Reaction Solvents

Easy

Ether, ethyl acetate, hexane and dichloromethane. You can simply dilute your reaction with more solvent and then wash with water. Ether is not as polar as the others, so look out for polar compounds that may choose to remain in the aqueous layer. Dichloromethane should be avoided for environmental reasons, but for small scale extractions it may be preferred.

Tricky

When you have to mix solvents for an aqueous workup, complications can occur.

• Acetonitrile: Soluble in water. If convenient, remove solvent before workup to avoid losing polar products. If product is very nonpolar, partition between hexanes and water and carry out aqueous extraction. On small scale, you can dilute with a lot of the extraction solvent, and washed several times. Acetonitrile will partition into the aqueous layer
• Alcohols: Miscible with both water and organic solvents, alcohols do not cooperate during the typical aqueous workup. Remove the solvent by rotoevaporation first.
• THF and Dioxane: These ethers are water soluble. If diluted sufficiently with extraction solvent, and washed several times, they will partition into the aqueous layer. However, sometimes product goes along with them, and sometimes emulsions form. It is safer to remove THF by rotoevaporation before workup if practical, especially for large scale procedures. Dioxane is high boiling, usually making rotoevaporation impractical.
• Aromatic solvents: These are very nonpolar and will usually stay in the organic layer. Benzene is miscible with water and can lead to emulsion formation. It should be either removed by rotoevaporation before workup, or diluted well with the extraction solvent before washing with water.
• DMF or DMSO: 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: 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. Two 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. (submitted by Bill Spencer, Albany Molecular Research, Inc.)
• Amine Solvents: (pyridine, di- and trialkylamines) Amines will partition into the organic layer during a typical aqueous workup. However, they become water soluble if you Wash the organic layer several times with dilute HCl solution. The protonated amine will partition into the aqueous layer. For use with acid stable target compounds only. Wash the organic layer several times with 10% copper sulfate (aqueous and blue). The copper-complexed amine will partition into the aqueous solution, which turns purple. Continue to wash with the copper sulfate solution until no color change is observed. Rule of Thumb: For 5 mL of an amine solvent, use 5 X 10 mL of the 10% aq. CuSO₄ solution during the aqueous wash. This should remove all of the amine.

Aqueous Solutions

Mildly Acidic

• Ammonium chloride, pH 5-6 (to neutralize)
• 1N or 2N HCl, pH 1 (to neutralize or acidify)

Mildly Basic

• Saturated aqueous sodium bicarbonate pH 8 (to neutralize trace acid)
• 1N or 2N sodium hydroxide: pH 12 (to neutralize or basify)

Brine:

• Removes residual water from the organic layer. The last wash in every workup

Special Purposes

• Sodium thiosulfate (10%): to remove bromine or iodine
• Rochelle's salt (10%): to remove aluminum salts
• Copper sulfate (saturated): to remove amines
• Potassium fluoride: to remove trialkyltin byproducts
• Aqueous ammonium hydroxide/chloride (pH 8): to remove copper (I) salts

Drying Methods

• Magnesium sulfate: Fast, always works, but kind of messy.
• Sodium Sulfate: convenient for small scale drying- it is very easy to filter. You should start with a clear organic layer (washed with brine, and not poured into a wet flask). Drying takes longer than for magnesium sulfate. Sit it over the drying agent ~15 minutes for dichloromethane, ~30 minutes for ethyl acetate. It does not work well for ether.
• Celite: Sometimes it is useful to filter small scale reactions through Celite to remove trace water.

Tips and Tricks

• Azeotropes: Often traces of a high boiling solvent or other impurity can be removed from a product or reaction mixture by concentration of a solution of the compounds from an appropriate solvent. This works because higher boiling solvents often azeotrope with lower boiling solvents, forming an easy to remove binary distillate. For an extensive table of azeotropic mixtures, see The Chemists Companion.
• Pyridine: repeated (2-3 times) concentration of a reaction mixture containing pyridine from heptane, cyclohexane, or toluene.
• Water: organic compounds are conveniently dried by concentration (rotavap or on the vacuum pump) by concentrating the compound to be dried from benzene or especially tolunne. This technique is also useful for removal of water from organic hydrates (eg. NMO) by concentrating the compound from toluene 1-3 times followed by drying in a vacuum dessicator. To pull aqueous soluble organics out of the aqueous phase when CH₂Cl₂, EtOAc, Et₂O, etc. don't work. (submitted by Bill Spencer, Albany Molecular Research, Inc.)
• Rotoevaporation: If you think your product may be volatile (possible if MW is below 250), see How to Handle Difficult Compounds. If solvent is slow to evaporate, consider heating the bath- but be careful, some compounds decompose upon heating.