Synthesis of Racemic M3t HCl by the L3uckart Method (The Complete Guide)

Introduction

Introduction

Welcome TDC viewers. In this video, I will be synthesizing N-methyl-1-phenylpropan-2-amine by the Lückart method. There are numerous routes to producing N-methyl-1-phenylpropan-2-amine, such as the reductive amination method utilizing aluminum-mercury amalgam and the Lückart method.

The Lückart reaction involves converting an alpha-ketone into the corresponding amine by heating with either ammonium formate or formamide as the nitrogen donor and reducing agent. It requires high temperatures over 165°C for the former variant to start the synthesis.

Materials and Setup

To start the synthesis, add 5.4 mL of 1-phenyl-2-propanone into a suitable flask with stirring. Add 13.4 mL of N-methyl formamide into the flask. The mixture has a clear light yellow color.

Next, prepare for heating under reflux. Attach a Liebig condenser to the flask and a calcium chloride drying tube to the end of it. Connect a cold water pump to the condenser and turn the pump on. Stir the mixture and heat it to 165°C. Wrap the flask with aluminum foil and heat the reaction mixture at 165°C for 36 hours.

Observation

• 1 hour: The reaction mixture turns light orange.
• 6 hours: The mixture turns red.
• 11 hours: The mixture becomes deep red.
• 24 hours: The mixture resembles a darker polar color.
• 36 hours: The reaction is complete. Remove the aluminum foil and turn off the heating. Allow the mixture to cool to room temperature.

Chemical Reaction Explanation

At this point, 1-phenyl-2-propanone reacts with N-methyl formamide at 165°C over 36 hours to produce N-methyl-N1-phenylpropan-2-formamide. The Lückart method has been satisfactorily applied to many ketones and alkyl groups.

Post-Reaction Processing

Once the reaction mixture is cooled, add 24 mL of 10M sodium hydroxide solution into the flask. Start stirring and reflux the reaction mixture for 2 hours, wrapping the flask again with aluminum foil. After 1 hour, the mixture becomes reddish-brown. After 2 hours, turn off the heating and allow the mixture to cool to room temperature. Two layers will form: an organic layer (top) and an aqueous layer (bottom). Pour the contents into a separatory funnel and extract the bottom aqueous layer, discarding it.

To the extracted organic layer, add 12.4 mL of 32% hydrochloric acid solution, which emits white smoke. Stir and set up for reflux for another 2 hours while wrapping the flask with aluminum foil. The reaction mixture turns dark green, indicating the formation of crude N-methyl-1-phenylpropan-2-amine hydrochloride solution.

Base Conversion

Slowly add around 30 mL of 8.3M sodium hydroxide solution into the crude mixture, maintaining a pH around 12. The mixture emits white smoke and warms up. The mixture turns into a brown-colored oil, which is the crude racemic N-methyl-1-phenylpropan-2-amine base.

Extraction and Purification

Extract the crude base three times with 20 mL of diethyl ether, combining the organic layers. Dry the solution over anhydrous magnesium sulfate. Filter the dried solution through some cotton wool. The resulting solution should contain purified racemic N-methyl-1-phenylpropan-2-amine base. Convert this base to the hydrochloride salt by bubbling anhydrous hydrochloric acid gas through the solution until a precipitate forms. Use a hydrochloric acid gas generator built by dropping 98% concentrated sulfuric acid into sodium chloride powder.

After forming the solids, remove the diethyl ether under vacuum or by slow heating. The final product is a dark, thick, waxy brown solid. Distillation of the base under vacuum is required for further purification.

Verification

To verify the product, conduct the Mandelin test. The test reagent, composed of ammonium vanadate and concentrated sulfuric acid, changes color from yellow to dark olive green upon contact with the product, confirming its identity. Transfer the product into a glass vial, yielding 1.5 grams. Store the product in a dark, cool, and dry place.

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Keywords

• N-methyl-1-phenylpropan-2-amine
• Lückart reaction
• alpha-ketone
• ammonium formate
• formamide
• hydrochloric acid gas
• sodium hydroxide
• diethyl ether
• Mandelin test

FAQ

1. What is the Lückart reaction?

The Lückart reaction is a method of converting an alpha-ketone into the corresponding amine by heating with either ammonium formate or formamide as the nitrogen donor and reducing agent.

2. What is the significance of using high temperatures in this synthesis?

High temperatures, over 165°C, are required for the Lückart reaction to progress effectively in converting 1-phenyl-2-propanone to N-methyl-1-phenylpropan-2-amine.

3. Why is it necessary to use a separatory funnel during the extraction step?

A separatory funnel is used to separate the aqueous layer from the organic layer efficiently, ensuring the correct extraction of the desired compound.

4. How can the presence of N-methyl-1-phenylpropan-2-amine be verified?

The presence of N-methyl-1-phenylpropan-2-amine can be verified using the Mandelin test, where a positive result is indicated by a color change from yellow to dark olive green.

5. Why should the product be stored in a dark, cool, and dry place?

The product should be stored in a dark, cool, and dry place to maintain its stability and prevent it from degrading or reacting with environmental factors.