Question

Rimantadine was among the first antiviral drugs to be licensed in the United States for use against the influenza \(A\) virus and in treating established illnesses. It is synthesized from adamantane by the following sequence (we discuss the chemistry of Step 1 in Chapter 8 and the chemistry of Step 5 in Section \(16.8 \mathrm{~A}\) ). Rimantidine is thought to exert its antiviral effect by blocking a late stage in the assembly of the virus. (a) Propose a mechanism for Step 2. Hint: As we shall see in Section 21.1A, reaction of a bromoalkane such as 1-bromoadamantane with aluminum bromide (a Lewis acid, Section 4.7) results in the formation of a carbocation and \(\mathrm{AlBr}_{4}{ }^{-}\). Assume that adamantyl cation is formed in Step 2 and proceed from there to describe a mechanism. (b) Account for the regioselectivity of carbon-carbon bond formation in Step 2 . (c) Describe experimental conditions to bring about Step \(S\). (d) Describe experimental conditions to bring about Step \(4 .\)

Short answer

Short Answer: (a) The mechanism for Step 2 involves the activation of the nitrile by the Lewis acid AlBr3, followed by nucleophilic attack by adamantane and rearrangement to form the carbon-carbon bond. (b) The regioselectivity of the carbon-carbon bond formation in Step 2 can be explained by the stability of the intermediates, where the formation of a new carbon-carbon bond with 1-position of adamantane leads to a more stable intermediate compared to other positions. (c) Experimental conditions for Step 3 likely involve the use of a reducing agent (such as a hydride donor) to reduce the nitrile to the amine, with the reaction carried out in a polar solvent at moderate temperature. (d) In Step 4, experimental conditions may include the use of a suitable electrophilic source of the amantadine substituent, such as alkyl halides or tosylates, with the reaction carried out under basic conditions to promote nucleophilic substitution at the amine nitrogen. Optimal conditions will depend on the specific electrophile chosen.

Step-by-step solution

1. Identify reactants and products

Note the structures of the reactants and products in Step 2 of the synthesis.

2. Identify the Lewis acid and its role

In this step, aluminum bromide (\(\mathrm{AlBr_3}\)) is mentioned as a Lewis acid. It plays a role in the formation of a carbocation and \(\mathrm{AlBr_{4}}^{-}\).

3. Write the stepwise mechanism

Using the given hint and knowledge of reaction mechanisms, write each step in the mechanism including the formation of intermediates and movement of electrons. (b) Regioselectivity of carbon-carbon bond formation in Step 2

1. Identify the key step in bond formation

In the proposed mechanism, point out the step where the new carbon-carbon bond is formed.

2. Analyze the stability of intermediates

Explain why one intermediate is more stable than other possible intermediates, leading to the observed regioselectivity in the reaction. (c) Experimental conditions for Step 3

1. Identify required reagents

Determine the reagents necessary for Step 3 based on the transformation occurring in the synthesis.

2. Define optimal reaction conditions

Describe the optimal temperature, solvent, and any other relevant conditions for the reaction to proceed efficiently. (d) Experimental conditions for Step 4

1. Identify required reagents

Determine the reagents necessary for Step 4 based on the transformation occurring in the synthesis.

2. Define optimal reaction conditions

Describe the optimal temperature, solvent, and any other relevant conditions for the reaction to proceed efficiently.

Key concepts

Reaction Mechanisms

Understanding the reaction mechanism is crucial for chemists to predict how different chemicals will interact with each other. In the context of rimantadine synthesis, the reaction mechanism involves a series of steps which dictate how reactants are transformed into products.

During Step 2, a Lewis acid, specifically aluminum bromide (\textbf{AlBr}\(_3\)), initiates the reaction. It does so by accepting an electron pair, forming a stable complex with the bromoalkane and facilitating the formation of a carbocation—this step shows the aluminum's role as a Lewis acid. The carbocation then acts as an electrophile, or an electron-seeking species, which is highly reactive and can easily form new bonds with other atoms or molecules, eventually leading to the desired product.

The beauty of studying reaction mechanisms lies in the ability to visualize each electron movement step by step, which is pivotal for synthesis strategies in organic chemistry.

Regioselectivity in Organic Chemistry

Regioselectivity is an essential concept in organic chemistry as it explains why certain chemical reactions produce one structural isomer over another. In rimantadine’s synthesis, regioselectivity is evident in Step 2 when forming the carbon-carbon bond. The prevailing outcome is largely influenced by the stability of the carbocation intermediate.

Generally, more substituted carbocations are more stable due to hyperconjugation and the inductive effect of adjacent carbon atoms. The specific positioning of atoms within the adamantane structure leads to particular carbon atoms being more favorable for bond formation. Understanding these electronic effects allows chemists to predict and influence the course of the reaction, ensuring the synthesis proceeds in the most efficient manner possible towards the target molecule.

Lewis Acids in Organic Reactions

Lewis acids play a pivotal role in organic synthesis. They are substances that can accept electron pairs, often facilitating the formation of new bonds by increasing the reactivity of other compounds. In Step 2 of the rimantadine synthesis, aluminum bromide acts as a Lewis acid, accepting electrons from 1-bromoadamantane and leading to the formation of an adamantyl cation and \textbf{AlBr}\(_4$$^-\).

This interaction exemplifies how Lewis acids can be used to generate carbocations, which are key intermediates in many organic reactions. The aluminum in \textbf{AlBr}\(_3\) possesses vacant p-orbitals that can overlap with the filled orbitals of the bromoalkane, enabling the transfer of electrons. Understanding the role of Lewis acids like aluminum bromide is fundamental for chemists to leverage their utility in synthesis design and develop novel pharmaceuticals.

Carbocation Intermediates

Carbocation intermediates are positively charged, carbon-containing ions that are formed when carbon atoms lose an electron pair. They are a common occurrence in many organic reactions, including the synthesis of rimantadine.

In the given reaction mechanism for Step 2, the formation of the adamantyl cation is a critical juncture. The stability of this intermediate directly affects the reaction's direction and efficiency. The adamantyl cation is stabilized by the three-dimensional structure of the adamantane, making certain reaction pathways more favorable than others.

Understanding the factors that stabilize carbocations—such as the inductive effect, resonance, and hyperconjugation—is vital, as these will dictate the regioselectivity and outcome of the reaction. The science of organic synthesis often revolves around the strategic generation and stabilization of carbocation intermediates to achieve complex molecular constructions.