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CHEM 286L Organic Chemistry Laboratory II

Synthesis of Lidocaine (Part 1)

Introduction Lidocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to
relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic, and in minor surgery. The most commonly encountered lidocaine preparations are marketed under the brand names Xylocaine and Xylocard.

Chemical reaction

In the first step of your experiment, -chloro-2,6-dimethylacetanilide is synthesized by the reaction of 2,6-dimethylaniline with chloroacetyl chloride. The desired product, lidocaine, is then obtained in the reaction between -chloro-2,6-dimethylacetanilide and diethylamine (see chemical reaction).

CH3 NH2 Cl CH3 2,6-dimethylaniline

O Cl

CH3

H N O CH3 HNEt2

Cl

CH3

H N O CH3

CH3 CH3

Lidocaine

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Textbook reference

The first reaction, between 2,6-dimethylaniline and chloroacetyl chloride, is an example of a nucleophilic acyl substitution reaction in which the attacking nuclephile is a neutral species.

O C

+ Nu-H

O R C Y Nu B H

O R C Y Nu HB

O C

+ Y Nu

Safety Concerns

Aniline and its derivatives are very harmful if inhaled, ingested, or absorbed through the skin. Some aromatic amines may be potentially carcinogenic Wear gloves and dispense aniline in the fumehood; avoid contact and do not inhale its vapors. Chloroacetyl chloride is very corrosive, its vapors are irritating and toxic and it is a lacrymator (tearing agent). Use gloves and dispense it in the fumehood ONLY! Avoid contact and do not breathe its vapors.

Procedure Part A Step 1

Synthesis of -chloro-2,6-dimethylacetanilide
In a beaker, prepare a solution by dissolving 0.75 g of sodium acetate in 15 mL of water. Carry out the following reaction in the fumehood.

Step 2
To a 50 mL Erlenmeyer flask, add 0.5 g dimethylaniline (handed out preweighed), 3.6 mL of glacial acetic acid and 0.37 mL of chloroacetyl chloride, in that order. Chloroacetyl chloride has highly irritating vapors and should be dispensed and transferred in the fumehood.

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Warm the solution in a water bath to 40-50C, remove and add the sodium acetate solution.

Step 3

Cool the mixture and collect the product on a Hirsch funnel. Rinse the solid on the funnel with water until the acetic acid odor is gone and dry as much as possible by pressing and drawing air through the filter cake on the funnel for about 15 min. Transfer the product to a large filter paper, place it under a heating lamp, finely divide it with a spatula and let it air-dry for about 1015 min.

Step 4

Weigh the product, then transfer 0.30 g of the -chloro-2,6-dimethylacetanilide into a 10 mL round-bottom flask and start the reflux for Part B of the lidocaine synthesis (see below). During the reflux, determine the melting point of -chloro-2,6-dimethylacetanilide, prepare an IR and calculate the percentage yield.

Part B

Synthesis of a-Diethylamino-2,6-dimethyl-acetanilide (Lidocaine)

In a 10-mL round-bottom flask, place 0.3 g of -chloro-2,6-dimethylacetanilide obtained from the preceding experiment, 4.5 mL of toluene and a stirbar.. Using a graduated pipette, measure 0.42 mL diethylamine and add it to the reaction mixture. Attach a reflux condenser to the 10-mL round-bottom flask and reflux vigorously for 60 minutes.

Step 1

Step 2

After 60 minutes of refluxing, allow the reaction mixture to cool to room temperature, remove the reflux condenser and cap the round bottomed flask. Draw a line with a permanent marker on the flask in order to mark the level of the liquid. Store the reaction flask in a beaker inside your drawer.

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Set-up

Water out Jacketed condenser Water in

Round bottom flask

Stir bar

Questions and Exercises

1. What is the purpose of adding the glacial acetic acid to your reaction mixture (in step 1 of part A)? 2. Write the formula and name the compound isolated as crystals in step 2 of part B. 3. Identify the limiting reagent in the synthesis of lidocaine (part B). Show calculations. 4. There are two nitrogen atoms in the structure of lidocaine (labeled a, b). Which nitrogen atom is the most basic? Explain.
CH3

(not mandatory, for your practice)

H N (a) O CH3

(b) N

CH3

CH3

Lidocaine

5. Write the reaction mechanism for both reactions.