How do I purify ionizable organic amine compounds using flash column chromatography?

For most organic reaction mixture purifications the process is fairly straightforward. Use hexane/ethyl acetate or, for polar compounds, DCM/MeOH.  But what do you do if this doesn’t work and your compounds are basic organic amines?

In this post, I re-examine the options available to achieve an acceptable organic amine purification when typical separation methods are insufficient.

Learn more here.

Published by

Bob Bickler

Technical Specialist, Biotage

4 thoughts on “How do I purify ionizable organic amine compounds using flash column chromatography?”

  1. Hey Bob,

    What do you think might be the reason that your TLC separation didn’t translate to the column?
    Regarding normal phase mode chromatography, I often use 2M ammonia in MeOH (anhydrous) mixed with DCM at various ratios (typically 1-10%). Many times it works wonders.
    When running RP mode. Addition of formic acid also gives you usually good separation. And this is a generic method we use for LC-MS so you already have an idea how your separation will look like. And there is also an ion-pair mode with TFA. Then you end up with TFA salt, but SCX afterward can take care of that.
    Great blog. Keep up the good work.

    1. Hi Tomasz,

      You ask a really good question. In my experience, DCM/MeOH solvent blends used with TLC often do not translate to flash. I believe this is due to the fact that there is no pre-wetting of the silica on the TLC plate whereas with flash the columns are usually pre-wetted. So, when TLC is performed the methanol is preferentially adsorbed to a greater extent on the dry TLC silica as compared to the wetted flash silica. So, with the methanol removed (or its concentration greatly reduced in the TLC solvent), the compounds are better able to interact with the TLC silica and separate. That is my theory anyway.

  2. Amine additives are very useful, but not so long ago I made the mistake of storing a pre-mixed solution of triethylamine in dichloromethane. The grams of wonderful white solid I isolated after chromatography seemed like overkill for my milligram-scale reaction. Alkylation of amines (at least triethylamine) with dichloromethane to give ammonium salts occurs slowly over time.

    1. Chris,

      You bring up a great point about storing base (and likely acid) modified solvents – reactions can occur. This is one reason I like to have the pH modifier solution as a totally separate solvent and add it isocratically while running a gradient with the other two solvents.

      Bob

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