Diethylamine Lidocaine

Figure 5.4. Stmctures of cocaine (the first local anaesthetic), the standard local anaesthetic agent lidocaine, and the model compounds aniline and diethylamine.

Local anesthetics make use of the lipophobic property of an aromatic amine moiety, or its acyl derivative, that links with a hydrophilic amino acid. The products include the anilide lidocaine, or 2-(diethylamino)-A-(2,6-dimethylphenyl)acetamide (153), the toluidine derivative prilocaine and the century-old procaine, 2-diethylaminoethyl 4-aminobenzoate (154)84. The ester is prepared by reacting p-aminobenzoic acid with ethylene chlorohydrin and diethylamine. 

Diethylamine, N-nitroso-. See N-Nitrosodiethylamine a-Diethylaminoaceto-2,6-xylidide. See Lidocaine... 

The reaction of the alkyl chloride 37 with diethylamine, which is an S[ 2 process (Sec. 14.2), completes the synthetic sequence and is another example of a selective reaction. In this case, nucleophilic attack at the carbonyl function of the amido group is disfavored relative to reaction at the a-carbon atom because of the disruption of amide resonance that would accompany attack at the carbonyl group. The diethylamine serves the dual roles of acting as a nucleophile and as a base in this step. Namely, it displaces a chloride ion from 37, and it reacts with the hydrogen chloride formed in the reaction (Eq. 21.23). Because of this latter reaction, it is necessary to use an excess of diethylamine in order to obtain high yields of lidocaine (25). 

What would be the expected effect on yield if only one mole of diethylamine per mole of 37 were used in the final step of the preparation of lidocaine Explain. 

Why does sulfuric acid protonate the nitrogen atom of the diethylamine group of lidocaine preferentially to that of the amido group, as shown by formation of 42 ... 

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