[KAKA]

Hi guys, can anyone comment on my analysis so far on this synthesis reaction?

Despite having attached a diagram of the reaction, these questions require some knowledge of the synthesis process...so i have attached a website for those who havent seen this reaction before:
http://chemistry.bd.psu.edu/kociolek/images/lidocaine.pdf

These are some questions im trying to address:

1. Why is sodium acetate is used in step 1?

2. Why product 3 (the intermediate amide for the reaction, formed after step 1) is not soluble in acid even though it contains a nitrogen atom?

3. Why do we use a three-fold excess of diethylamine in step #2

4. Why do we use toluene as a solvent in step 2 and reflux?

5. Why is NaOH added after HCl in the extraction Lidocaine from toluene?

For question 1,
I thought that the sodium acetate is used to react with the side product HCl formed when the 2,6-dimethylaniline reacts with chloroacetyl chloride. This is as HCl will reaction with 2,6-dimethylaniline and form an insoluble salt, which will precipitate with product 3 (as shown in the attached diagram).

Sodium acetate added not only consumes the HCl, but also reacts with 2,6-dimethylaniline to form a salt which is soluble in aqueous acid. Therefore the precipitate, product 3, can be isolated without any impurities.

But i am quite confused...is 2,6-dimethylaniline soluble in aqueous acid? If 2,6-dimethylaniline is not soluble then its the sodium acetate which makes it soluble by forming a salt with it?

For q2,
really confused. Is it because the neighbouring carbonyl group makes N partial positive, reducing the availability of the lone pair for hydrogen bonding with water?

For q3,
Is it because diethylamine has to react with product 3 to form lidocaine and at the same time act as a base to neutralize the HCl side product formed from the reaction of product3 and diethylamine?

For q4,
sorry, no idea! couldnt find anything in books nor on the net!!! Though my guess is that toluene is a good solvent to dissolve these organic compounds and also play a part in the acid extraction of lidocaine since lidocaine is soluble in aq. acid and can be extracted from any unreacted reagents dissolved in toluene.

For q5,
As acid is added, lidocaine forms a lidocaine hydochloride salt which is soluble in aq. acid. This acid will be in a different phase from toluene in the aq. acid layer. After running out the aq. acid layer, we can add NaOH to neutralize the acid and obtain lidocaine product.

The step of acid extraction from toluene is often done by first adding acid and running out the aq. acid layer. Then adding water and running out the water layer. By combining the water layer and the aq. acid layer, we get a solution of lidocaine hydrochloride salt solution.

So i was wondering why specifically use an acid? why not just use water to extract lidocaine since lidocaine is soluble in water?

[lutesium]

1. I dont think so. It might be added to saturate the solution even more to allow the preticipation of the amide. Or you may be right to think that it consumes the HCl formed therefore allowing us to achieve our goal the freebase Amide.

2. Amides are generally insoluble in organic acids.

3. It is due to the price/yield constants I think. You use more of the reagent that's easier to produce.

4. Refluxing a solution is an absolute must to 'force' a reaction to get to completition. Toluene might be a good solvent for the reactants therefore it is used.

5. Its called freebasing. When a HCl salt of a Nitrogen containig compound is dissolved in water addition of NaOH will freebase it and the N containing compound will seperate as a freebase oil or crystal depending on the Melting Point.


Lutesium...