Question

Barbiturates are prepared by treating a derivative of diethyl malonate with urea in the presence of sodium ethoxide as a catalyst. Following is an equation for the preparation of barbital, a long-duration hypnotic and sedative, from diethyl diethylmalonate and urea. Barbital is prescribed under one of a dozen or more trade names. (a) Propose a mechanism for this reaction. (b) The \(\mathrm{p} K_{\mathrm{a}}\) of barbital is 7.4. Which is the most acidic hydrogen in this molecule? How do you account for its acidity?

Short answer

Question: Explain the preparation of barbital from diethyl diethylmalonate and urea. Identify the most acidic hydrogen in barbital and provide reasoning for its acidity, given its pKa value as 7.4. Answer: Barbital is prepared from diethyl diethylmalonate and urea through a reaction mechanism that involves the formation of a resonance-stabilized enolate ion, nucleophilic attack, proton transfers, and ring formation. The most acidic hydrogen in barbital is the one attached to the nitrogen atom within the ring. Its acidity is attributed to the stabilization of the resulting resonance-stabilized conjugate base and the electron-withdrawing nature of the adjacent carbonyl groups. This results in a relatively low pKa value of 7.4.

Step-by-step solution

Identify the starting materials and the product

The starting materials for this reaction are diethyl diethylmalonate and urea, and the product is barbital.

Propose a mechanism for the reaction

The mechanism for this reaction can be described as follows: 1. The sodium ethoxide acts as a base and deprotonates one of the acidic hydrogens in diethyl diethylmalonate, forming a resonance-stabilized enolate ion. 2. The enolate ion nucleophilically attacks the carbonyl carbon on urea, which leads to the formation of an intermediate and kicks out the amine group (NH2) as a leaving group, forming a new C-N bond. 3. Proton transfer occurs between the oxygen atom on the intermediate and the amine group that was kicked out in the previous step. This generates an intermediate imine-like species. 4. The imine-like species undergoes a proton transfer to produce a neutral imine product. 5. The protonated enolate ion from step 1 is regenerated through deprotonation by the sodium ethoxide base. This reaction step closes the 6-membered ring that forms the barbital structure. 6. The imine group is tautomerized into the final desired barbital structure.

Identify the most acidic hydrogen in barbital

In the molecule, the most acidic hydrogen is the one attached to the nitrogen atom within the ring. This is due to the fact that once this hydrogen ion is removed, the resulting negative charge formed on the nitrogen atom is stabilized through resonance structures. Therefore, the acidity of this hydrogen atom can be attributed to the stability of the resulting resonance-stabilized conjugate base.

Reason for the acidity of the most acidic hydrogen

The acidic nature of this hydrogen can be accounted for by the electron-withdrawing nature of the carbonyl groups (C=O) adjacent to the nitrogen atom. The carbonyl groups are highly electronegative and result in stabilization of the negative charge on the nitrogen atom in the conjugate base once the hydrogen ion is removed. This increased stabilization of the conjugate base results in the hydrogen having a relatively low pKa value of 7.4.

Key concepts

Diethyl Malonate

Diethyl malonate is a critical component in organic synthesis, commonly used as a building block in the preparation of barbiturates through its active methylene group. This active group is very important because it contains hydrogens that are relatively acidic, meaning they can be deprotonated easily. When diethyl malonate is used in reactions, it often undergoes a deprotonation step to form a resonance-stabilized enolate ion.

This ion is then ready to participate in further reactions, such as nucleophilic attack on other reactive groups. In the context of barbiturate synthesis, the enolate ion formed from diethyl malonate attacks the carbonyl carbon of urea, initiating a series of transformations that ultimately lead to the desired product.

To help students grasp this concept better, it's useful to visualize the process as the activation of a normally nonreactive carbon atom next to a carbonyl group, allowing it to participate in chemical reactions as a nucleophile or an electron-rich species.

Urea and Sodium Ethoxide Reaction

When urea, a compound with two amine groups (NH2), reacts with sodium ethoxide, a fascinating transformation occurs – a step critical in the synthesis of barbiturates. Sodium ethoxide serves as a strong base, deprotonating the acidic hydrogen from diethyl malonate to form the enolate ion. This ion then attacks urea, leading to a series of steps that build up the barbital structure.

Understanding this reaction requires a recognition of how the base facilitates the reaction by making the malonate more reactive. The initial step creates an enolate which is a strong nucleophile, capable of attacking the electrophilic carbonyl carbon of urea. This reaction is not only a great example of nucleophilic acyl substitution but also demonstrates how simple starting materials can be transformed into more complex compounds through a sequence of well-orchestrated steps.

Acidic Hydrogen in Barbiturates

Barbiturates possess a hydrogen which exhibits surprising acidity, particularly for a compound largely composed of carbon, nitrogen, and oxygen atoms. This hydrogen is located on a nitrogen atom within the ring structure of barbiturates. It's unusually acidic because, when deprotonated, the negative charge residing on the nitrogen can resonate throughout the molecule.

This resonance allows for distribution of the negative charge across several atoms, greatly stabilizing the anion and thus favoring the loss of the acidic hydrogen as a proton. It's critical for students to recognize that the acidity of a hydrogen atom is intimately related to the stability of its conjugate base – a key concept in acid-base chemistry which also applies here in the context of barbiturate chemistry.

Resonance Stabilization

Resonance stabilization is a pivotal concept in organic chemistry that explains the stability of molecules with conjugated systems of electrons. In the case of barbiturates, once the acidic hydrogen is removed, the resulting anion is stabilized by resonance. This means that the negative charge can be delocalized over the structure, reducing the energy of the molecule and making it more stable.

Through resonance, a compound has several structures of equivalent energy, and the actual distribution of electrons is a hybrid of these structures. For barbiturates, this delocalization is crucial as it explains why the acidic hydrogen is so easily deprotonated – because its removal leads to a highly stable conjugate base. Teaching this concept with the analogy of spreading out risk by diversifying investments can make it more relatable and easier to grasp for students.