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

Based on the step-by-step solution provided above: a) Propose a mechanism for the synthesis of N-adamantylacetamide from 1-bromoadamantane and acetonitrile in sulfuric acid. The mechanism for this synthesis involves three steps: 1. Protonation of acetonitrile in the presence of sulfuric acid 2. Nucleophilic attack by 1-bromoadamantane on protonated acetonitrile, forming an intermediate complex and releasing a bromide ion 3. Deprotonation of the intermediate complex by a bromide or bisulfate ion, resulting in the formation of N-adamantylacetamide b) Describe experimental conditions to convert N-adamantylacetamide to amantadine. To convert N-adamantylacetamide to amantadine, follow these steps: 1. Reduction of N-adamantylacetamide using lithium aluminum hydride (LiAlH4) in an ether solvent (diethyl ether), and heating the mixture to reflux for an appropriate amount of time 2. Hydrolysis to remove excess lithium aluminum hydride by quenching the reaction mixture with water or aqueous acid 3. Isolation and purification of amantadine through methods such as evaporation or extraction, followed by purification techniques like crystallization, chromatography, or distillation.

Step-by-step solution

(a) Proposed Mechanism for the Synthesis of \(N\)-adamantylacetamide

The transformation of 1-bromoadamantane to \(N\)-adamantylacetamide proceeds as follows: Step 1: Protonation of acetonitrile In the presence of sulfuric acid, the acetonitrile molecule will be protonated at the nitrogen atom. \[H_2SO_4 + CH_3CN \rightarrow CH_3CNH^+ + HSO_4^-\] Step 2: Nucleophilic attack by 1-bromoadamantane 1-bromoadamantane acts as a nucleophile and attacks the protonated nitrogen atom in the protonated acetonitrile to form a cationic, intermediate complex. Simultaneously, a bromide ion is released. \[CH_3CNH^+ + BrC_{10}H_{15} \rightarrow [CH_3C(NH_2)C_{10}H_{15}]^+Br^-\] Step 3: Deprotonation of the intermediate complex A bromide ion or bisulfate ion acts as a base, deprotonating the nitrogen atom of the intermediate complex and creating \(N\)-adamantylacetamide. \[[CH_3C(NH_2)C_{10}H_{15}]^+Br^- \rightarrow BrC_{10}H_{15} - CH_3CONH_2 + HBr\]

(b) Experimental Conditions for Step 2

To convert \(N\)-adamantylacetamide to amantadine, we will proceed with the following steps: Step 1: Reduction of \(N\)-adamantylacetamide To reduce the amide group to an amine group, use a reducing agent such as lithium aluminum hydride (LiAlH4) in an ether solvent like diethyl ether. Heat the mixture to reflux (boil and condense the solvent back into the reaction) for an appropriate amount of time. \[C_{10}H_{15} - CH_3CONH_2 + 4 \ LiAlH_4 \rightarrow C_{10}H_{15} - CH_3CH_2NH_2 + 4 \ LiAlH_3O\] Step 2: Hydrolysis To remove the excess lithium aluminum hydride, quench the reaction mixture with water or aqueous acid. \[LiAlH_3O + 4 \ H_2O \rightarrow LiOH + Al(OH)_3 + 4 \ H_2\] Step 3: Isolation and purification of amantadine Remove the solvent through evaporation or extraction, followed by purification methods such as crystallization, chromatography, or distillation.

Key concepts

Organic Synthesis Mechanism

Understanding the mechanism behind an organic synthesis is crucial for achieving desired outcomes in chemical reactions. It involves predicting the movement of electrons to form new bonds or break existing ones, and it's a foundation block for organic chemistry.
In the case of amantadine synthesis, it starts with protonation, which makes a molecule more reactive and prepares it for the next step: a nucleophilic attack. This is when a nucleophile replaces a group on another molecule, typically resulting in a new product. These steps, demonstrated in the creation of N-adamantylacetamide from 1-bromoadamantane, follows a clear sequence of protonation, nucleophilic attack, and deprotonation.
Understanding this flow is key, as it shows how specific reagents and conditions can influence the results. For example, sulfuric acid's role as both a catalyst and reagent in the protonation of acetonitrile simplifies the transformation process, illustrating the careful orchestration of multiple components in synthesis mechanisms.

Nucleophilic Substitution Reaction

Nucleophilic substitution is a type of reaction central to the field of organic chemistry. In such reactions, a nucleophile, which is a species rich in electrons, targets and attacks a positive or partially positive charge on another molecule, known as the electrophile.
The synthesis of amantadine showcases a nucleophilic substitution when 1-bromoadamantane, the nucleophile, attacks the protonated acetonitrile. This leads to the bromide ion's departure and forms an intermediate complex before ultimately yielding N-adamantylacetamide. These reactions are characterized by their two-step mechanism involving attack and loss, where the right conditions, such as the presence of a good leaving group like the bromide ion, are essential for success.

Key Takeaways of Nucleophilic Substitution

• A nucleophile is electron-rich and seeks positive charges.
• The electrophile must possess a suitable leaving group to be replaced.
• Reagents and solvent can dictate the reaction's course and rate.

It’s the understanding of these principles that aids students in predicting reaction outcomes and experimenting with synthesis in the lab.

Amantadine Synthesis Conditions

The successful synthesis of a compound like amantadine requires specific and controlled conditions to guide the reaction steps in the desired direction. These conditions often involve temperature, pH, solvent choice, and the presence of catalysts or special reagents.
For instance, to form N-adamantylacetamide, a protonated environment achieved with sulfuric acid is necessary, initiating the overall reaction. Next, the conversion of N-adamantylacetamide to amantadine necessitates a reducing environment furnished by a potent reducing agent like lithium aluminum hydride (LiAlH4). Additionally, refluxing the reaction helps to drive the transformation to completion by maintaining a consistent temperature.

Essential Factors in Synthesis Conditions

• Correct reagent selection for specific reaction steps.
• Proper solvent that will dissolve the reactants and transfer heat efficiently.
• Meticulous temperature control to optimize the reaction rate and yield.

Careful attention to these factors ensures the synthesis proceeds smoothly, yielding the desired amantadine, and emphasizing the influence of conditions on reaction success.

Reduction Reactions in Organic Chemistry

Reduction reactions are pivotal in organic chemistry, as they involve gaining electrons or losing oxygen to convert functional groups to more hydrogenated forms. In the process of synthesizing amantadine, a reduction plays a vital role when transforming an amide into an amine.
Using lithium aluminum hydride (LiAlH4), one of the most common and powerful reducing agents, converts the N-adamantylacetamide into amantadine by adding hydrogens to the nitrogen in the amide group. This type of chemical reduction is crucial for altering the reactivity and properties of molecules, rendering them useful for various applications, including pharmaceuticals.

Reduction Reaction Highlights

• Electron-rich reagents are necessary to reduce compounds effectively.
• Choice of solvent can influence the reaction's effectiveness and safety.
• Controlling the addition of water or aqueous acid is paramount to prevent violent reactions when quenching excess reducing agents.

This reduction step in the synthesis of amantadine illustrates how introducing hydrogens can fundamentally change a molecule, spotlighting the transformative power of reduction in organic synthesis.