Most organic reactions are quenched by adding an aqueous phase into the reaction vessel followed by some appropriate workup protocol. At some point, the water-rich phase is cut away and usually discarded since usually the molecule of interest is more soluble in some hydrophobic organic solvent. If one hopes to achieve a good ‘isolation yield’ the aqueous phase must not retain any product. This may require back-extractions of the aqueous layer depending upon the solubility which in turn depends upon the number of carbons in the product and the functional groups that comprise it. Since a standard reactor is emptied through a valve in its bottom, multiple extractions of an aqueous layer are most convenient when the organic layer that will hold the product is denser than water and is the layer closest to the bottom valve. Unfortunately, this is rarely the case. Most organic solvents are less dense than water; that is, the aqueous phase is at the bottom of the reactor and if more than a single extraction is to be performed on the aqueous layer, an extra vessel is needed for the operation.
It would be useful to know whether multiple extractions of an aqueous layer are likely to be required at the time a process step is being planned. This can be estimated roughly by tallying the balance between hydrophilic and hydrophobic fragments in the anticipated desired product.
We can get a rough idea of what the balance is between hydrocarbon elements and different functional groups by looking at the solubility of some small organic molecules in water. For example, N-butanol is not miscible with water while 2-methyl-2-propanol (t-butanol) is. All the simple pentanols give two separate layers when mixed with water suggesting that one hydroxy balances four to five carbons worth of a substrate. For the ketone functionality, acetone is completely miscible with water while methylethylketone will lead to two phases so the carbonyl is sort of balanced by three more carbons. The hydrophilicity of polyethyleneglycol suggests the number two for the balancing carbons for an ether link and three may be an approximate number to balance an ester group. An amino group would need about 6 carbons to balance it. A free carboxyl would also be balanced by about 6 carbons.
What am I getting at? If you were to try to prepare for example 7-(carboxypropyl)-18-hydroxy-13-oxa-10-oxo-octadecanoic acid and needed to extract it completely from an aqueous phase, it would be wise to extract with at least two portions of your organic extractant since this molecule is likely to have its hydrophilicity and hydrophobicity close to being balanced giving appreciable water solubility.
Let us look at a different example for which we actually have some quantitative experimental data. Herbert Feltkamp and Wolfgang Kraus published [Ann. 651, 11-17 (1962)] a study of the liquid-liquid partitioning of 6 possible stereoisomers of decahydro-1,4-naphthalenediol. Now, if as I have suggested, one hydroxyl function’s contribution to hydrophilicity would be balanced by about five saturated carbons then these decahydronaphthalendiols should have significant solubility in both water as well as an organic extraction solvent. In fact, this is what the authors found.
Although it is not pertinent to the point being made here, because none of these stereoisomers distributed themselves overwhelmingly either in a water phase or a 2:1 v/v mixture of ethyl acetate and petroleum ether (the organic phase they used) the authors were able to separate the isomers by a series of liquid-liquid partitioning extractions!
Why might it be useful to know in advance that several organic extracts might be needed to clear a substrate from the aqueous phase? Suppose we are trying to isolate some product from a reaction mixture. We have taken this molecule of interest into an aqueous phase either as a complex or a salt and we then have broken the complex or neutralized the salt and intend to extract it back into a lighter-than-water organic phase. From the structure of our desired product, we might be able to correctly predict that is still going to have significant solubility in water and may require several organic extractions to essentially recover it quantitatively. We now want to extract that molecule back into an organic layer. But if our molecule of interest retains some water solubility we wouldn’t be able to quantitatively take it up willy-nilly with just one extraction using any old organic solvent.
We can do one or both of three things:
We can select an organic extractant that will dissolve the rather polar substrate very well. Heptane or cyclohexane would not be good choices but amyl or isobutylene alcohols might work well
or
and this is the choice that is likely to be most often overlooked, we could add inorganic salt into the aqueous layer to salt out that product so the fraction partitioned into the organic layer is very substantially increased so that only one extraction is necessary to take up essentially everything. This is the more flexible expedient because, if it turns out that just one extract is needed, the salting-out can be scrapped without any other change in your isolation/purification plan
or
we could take up the organic solute by multiple extractions using an organic solvent denser than water such as methylene chloride, chloroform, trichloroethylene, chlorobenzene etc.
Whatever the situation with which you, the process chemist, are confronted you should have anticipated how extractions are likely to proceed and have planned so that the number of transfers and vessels dirtied are minimized so as to minimize costs.
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