Meeting 8 (Lidocaine synthesis Part 1+2)

Meeting 8 (Condensed Key)

1. a. The reaction of iron(II) ions with borohydride can be described by

Note that the iron containing product in the reaction highly depends on various parameters i.e., the solvent used in the reaction. In the absence of oxygen, iron borohydride (Fe(BH₄)₂) or iron borides (FeB, Fe₂B) are formed.

b. The main advantage is the use of non-toxic iron versus the use of toxic stannous chloride (SnCl₂). In addition, lower amounts of concentrated acids (i.e., HCl, CH₃COOH) are used in the reaction. A disadvantage is that the reaction takes much longer (about one hour for the reduction using Fe(np) vs. 10 min (SnCl₂)) and also requires some heat while the reduction with stannous chloride is performed at room temperature.

c. The 'optimal temperature' for the reaction is about 40 ^oC (± 2^oC). At lower temperatures, the reaction proceeds too slow (requiring 2-4 hours) while at higher temperatures, the reaction of water with the iron nanoparticles appears to play a more important role as well, reducing the amount of available reducing agent for the reduction of the nitro compound.

d. The addition of solid sodium chloride increases the polarity of the aqueous layer and therefore decreases the solubility of the organic compounds (amine, nitro compound, etc.). This will make it easier to extract these compounds from the aqueous layer.

e. The gas chromatogram helps to determine the degree of conversion of the nitro compound to the amine. While the reaction usually displays conversion rates well over 90 %, in some cases the conversion rate is much lower due to improper temperature control, poor quality sodium borohydride, etc.

f. The crude consists of the xylidine (amine) and the nitro compound. The extraction of the organic layer with hydrochloric acid moves xylidine as xylidinium salt into the organic layer. The nitro compound remains in the organic layer.

2. a. The procedure in the reader asks to use 1.1 equivalents of the acyl chloride. The given amount of 2,6-dimethylaniline is equal to 12.4 mmol (=(1.50 g)/(121.18 g/mol). Thus, 13.6 mmol of α-chloroacetyl chloride should be used, which is equal to 1.08 mL (=(12.4 mmol*112.94 g/mol)/1.42 g/mL).

b. Acyl chlorides are very reactive and among other compounds also react with water (i.e., moisture) to form the corresponding carboxylic acid. The carboxylic acid reacts with the amine in an acid-base reaction, which results in the formation of a salt. The overall yield of the reaction decreases.

c. The addition of sodium acetate causes the anilide to precipitate because the protonated form of the anilide is deprotonated. The xylidinium salt is is not deprotonated under these conditions and remains in solution.

d. Any amount of water in the anilide will be detrimental to the formation of lidocaine. The water in the anilide reacts with diethylamine in an acid-base reaction. The resulting ammonium salt is not a nucleophile anymore.

e. The ¹H-NMR spectrum of the α-chloro-2,6-dimethylacetanilide displays a peak at δ=7.88 pm (1 H) for the amide proton and a methylene group at δ=4.20 ppm. The NH₂ group in 2,6-dimethylaniline is observed at δ=3.46 ppm and there is no methylene group.