Switching Solvent at Scale: Using a Minimal Stirrable Volume Chaser

Working at laboratory scale one can switch from a reaction solvent to a work-up/extracting/crystallizing solvent by evaporating the reacting solvent to dryness on the rotary evaporator adding the second solvent and scrapping and stirring the oily neat solid off the walls of the flask and back into solution. So long as consideration is given to not decompose the solutes there is no problem.

With a few kilograms, using a large rotovap containing polypropylene beads to trap solids, the same thing can be done. The free-flowing beads trap the solutes; then, they can be redissolved in the second solvent and the polypropylene beads filtered.

In the pilot plant removing polymeric beads from the reactor is not possible. Evaporation to dryness is not possible. A possible solution might be to add into the reactor an inert, high boiling fluid in a volume such that the total volume of the non-volatile solutes plus this fluid reached the minimum stirrable volume. Now the first solvent could be distilled out of the reactor completely because at the end there would remain the minimum stirrable amount of non-volatiles containing all the non-volatile reaction pot contents.

What should be the properties of a minimum stirrable volume chaser? Well if we are going to get it separated from the reactor components of interest by extraction it must be immiscible with some standard organic solvents. This suggests that if the reaction products of interest are at least moderately polar the volume chaser should be a high-boiling paraffin. Such a chaser would be immiscible with either methanol or acetonitrile. Polar or semi-polar compounds would easily be extracted out of the paraffin phase. The paraffin chaser could be saved, drummed off, and reused for repeats of the same reaction.

Traces of paraffin can be removed from methanol by forming the insoluble complex with urea. The complex and excess free urea would be filtered off from the methanol solution.

In the event that the desired reaction products are more nearly apolar, the volume chaser should be itself polar. Liquid polypropylene glycol or glycerol can be used. These will work because the desired reaction components as an oil in either of these can be separated by liquid-liquid extraction with any organic solvent that isn’t appreciably miscible with them. Traces of either polypropylene glycol or glycerol can be precipitated as complexes with anhydrous calcium chloride at an appropriate point in the work-up.

A final possibility is to use a chaser fluid that can be removed in some other way. A possibility of this type would be to use acetic anhydride bp. 140 C which would drive over many solvents that are not reactive with it and that can be subsequently hydrolyzed to acetic acid which can be removed in water followed by an aq. bicarbonate extraction.

In a similar way, quinoline could be used as a chaser then washed out as a salt in water and recovered by subsequent basification of the aqueous extract.