Tips for Flash Column Chromatography

• If your compound is sensitive to acid: Use a different type of solid phase for your column, or deactivate your silica gel as follows: Identify a solvent system that contains 1-3% triethylamine, and puts your compound at an appropriate Rf. You will use less of the polar component of your solvent system than usual. Pack your column using this system and flush with solvent equaling the volume of the silica. Discard the eluant. The silica should be deactivated, and you can run the column with either the triethylamine system or with your usual solvent system.
• For difficult separations, run a gradient. Begin with a solvent system in which your compound runs at an Rf of about 0.2 (or less) and increase the percentage of the polar component of the solvent system slightly each time you replenish the solvent in the column. You will need to experiment with degrees of gradient before you find conditions that give optimal separation. If you are impatient, you might prefer to run two columns instead of one. Even with a gradient, you might end up with a lot of mixed fractions, and still need to run a second column.
• Filter through silica as a purification shortcut. Prepare a short, fat plug of silica, and run your compound through it to remove baseline impurities. This can be effective for reactions that are spot-to-spot, and when workup effectively removes leftover reactants and reagents. This allows you to skip the fraction-collecting stage of chromatography.
• Using dichloromethane as the non-polar elution solvent is tempting because certain compounds dissolve so much better. However, column execution will be SLOW. Dichloromethane takes longer to pass through silica, and the column is more prone to crack from the pressure.
• Using benzene as the non-polar elution solvent can work magic, because some compounds will have very different Rfs. Few choose this option because of toxicity concerns.
• Run a column on small scale using a pipette – link to How to Run a Small Scale Flash Column
• Load an insoluble product on the column: You can mix your crude reaction mixture into a small quantity of silica, and load your sample as a solid. Pack your column as usual with solvent-infused silica, but do not top with a layer of sand. Using a large round-bottomed flask, dissolve your compound in an appropriate solvent and add enough silica gel to form a thin (not thick) layer on the top of your column. Remove the solvent by rotoevaporation. You should have a flask of free-flowing silica gel that you can pour on the top of your column. Add a layer of sand and elute as usual.