SolutionsLidocaine
Exercise 1
Chloroacetyl chloride is used in the first step of the synthesis of lidocaine. Why does the aniline react with the acyl chloride and not with the CH2Cl? What is the sodium acetate for?
Addition–elimination at the carbonyl of the acyl chloride is much faster than SN2 at the CH2Cl, especially with an aniline hindered by the two ortho methyls and of low nucleophilicity. The acetate neutralizes the HCl formed: without it, the aniline would be protonated and would no longer be nucleophilic.
Exercise 2
Procaine is 2-(diethylamino)ethyl 4-aminobenzoate. Propose its retrosynthesis and synthesis, and explain why its duration of action is shorter than that of lidocaine.
Disconnection of the ester: 4-aminobenzoic acid (with the NH2 as NO2: FGI) and 2-(diethylamino)ethanol, which comes from ethylene oxide and diethylamine. Synthesis: 4-nitrobenzoyl chloride + 2-(diethylamino)ethanol → ester; reduction of the nitro group (H2, Pd/C, or Fe/HCl) → procaine. Being an unhindered ester, it is quickly hydrolysed by plasma esterases; the hindered amide of lidocaine is much more resistant.