A reaction may proceed quite well to give an 80% yield of the desired product but be very difficult to work up if it is a mixture of neutral compounds. In this situation acid-base extraction cannot help to obtain some partitioning between organic and aqueous phases.
Furthermore, most often the two compounds making up the reaction mixture are both essentially insoluble in water. When there is 20% by weight of an impurity, even when you can find a solvent which gets the major compound to selectively crystallize, the recovery is usually quite poor simply because by the time you have crystallized 60% of the major compound the mother liquors are a 1:1 mixture of desired and undesired compounds. At this point, the rate of crystallization normally becomes impractically slow and for practical purposes, the crystallization has stopped.
Usually, thin layer chromatography in more than one solvent system can quickly tell you whether the main impurity, which most probably is the one blocking the crystallization, is, by-and-large, less polar or more polar than the desired major component. When the minor component is the more polar, what we intuitively would like to do is triturate with water, modified so that it can dissolve more of the mixture, hoping that the additional material dissolved into the water-rich phase will be disproportionately the more polar impurity component.
A co-solvent for water to be effective must prefer to mix with the water rather than forming an oil phase with the products. Only experimentally can we find something guaranteed to work, but perhaps KiloMentor can propose a rule of thumb, which could increase the likelihood of success. This aqueous phase modifier should be completely miscible in all proportions with water. If a diluent is only partially miscible with water it is more likely that when mixed with the neat reaction oil it will simply migrate into the oil.
The most lipophilic solvents that are completely miscible in all proportions with water are: acetone, methyl ethyl ether, methyl acetate, and t-butanol. The lower homologs of each of these function group types will also be completely miscible. That is: methanol, ethanol, propanol, isopropanol are also completely miscible and could be used as diluents. With esters, ethyl formate is not completely stable in water so it should not be used. Acetonitrile is completely miscible but propionitrile is not. Nitromethane is not completely miscible, while dimethylformamide, N-methyl formamide, formamide, DMSO, and pyridine are.
In addition to adding small quantities of these solvents to a large excess of water to increase the leaching power of the polar phase, recrystallization from the less polar of these, at least: acetone, t-butanol, pyridine or methyl acetate, by the gradual addition of water, could be fruitful.
Once the level of the impurity is reduced below 10% from the 20% range, crystallization, in general, can be expected to give a much-improved recovery. From a mixture containing just 10% impurity, one could crystallize 80% of the major component before the mother liquors would be 50:50 product: impurity.
Even on scale, a reaction mixture can be freed of organic solvent by concentration in the presence of a water phase to give a reaction product oil as an oil in water. The aqueous phase modifier could be added into this mixture to achieve an in situ trituration.
When trituration is not working, an alternative is to dissolve the compounds into isooctane and extract with some mixture of acetonitrile, water, or ethylene glycol.
When trituration is not working, an alternative is to dissolve the compounds into isooctane and extract with some mixture of acetonitrile, water, or ethylene glycol.
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