Question

Procaine (its hydrochloride is marketed as Novocain) was one of the first local anesthetics for infiltration and regional anesthesia. See "Chemical Connections: From Cocaine to Procaine and Beyond." According to the following retrosynthetic scheme, procaine can be synthesized from 4 -aminobenzoic acid, ethylene oxide, and diethylamine as sources of carbon atoms. Provide reagents and experimental conditions to carry out the synthesis of procaine from these three compounds.

Short answer

Question: Describe a synthetic route to procaine from 4-aminobenzoic acid, ethylene oxide, and diethylamine. Answer: To synthesize procaine from 4-aminobenzoic acid, ethylene oxide, and diethylamine, the following steps can be followed: 1. Convert 4-aminobenzoic acid to ethyl 4-aminobenzoate by reacting it with ethyl alcohol and an acid catalyst under reflux. 2. Protect the amine group on ethyl 4-aminobenzoate using acetic anhydride, forming N-acetyl-ethyl 4-aminobenzoate. 3. Attach the ethylene group by performing a Williamson ether synthesis with ethylene oxide and a base, yielding N-acetyl-ethyl 4-(2-hydroxyethylamino)benzoate. 4. React N-acetyl-ethyl 4-(2-hydroxyethylamino)benzoate with diethylamine and a strong base to form the tertiary amine group, resulting in N-acetyl-procaine. 5. Deprotect the amino group on N-acetyl-procaine using hydrochloric acid and heat under reflux to obtain the desired procaine molecule.

Step-by-step solution

Procaine consists of an aromatic ring (benzene) with an amine group (NH2) at position 4, an ester group at position 1, and a tertiary amine (diethylamino) group connected via an ethylene group (2 carbons) to the ester group. #Step 2: Identify the role of each starting material#

4-aminobenzoic acid provides the benzene ring and the amine group. Ethylene oxide provides the ethylene group, and diethylamine provides the tertiary amine group. #Step 3: Formation of the ester group#

Convert 4-aminobenzoic acid to ethyl 4-aminobenzoate

To convert 4-aminobenzoic acid into the corresponding ester, react 4-aminobenzoic acid with ethyl alcohol (CH3CH2OH) and a catalytic amount of an acid catalyst (e.g., concentrated sulfuric acid, H2SO4) under reflux. This forms ethyl 4-aminobenzoate. #Step 4: Protection of the amino group#

Protect the amine group on ethyl 4-aminobenzoate

The amino group can be protected using an acetyl group (CH3CO-) by reacting ethyl 4-aminobenzoate with acetic anhydride (CH3COOCOCH3) at room temperature. This forms N-acetyl-ethyl 4-aminobenzoate. #Step 5: Williamson ether synthesis#

React N-acetyl-ethyl 4-aminobenzoate with ethylene oxide

To attach the ethylene group, perform a Williamson ether synthesis by reacting N-acetyl-ethyl 4-aminobenzoate with ethylene oxide (CH2CH2O) in the presence of a base (e.g., potassium carbonate, K2CO3) and heat. The ester group on N-acetyl-ethyl 4-aminobenzoate acts as the leaving group, and a new ether linkage is formed with the ethylene group. The product is N-acetyl-ethyl 4-(2-hydroxyethylamino)benzoate. #Step 6: Reacting with diethylamine#

Form the tertiary amine group

React N-acetyl-ethyl 4-(2-hydroxyethylamino)benzoate with diethylamine (HNEt2) and a strong base (e.g., sodium hydride, NaH) to replace the hydroxy group with the diethylamine, forming N-acetyl-procaine. #Step 7: Deprotection of the amino group#

Deprotect the amino group on N-acetyl-procaine

Finally, to deprotect the amino group, react N-acetyl-procaine with a suitable deprotecting reagent like hydrochloric acid (HCl) and heat under reflux. This will remove the acetyl group and yield the desired procaine molecule.