Emulsions are a nasty. When the phases won’t separate add some brine and gently swirl around (no shaking). If this does not help try to add some ethanol and swirl again. If possible, acidify with diluted HCl or sulfuric acid. If nothing else helps, filter the whole damned emulsion through, using a medium-to-fine-porosity large sintered glass Buchner funnel. This takes some time and effort but it usually does the trick of breaking the milkshake. You can also do the filtration through a plug of charcoal for the extra emulsion-busting effect but you may end up losing some material on the charcoal. (Be sure to use fine porosity funnel as to prevent the charcoal from getting through).
In extreme desperation, chemists were using centrifuge to break emulsions.
You have to expect emulsions with greasy acids in basic conditions and greasy amines in acidic condition. Some compounds are natural detergents – phospholipids for example. One can pair up quartenary ammoniums with greasy anions like perfluorobutyrate or tetraphenyl borate to obtain salts that will extract into organic – and even separate reasonably on silica column – but these classes of compounds are best not purified by aqueous extraction.
What therefore God hath joined together, let not man put asunder.
Highly soluble compounds
Another class of compounds that should not be purified by aqueous workup are the highly water soluble compounds like polyamines, polyols, unprotected peptides etc. If you have to do aqueous workup, use a minimal volume of water and best saturate it with some salt. Ethyl acetate is the usual choice for the polar compound extraction but in desperate cases one can do multiple re-extractions with a solvent like methyl ethyl ketone, n-butanol or chloroform+methanol 2:1(v/v) mixture. One shoud expect to extract large quantities of water and salts (sodium acetate for example) into the organic phase when using these alcohol-containig solvents.
In the most unfortunate cases people set up continuous extraction apparatus and let it run overnight – though it is not something commonly seen in the organic lab nowadays. There is always some more convenient non-aqueous workup/isolation alternative.
Please be sure to collect all your aqueous washing and save them until the moment when you hold a flask with your crude product that you can weight. If you are not sure that you extracted all your product from aqueous phases, run HPLC on them (you can take a sample, blow off organics from it by a stream of nitrogen and apply undiluted onto the column; strongly basic solutions must be acidified to protect the column. It is very pleasing to compare an HPLC of your crude product extract – with the HPLC from the combined aqueous washings that contain all the baseline grass of the impurities you just removed).
If you don’t have a miniature sep funnels the polypropylene 20 mL syringes will work fine for the purpose (the all-plastic kind, without a rubber plunger; the slip-tip syringes are preferable over the luer-lock). I like a needle with sawed-off tip that can be stopped by finger – but other people like to use a sharp needle with a rubber or silicone piece as a stopper. When you are unstopping the needle do it always with the needle pointed up and with slight negative pressure produced by a pull on the plunger. Squeeze out all air void before inverting the syringe needle down as to prevent your mix from squirting out due to the changing vapor pressure
Please note that polypropylene syringes swell in organic solvents: toluene and dichloromethane swell it quite fast but even ethyl acetate will mis-shape the syringes after while. This will cause syringes to leak over time so it is best to discard the syringes after the extraction.
For small volume extraction done in syringe I like chloroform inplace of dichloromethane – it separates a bit faster (its heavier) and it has a lower vapor pressure.
Small extract volumes can be conveniently dried by direct filtration trough a plug of MgSO4 in a small Buchner funnel (14/20 joint).
Order of washing
The recommended order of washing is diluted acid followed by water (or brine) followed by bicarbonate. One can dry extracts after bicarbonate directly, no additional washing with brine is needed – drying with MgSO4 takes care of the mild residual basicity – but one should re-wash the extract after an acid wash. (For example citric acid is pretty soluble in ethyl acetate.) Also washing the extract after acid wash directly with bicarbonate will produce effervescence and pressure buildup in the sep funnel so it is best to add one neutral wash inbetween.
MgSO4 is much more powerful drying agent than Na2SO4 and it comes in different grades – use the the powdered grade, the one that has the consistency of confectioner sugar; the lumpy grade is useless. When MgSO4 fails (typically the mixtures that form stable emulsions also provide milky extracts that are difficult to dry) the comercial 4A powdered activated sieves will work; use Celite plug for filtration from sieves since the powdered 4A sieves have rather fine particles.
Another good drying agent is Na3PO4 and Na2CO3; it works better than K2CO3. (I am not a great fan of KOH or NaOH as drying agents). Since Na-triphosphate and carbonate are strongly alkaline, they are not compatible with ethyl acetate.
You may want to give the drying agent some time to do its work, like 20 min stirring in a round flask. If you are concerned about dropplets of moisture stuck above the level + on the neck of the flask, you can sprinkle some drying agent onto a funnel that was wetted with the solvent and then wash down the drying agent stuck on the funnel with some additional solvent; that takes care of the problem.
Washing away DMF, DMAc
Both ether and ethyl acetate are the recommended solvets for washing away small volumes of DMF, DMAc, DMSO and tetramethyl urea with water and bicarbonate solution. I don’t know the exact reason why they work better than chlorinated solvents (which tend to extract DMF and others into organic phase) but I suspect the relatively high water solubility of ether and ethyl acetate in water helps to improve the partitioning of DMF, DMAc, etc. into the aqueous phase.
Ether and ethyl acetate can cause some precipitation of salts from saturated salt wash solution (sat NaCl, NaHCO3, NH4Cl) – in that case one should want to dilute the mixture with additional water, to bring the inorganics back into the aqueous phase.
More on extractions here