SP

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.
    NameFormulaMol.-eq.MWmmolDensity/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.