Experiment 2 – Reductive Amination

Reductive Amination of Unknown Aldehydes and Amines

Introduction to Amines

• Amines constitute a crucial class of compounds with diverse applications:
  • Pharmaceuticals
  • Petrochemicals
  • Materials
• Amines serve as essential building blocks for synthesizing valuable heterocycles used in both synthetic and medicinal chemistry.
• Numerous synthetic methods exist for:
  • Converting compounds into amines.
  • Reacting functional groups with amines to produce complex amine products.
• Amines can undergo oxidation to yield various functional groups, including:
  • Nitroso groups
  • Diazo groups
  • Nitro groups

Condensation Reactions

• Condensation reactions between amines, aldehydes, and ketones are particularly significant.
• The resulting imines are also referred to as Schiff bases.
• Schiff base formation is reversible, however:
  • Intermediates can be reduced to form amines with an additional substituent.
• Aldehydes exhibit higher reactivity compared to ketones in condensation reactions.
• Harsh conditions are often necessary to facilitate condensations with ketones.
• Secondary amines are commonly synthesized through reductive amination using aldehydes, but rarely with ketones.
• Secondary amines are generally less reactive than primary amines in these reactions.
  • They form highly electrophilic iminium ions instead of imines.
  • Dehydrating conditions can be used to promote the reaction.

Experiment Scenario

• The experiment simulates an interview scenario with a pharmaceutical company.
• The task involves performing a reductive amination reaction with an unknown aldehyde and amine.
• The product is then analyzed to determine the identities of the unknowns.
• A list of possible unknowns is provided to simplify the task.

Prelab Questions

1. Hazard Identification:

   • Identify the most hazardous compound based on Material Safety Data Sheets (MSDS).

2. Reagent Table and Reaction Scheme:

   • Complete the reagent table and reaction scheme in the lab notebook.
   • Include:
     • Name
     • Formula
     • Mol.-eq.
     • MW
     • mmol
     • Density/Conc.
     • Amount
   • Leave parts blank until the unknowns are identified.

   Name	Formula	Mol.-eq.	MW	mmol	Density/Conc.	Amount
   Unknown Aldehyde	???	???	???	???	???	???
   Unknown Amine	???	???	???	???	???	???
   Sodium Triacetoxyborohydride	-	-	163 mg	-	-	-
   Dichloromethane	-	-	-	-	2 mL	-
   Product	???	???	???	???	-	???

3. Impurity Identification by ^1H NMR:

   • Describe how to identify aldehyde starting material or alcohol by-product using ^1H NMR.

4. Aldehyde Identification by IR Spectroscopy:

   • Explain how to identify an aldehyde using IR spectroscopy.

Procedure

1. Reaction Setup:

   • Obtain an assigned aldehyde and amine from the TA; record the mass or volume in the lab notebook.
   • Add the following (in order) to a dry 10 mL round bottom flask with a magnetic stir bar:
     • Unknown aldehyde
     • Unknown amine
     • Sodium triacetoxyborohydride (163 mg)
     • Methylene chloride (2 mL)
   • Stir the reaction for 2 hours; TLC can monitor the reaction.
   • The reaction can be stopped early if either the aldehyde or amine is fully consumed.
   • Use both UV/Vis and phosphomolybdic acid stain to visualize the TLC plate.
   • Check the TLC every 30 minutes, using 1:1 ethyl acetate/hexanes as the eluent.

2. Isolation and Purification of Product:

   • Quench the reaction with saturated aqueous sodium bicarbonate solution (5 mL).
   • Transfer the mixture to a separatory funnel and add 10 mL of dichloromethane to improve separation.
   • Separate the organic (lower) layer into a 50 mL Erlenmeyer flask.
   • Wash the aqueous layer with 5 mL of methylene chloride.
   • Remove the aqueous layer and combine the organic layers in the separatory funnel.
   • Wash the combined organic layers with:
     • Saturated aqueous sodium bicarbonate (5 mL)
     • Brine (5 mL)
   • Transfer the organic layers to a 50 mL Erlenmeyer flask and dry over sodium sulfate.
   • Remove the sodium sulfate by gravity filtration.
   • Discard the solid and transfer the solution to a pre-weighed flask or beaker.
   • Evaporate the solvent under gentle heating, being cautious of products with low boiling points (~90 °C).

3. Product Analysis:

   • Weigh the product and take the IR spectrum.
   • Obtain ^1H NMR and MS data from Blackboard.

Questions to be Addressed in Results/Analysis

1. Product Structure Identification:

   • Identify the structure of the product based on spectral data (^1H, IR, MS).
   • Justify the choice based on the spectroscopic data to receive full marks.

2. Product Purity Assessment:

   • Assess the purity of the product based on IR data.
   • Identify any significant impurities and their nature.

Postlab Questions

1. Imine Formation Mechanism:

   • Draw the arrow-pushing mechanism for the condensation reaction to form an imine from methylamine and acetaldehyde.

2. Amine Formation Mechanism:

   • Draw the arrow-pushing mechanism of the second step of the reductive animation mechanism to convert the imine from Q1 to an amine using sodium borohydride.

3. Biological Reductive Amination:

   • Name a major class of biomolecules prepared via reductive amination.