Question

The following bicyclic ketone has two \(\alpha\)-carbons and three \(\alpha\)-hydrogens. When this molecule is treated with \(\mathrm{D}_{2} \mathrm{O}\) in the presence of an acid catalyst, only two of the three \(\alpha\)-hydrogens exchange with deuterium. The \(\alpha\)-hydrogen at the bridgehead does not exchange.

Short answer

Short Answer: When a bicyclic ketone with two α-carbons and three α-hydrogens is treated with D2O in the presence of an acid catalyst, only two of the three α-hydrogens exchange with deuterium because the base has a hard time accessing the bridgehead hydrogen due to steric hindrance. This restriction prevents enolization at the bridgehead position, leading to selective deuteration where only two α-hydrogens are replaced with deuterium.

Step-by-step solution

Understanding the given bicyclic ketone

Look at the structure of the bicyclic ketone - it has a carbonyl group, two α-carbons (adjacent to the carbonyl group), and three α-hydrogens. We also know that the bridgehead hydrogen does not participate in the reaction.

Analyzing the deuterium exchange reaction

When the bicyclic ketone is treated with D2O in the presence of an acid catalyst, an enolization reaction occurs where the α-hydrogens (except for the bridgehead hydrogen) exchange with deuterium from D2O. The acid catalyst protonates the carbonyl oxygen, making the carbonyl carbon more electropositive and more susceptible to attack by a nucleophile (a qualified base). The base reacts with these α-hydrogens and forms an enolate intermediate, which then reacts with D2O, substituting the α-hydrogen with deuterium.

Understanding why the bridgehead hydrogen does not exchange

The bridgehead hydrogen does not participate in the reaction because it is in a more sterically hindered environment compared to the other two α-hydrogens. The base would have difficulty accessing the bridgehead hydrogen due to the crowded nature of this position, preventing enolization of the molecule at that site. This steric hindrance restricts the reaction from happening at the bridgehead position, and therefore, only two of the three α-hydrogens are able to exchange with deuterium.

Writing the overall reaction

The overall deuterium exchange reaction can be written as follows: Ketone + D2O + Acid Catalyst -> Transient Enolate Intermediate -> Deuterated Ketone (2 of the 3 α-hydrogens replaced with deuterium) This reaction demonstrates the selective deuteration of the bicyclic ketone, where only two of the three α-hydrogens are replaced with deuterium, and the bridgehead hydrogen remains unchanged due to steric hindrance.

Key concepts

Deuterium Exchange

Deuterium exchange is a fascinating chemical process where hydrogen atoms in a molecule are replaced by deuterium. In our example, a bicyclic ketone undergoes this reaction when exposed to deuterium oxide ( D_2O), aided by an acid catalyst.

Here's how it works:

• The acid catalyst protonates the carbonyl oxygen, making the ketone more reactive.
• The α-hydrogens (those on the carbons next to the carbonyl group) become susceptible to nucleophilic attack.
• An enolate intermediate is formed, which facilitates the exchange of α-hydrogens with deuterium from the D_2O.

Importantly, this exchange does not occur at the bridgehead hydrogen because of its unique position and surrounding environment.

Bicyclic Ketone

Bicyclic ketones are a type of organic compound featuring two connected ring structures. Their distinctive architecture influences chemical reactivity and selectivity.

The bicyclic ketone in our case has two α-carbons and three α-hydrogens. These hydrogens are crucial for the enolization reaction leading to deuterium exchange.

The bridgehead position, a key structural feature here, contributes to the complexity of reactions due to its less accessible location. This inaccessibility plays a crucial role in why some hydrogens don't undergo deuterium exchange.

Steric Hindrance

Steric hindrance is a concept that refers to the physical blocking of reactive sites in a molecule by surrounding atoms or groups. In the deuterium exchange of our bicyclic ketone, steric hindrance is particularly crucial.

Here's why it matters:

• The bridgehead hydrogen is blocked by the complex structure around it.
• This prevents the base from accessing and attacking this hydrogen during the reaction.

Thus, only two of the three α-hydrogens participate in the exchange process with deuterium, while the bridgehead hydrogen remains unchanged.

Enolate Intermediate

During the deuterium exchange reaction, an enolate intermediate forms, which is a crucial step in the process.

An enolate is a negatively charged species generated by removing an α-hydrogen from a carbon next to a carbonyl group.

Its formation is essential because:

• It creates a reactive site that allows the α-hydrogen to be replaced by deuterium.
• It is stabilized by resonance with the carbonyl group, which aids in the substitution.

The enolate's role emphasizes the interplay between structure and reactivity, enabling selective deuterium incorporation in the ketone.