is thoroughly monitored, and upon its conclusion, the Amantadine is meticulously isolated and purified.

SN2 Reaction Mechanism

The SN2 reaction mechanism, which stands for bimolecular nucleophilic substitution, is at the heart of the first step in synthesizing Amantadine. In an SN2 reaction, the nucleophilic attack and the departure of the leaving group occur simultaneously in one step. It characteristically proceeds with the nucleophile approaching the electrophilic carbon from the side opposite to the leaving group, leading to an inversion of stereochemistry called the 'backside attack'.

This is exemplified in the reaction between acetonitrile and 1-bromoadamantane, where acetonitrile, activated by protonation through sulfuric acid, acts as a nucleophile attacking the electron-deficient carbon atom bonded to the bromine (leaving group) in 1-bromoadamantane. The SN2 reaction's success often depends on factors such as the strength of the nucleophile, the nature of the leaving group, and the solvent used.

Nucleophilic Substitution

Nucleophilic substitution is a versatile reaction type in organic chemistry, wherein a nucleophile replaces a leaving group in a molecule. The SN2 mechanism is a classic example of this process. A nucleophile, rich in electrons, is attracted to an electrophilic center (usually a carbon with a good leaving group). The strength and speed of a nucleophilic substitution can be influenced by several factors, including the electrophilicity of the carbon center, the type of leaving group, and the solvent polarity.

In the context of Amantadine synthesis, acetonitrile acts as the nucleophile after gaining a proton from sulfuric acid, which increases its willingness to donate electrons. The electrophilic carbon in 1-bromoadamantane, bearing a bromine atom as a leaving group, is prone to nucleophilic attack, facilitating the substitution process necessary to form N-adamantylacetamide. This interplay of nucleophilic attack and leaving group departure is crucial for the correct progression of the Amantadine synthesis.

Reduction of Amides

Turning an amide into an amine, as in the latter stage of synthesizing Amantadine, involves a chemical reduction. Reduction reactions are pivotal in organic chemistry, and in the context of amides, they transform the carbonyl group (>C=O) of an amide to a primary (or secondary) amine (-NH₂).

Lithium Aluminum Hydride (LiAlH₄) or Sodium Borohydride (NaBH₄), used as reducing agents in the experimental conditions for the second step of Amantadine synthesis, deliver the hydride ions (H^-) necessary for this conversion. Agents like LiAlH₄ are highly reactive and can be used to reduce many kinds of organic compounds, including amides like N-adamantylacetamide.

The conditions under which the reduction is carried out are paramount. There must be an absence of water and air (oxygen) to prevent side reactions. Typically, the reaction is performed in an inert atmosphere using dry solvents like ether or tetrahydrofuran (THF). After the amide has been successfully reduced to an amine, further steps are taken to purify the resulted Amantadine, which will be used as a pharmaceutical agent.