The Particular Advantage of a Solvent More Dense than Water as Reaction Solvent

The KiloMentor Blog has emphasized the usefulness of phase-shifting during the work up as a simple and powerful element in the isolation/purification of process intermediates. Separation into aqueous acid-soluble, aqueous base soluble, and neutral organic soluble fractions is often part of that effort. On scale, there is a cost advantage and also an advantage in simplicity if the phase in which the product is dissolved is retained in the reactor throughout the work up processing. If at any point it is in the phase that is drained off, an extra vessel is needed. If the expected product is to be concentrated and separated from byproducts and co-products by extraction into water at some pH or other, it is desirable that the organic phase that, after the phase shift, comprises the waste products and not the product, should be the lower phase. That way it can be drained off through the bottom port of the reactor, leaving the product dissolved as a salt, in the aqueous phase and still in the same reactor. The salt of this desired product can then be neutralized and taken up in another solvent less dense than water. The wastewater phase can then itself be drained off leaving the desired product still in the original reactor. This way only a single vessel is required since the waste fractions can be drummed off. 

For this to work dependably the first organic solvent must be distinctly denser than water. In the past, carbon tetrachloride, methylene chloride or chloroform were the common solvents that could function in this way; however, all of these are now less desirable for health and safety reasons. Some remaining solvents that are denser than water are trichloroethylene, tetrachloroethylene,  chlorobenzene, 1,2-dichlorobenzene, benzotrifluoride (BTF),  p-chlorobenzotrifluoride, and 3,4-dichlorobenzotrifluoride. It has been reported that   benzotrifluoride (BTF), one of the simplest of these, often does not separate easily into distinct phases.  
p-Chlorobenzotrifluoride has a much larger density difference compared to water and so is probably superior in this regard. Chlorobenzene may work but it might have the same slow separation as benzotrifluoride, since the density is closer to 1.00. 1,2-Dichlorobenzene has a price advantage on a volume basis over other choices. Since its function is to transport away only reaction wastes, the high bp. is not a disadvantage.

Thus, in situations where a reaction product can either be extracted into aqueous acid or aqueous base as part of the work-up, there is a benefit if the reaction solvent can be performed in one of these solvents that are denser than water.

If mixtures of one of these chlorinated solvents combined with some other lower boiling solvent turns out to provide improved yields in a particular transformation, you can still retain this advantage. The more volatile cosolvent used with the chlorinated one can be removed by simple distillation before the phase separation.