Question

Propose a synthesis of the local anesthetic ambucaine from 4-nitrosalicylic acid, ethylene oxide, diethylamine, and 1-bromobutane.

Short answer

Answer: The synthetic route to create ambucaine from the given starting materials involves the following steps: 1. Esterification of 4-nitrosalicylic acid to form ethyl 4-nitrosalicylate. 2. Amide formation by reacting ethyl 4-nitrosalicylate with diethylamine. 3. Nucleophilic attack of the carbonyl group of the amide with ethylene oxide. 4. Halogenation to convert the alcohol to a bromide. 5. S_N2 reaction with diethylamine to form the tertiary amine. 6. Replacement reaction of the nitroso-group with 1-bromobutane to obtain ambucaine.

Step-by-step solution

Identify the structure of ambucaine

First, we need to determine the structure of ambucaine and identify which parts can be derived from the given starting materials. Ambucaine has the following structure: \n Ambucaine: \n O=C(N(CC)CC)CN(CC)CC \n Now, we can identify which parts of the structure can be obtained from the starting materials: 1. 4-nitrosalicylic acid: Can be used as the core ring structure with the carboxylic acid group attached. 2. Ethylene oxide: Can be used to create the linker between nitrogen atoms in the amide and tertiary amine. 3. Diethylamine: Can be used as the amine group attached to the carbonyl in the amide and the tertiary amine group. 4. 1-bromobutane: Can be used as the alkyl chain attached to the nitrogen in the tertiary amine group.

Synthesize ambucaine from the starting materials

Now we will propose a synthetic route to synthesize ambucaine from the given starting materials. 1. Convert 4-nitrosalicylic acid to ethyl 4-nitrosalicylate (esterification): \n React 4-nitrosalicylic acid with ethanol in the presence of a catalytic amount of sulfuric acid to form ethyl 4-nitrosalicylate. 2. Convert ethyl 4-nitrosalicylate to the corresponding amide (amide formation): \n React ethyl 4-nitrosalicylate with diethylamine in the presence of a suitable dehydrating agent (e.g., DCC, EDC, or DMAP) to form the corresponding amide. 3. Attack the carbonyl group of the amide with ethylene oxide (nucleophilic attack): \n Treat the amide synthesized in step 2 with ethylene oxide in the presence of a catalytic amount of an acid or base catalyst (e.g., sodium hydroxide or sulfuric acid). This reaction opens the ethylene oxide to create the linker between nitrogen atoms in the amide and tertiary amine. 4. Convert the alcohol to a bromide (halogenation): \n Treat the alcohol, resulting from the ethylene oxide attack in step 3, with POBr_3 in pyridine to convert it into the corresponding bromide. 5. Convert bromide to tertiary amine (S_N2 reaction with amine): \n React the bromide synthesized in step 4 with diethylamine in the presence of an acid or base catalyst (e.g., sodium hydroxide or potassium carbonate) to form the tertiary amine via an S_N2 reaction. 6. Convert the nitroso- group to an alkyl chain (replacement reaction): \n Treat the nitroso-containing molecule formed in step 5 with 1-bromobutane in the presence of an acid or base catalyst (e.g., sodium hydroxide or potassium carbonate) to form the final ambucaine product via another S_N2 reaction.