REDUCTIVE AMINATION: Three Easy Pieces
Adapted from J. Chem. Ed.; Kim Touchette: Bard College, Annandale-on-Hudson, NY
CH3
O
CH3
H
H
O
H
NH2
OCH3
- H2 O
Step 1
O
CH3
OH
H3 CO
N
1. NaBH4
H
2. AcOH/AcOAc
OCH3
Step 2 & 3
N
C
H3 C
O
Reductive amination is usually described as a one-pot procedure in which an aldehyde or ketone reacts
with ammonia or an amine to form an imine, which is selectively reduced as it is formed. Hydrogen over nickel
or a weakened hydride donor (NaBH3CN, NaBH(OAc)3) is commonly used to reduce the imine as these
reagents are slow to reduce the carbonyl compound.
In this experiment we will react ortho-vanillin with para-toluidine to generate an imine. The reaction
occurs between the two solids in a solvent free reaction. The imine is subsequently reduced with sodium
borohydride to the amine, followed by acetylation to afford a solid amide derivative. The entire reaction
sequence is performed in an open beaker.
Experimental Procedure:
A. Synthesis of 2-methoxy-6-(p-tolyliminomethyl)-phenol: Imine formation
Tare a 250 mL beaker and then add 0.76 grams (5 mmol.) of ortho-vanillin. Record the total mass of
the beaker plus the ortho-vanillin. Using weighing paper, accurately weigh an equivalent amount of paratoluidine (0.535 grams, 5 mmol.) and add this to the beaker. Observe this mixture for a few minutes and record
what is happening. Using a heavy glass-stirring rod or a mortar and pestle, mix and grind the solids until they
become a homogeneous dry powder. Weigh the beaker and record the mass. Determine the percent yield.
Remove a small sample of this material for NMR analysis. Compare the features of your spectrum with those of
the starting materials.
B. Synthesis of N-(2-hydroxy-3-methoxybenzyl)-p-methylaniline: Reduction of the Imine
Add about 15 mL of 95% ethanol and a stir bar to the beaker containing your imine product and stir the
mixture to partially dissolve the imine. Weigh out approximately 0.1 grams of sodium borohydride and slowly
add this to the beaker in small increments with continued stirring. Record all observations and explain what is
occurring in the reaction.
C. Synthesis of N-(2-hydroxy-3-methoxybenzyl)-N-p-tolylacetamide: Acetylation of the Amine
Add 2 mL of acetic acid to the amine to destroy the excess borohydride and to neutralize the phenoxide
ion. Add 2 mL of acetic anhydride and gently warm the solution on a hot plate for 5-10 minutes (do not boil).
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Turn the heat off and allow the reaction to slightly cool. Stir the solution fairly rapidly while slowly adding 75 mL
of water. Continued stirring should leach out the alcohol and acetic acid causing the amide product to
precipitate. Cool the mixture in an ice bath, collect the solid and rinse with a small amount of cold water. Allow
it to air-dry until next week and then analyze your product by melting point.
D. Preparing an NMR Sample
Each student will prepare an NMR sample of either the imine intermediate or the final amide. Listen
carefully to your TA, as you will need to know which compound to use as your sample, whether to prepare a
sample for 13C NMR or 1H NMR and what your sample number should be. Record this information in your
lab notebook. You will also be sharing data with a lab partner, so that you have access to a proton and carbon
NMR of the same compound. Record your partner’s sample number as well so you can access their data.

~15 mg compound and dissolve it in 0.6 mL CDCl3.

Make sure the sample is clear (it will be orange but translucent) and contains no solids.
Report/Post-lab questions:
1. Determine your overall percent yield for the three step synthesis and characterize your final product by
melting point.
2. The structure of capsaicin, the pungent ingredient in red pepper or capsicum annuum, is shown below.
Suggest a multi-step synthetic scheme analogous to the sequence used in this experiment to prepare
capsaicin.
O
HO
CH2NHC(CH2)4CH=CHCH(CH3)2
H3CO
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