DMF or DMSO

Workup for Reactions in DMF or DMSO

DMF and DMSO are very polar and high-boiling solvents that are difficult to remove. If your product is not dangerously polar, dilute with lots and lots of water before extracting with a nonpolar solvent. Then thoroughly wash the organic layer with water.

Rule of Thumb ( see all): For 5 mL of DMF or DMSO, use 5 X 10 mL of water during the aqueous wash. This should remove all of the DMF or DMSO.

If copious water doesn’t do the trick, here are a bunch of other ideas:

• You could try one of these aqueous washes to remove DMF:
  1. 5% LiCl (aq)
  2. 0.5 N HCl
  Boc groups will survive the dilute HCl wash. TMS groups may not.
  Suggestion submitted by Bill Spencer, Albany Molecular Research, Inc.
• Here is a step-by-step method for extraction of DMF and DMSO, provided by Dr. Philip G. Hultin at the University of Manitoba.
• Dilute in ether (EtOAc if polar product), LiCl washes, azeotrope from heptanes. (@geordifrere)
• 1:1 Ethyl acetate / hexane as the organic phase. Wash twice with aqueous phase. (@lreymond2)
• Use ice 4-5 times instead of brine. You can wash with brine after washing with ice. (@Kumar25633430)
• Lyophilization from tBuOH/H2O (@Karolalayed)

You can find more ideas for how to remove DMF from samples in this thread.

For a comprehensive discussion, below is a good article about phase separation of three component mixtures (water, water miscible polar solvents and nonpolar solvents). An analysis of extraction for ten dipolar and less dipolar aprotic reaction solvents is described (DMSO, DMF, NMP, DMAc, TMU, DMI, THF, 1,4-dioxane, diglyme and acetonitrile). Five extraction solvents were evaluated (toluene, EtOAc, iPrOAc, 1,chlorobutane, and heptanes). Thanks to Klaus Laue for the recommendation.

Removal of Reaction Solvent by Extractive Workup:  Survey of Water and Solvent Co-extraction in Various Systems Laurent Delhaye,*, Attilio Ceccato, Pierre Jacobs, Cindy Köttgen, and Alain Merschaert Organic Process Research & Development 2007 11, 160-164 DOI: 10.1021/op060154k. https://pubs.acs.org/doi/abs/10.1021/op060154k