Question

N-Nitrosamines by themselves are not significant carcinogens. However, they are activated in the liver by a class of iron-containing enzymes (members of the cytochrome P-450 family). Activation involves the oxidation of a \(\mathrm{C}-\mathrm{H}\) bond next to the amine nitrogen to a \(\mathrm{C}-\mathrm{OH}\) group. \(N\)-Nitroso- piperidine \(\begin{array}{cc}\text { 2-Hydroxy- } N \text { - } & \text { An alkyl diazonium ion } \\ \text { nitrosopiperidine } & \text { (a carcinogen) }\end{array}\) Show how this hydroxylation product can be transformed into an alkyl diazonium ion, an active alkylating agent and therefore a carcinogen, in the presence of an acid catalyst.

Short answer

Question: Describe the transformation of 2-Hydroxy-N-nitrosopiperidine into an alkyl diazonium ion in the presence of an acid catalyst. Answer: In the presence of an acid catalyst, 2-Hydroxy-N-nitrosopiperidine undergoes a series of reactions leading to the formation of an alkyl diazonium ion. The acid catalyst protonates the hydroxyl group, forming a good leaving group (H2O) and a carbocation intermediate. The nitrogen atom from the N-nitrosamine moiety then attacks the carbocation, forming a positively charged three-membered ring. Finally, a rearrangement occurs within the ring, creating a nitrogen-nitrogen double bond and releasing a water molecule, resulting in the formation of the alkyl diazonium ion, an active alkylating agent and carcinogen.

Step-by-step solution

Draw the structure of the 2-Hydroxy-N-nitrosopiperidine

First, draw the structure of the 2-Hydroxy-N-nitrosopiperidine, identifying the key functional groups, such as the hydroxyl (-OH) group next to the amine nitrogen.

Add the acid catalyst to the reaction

Introduce an acid catalyst (H+) to the reaction. The acid catalyst will protonate the hydroxyl group (-OH), producing a good leaving group (H2O) and increasing the nucleophilicity of the nitrogen atom.

Formation of a carbocation intermediate

With the help of the acid catalyst, the hydroxyl group (-OH) leaves as a water molecule (H2O), creating a carbocation at the carbon that previously was bound to the hydroxyl group (-OH).

Nucleophilic attack by the nitrogen atom

The nitrogen atom from the N-nitrosamine moiety acts as a nucleophile and attacks the carbocation generated in Step 3. This forms a three-membered ring containing a positively charged nitrogen atom.

Formation of the alkyl diazonium ion

Lastly, the three-membered ring undergoes a rearrangement, where a nitrogen-nitrogen double bond is formed, and one of the nitrogen atoms is protonated, releasing a water molecule (H2O) in the process. The final product is the alkyl diazonium ion, an active alkylating agent and carcinogen.