Question

Nitriles of the type \(\mathrm{RCH}_{2} \mathrm{CN}\) undergo an addition reaction analogous to the aldol addition in the presence of strong bases such as lithium amide. Hydrolysis of the initial reaction product with dilute acid yields a cyanoketone, Show the steps that are involved in the mechanism of the over-all reaction and outline a scheme for its use to synthesize large-ring ketones of the type \(\left(\mathrm{CH}_{2}\right)_{n} \mathrm{C}=O\) from dinitriles of the type \(\mathrm{NC}\left(\mathrm{CH}_{2}\right)_{n} \mathrm{CN}\).

Short answer

In the presence of a strong base like lithium amide, nitriles (RCH2CN) undergo deprotonation, forming a nitrile anion which then performs a nucleophilic addition to another nitrile molecule. The resulting intermediate is hydrolyzed in the presence of dilute acid, forming a cyanoketone. To synthesize large-ring ketones from dinitriles, a similar reaction mechanism is followed, including deprotonation, nucleophilic addition, and hydrolysis, followed by an intramolecular cyclization reaction to form the desired large-ring ketone.

Step-by-step solution

Nitrile deprotonation

In the presence of a strong base such as lithium amide (\(\mathrm{LiNH}_{2}\)), the base abstracts the acidic α-hydrogen from the nitrile to generate the nitrile anion, as follows: \[\mathrm{RCH}_{2}\mathrm{CN} + \mathrm{LiNH}_{2} \rightarrow \mathrm{Li}^{+}\mathrm{RCHCN}^{-} + \mathrm{NH}_{3}\] Step 2: Nucleophilic Addition

Nucleophilic Addition

The resulting nitrile anion acts as a nucleophile and attacks another nitrile molecule at the electrophilic carbon of the nitrile group (C≡N). This reaction forms an intermediate, as shown below: \[\mathrm{Li}^{+}\mathrm{RCHCN}^{-} + \mathrm{RCH}_{2}\mathrm{CN} \rightarrow \mathrm{Li}^{+}\mathrm{RCH(CN)CH}_{2}\mathrm{CN}\] Step 3: Hydrolysis

Hydrolysis

Next, the intermediate from step 2 undergoes hydrolysis in the presence of dilute acid. The nitrile group is hydrolyzed to form a ketone, yielding the cyanoketone product: \[\mathrm{Li}^{+}\mathrm{RCH(CN)CH}_{2}\mathrm{CN} + 2\mathrm{H}_{2}\mathrm{O} \rightarrow \mathrm{RCH(CN)COCH}_{2}\mathrm{CN} + \mathrm{Li}^{+}\mathrm{OH}^{-}\] Step 4: Synthesis of Large-Ring Ketones

Synthesis of Large-Ring Ketones

To synthesize large-ring ketones of the type \(\left(\mathrm{CH}_{2}\right)_{n} \mathrm{C}=O\) from dinitriles of the type \(\mathrm{NC}\left(\mathrm{CH}_{2}\right)_{n} \mathrm{CN}\), we can follow a similar reaction mechanism. Initially, we would perform the similar reaction steps as discussed above (deprotonation of an α-hydrogen, nucleophilic addition, and hydrolysis). After obtaining the cyanoketone from the dinitrile, we would perform an intramolecular reaction to form the large ring ketone. A suitable reagent could then be used to close the cycle and form the large-ring ketone, such as a strong base followed by acid work-up. In summary, the overall process would involve the deprotonation, nucleophilic addition, and hydrolysis steps for the given dinitrile compound, followed by an intramolecular cyclization reaction to form the large-ring ketone.

Key concepts

Nucleophilic Addition

In organic chemistry, the process of nucleophilic addition is a crucial mechanism. It involves a nucleophile, which is a chemical species that donates an electron pair, attacking an electrophilic carbon, which is a carbon atom that accepts electron pairs. For nitriles like RCH₂CN, we see a nucleophilic addition when the nitrile anion, generated during deprotonation, attacks another nitrile molecule.
This attack occurs at the carbon of the nitrile group's C≡N bond. This step is vital as it leads to the formation of a new carbon-carbon bond, transitioning towards a more complex product. The result is an intermediate complex that sets the stage for subsequent reactions in the synthesis process. Understanding nucleophilic addition helps grasp how certain compounds are synthesized and how reaction mechanisms proceed.

Nitrile Hydrolysis

After nucleophilic addition, the next significant step involves hydrolysis. Hydrolysis is the chemical breakdown of a compound due to the reaction with water. In the context of our reaction, it is the nitrile group's conversion into a ketone through exposure to dilute acid.
This process involves adding water to the nitrile, breaking the carbon-nitrogen triple bond ( C≡N ), and substituting it with a carbonyl group (C=O). The outcome is the formation of a cyanoketone. Hydrolysis is crucial in the mechanism because it transforms the intermediate, formed post-nucleophilic addition, into a functional ketone. This transformation is key in synthetic routes that target complex organic compounds like large-ring ketones.

Deprotonation

Deprotonation is typically the preliminary step in many organic reactions involving nitriles. It involves the removal of a hydrogen atom from a molecule, turning it into a reactive anion. This is crucial because the anion acts as a nucleophile in the subsequent reaction steps.
In our mechanism, a strong base like lithium amide ( LiNH₂ ) abstracts the acidic α-hydrogen from the nitrile ( RCH₂CN ), forming an anionic species ( Li⁺RCHCN⁻ ). This nitrile anion is highly reactive and instrumental for the nucleophilic attack that follows in the next step. Deprotonation sets the groundwork for the reaction mechanism by creating a nucleophile ready to engage in further chemical transformations.

Large-Ring Ketone Synthesis

Synthesis of large-ring ketones is an intriguing application of these reaction mechanisms. To achieve this, one often starts with a dinitrile compound. After performing the established sequence of deprotonation, nucleophilic addition, and hydrolysis, the intermediate cyanoketone is formed.
The challenge lies in inducing the intramolecular cyclization to yield a large ring structure. This typically involves arranging a chemical environment conducive to the ring closure, often using another round of deprotonation followed by an acid work-up. The large-ring ketone synthesis is essential for producing intricate molecular structures found in natural and pharmaceutical compounds. Understanding the step-by-step mechanism provides valuable insight into constructing these complex molecules from simpler precursors.