Importance of Solvent Choice
In the reaction of two generalized chemical species, A with B, the most significant variable invariably affecting the yield is the stoichiometry. The optimal stoichiometry is usually something close to the molecular proportions in the balanced chemical equation representing the desired reaction. Certainly, these are the proportions that chemists hope will be best because any excess of either substrate will cost extra money.
Frequently, the second most significant variable is the choice of solvent. This makes intuitive sense. In an uncatalyzed reaction, the solvent is the only other chemical next to the reactants that is present within the transition state and it is the reduction of the transition state energy that makes the conversion to desired product preferred over unreacted starting materials or byproducts.
The more solvents to choose from, the greater the opportunity to improve a reaction’s selectivity. Of course, some solvents are preferred on the basis of cost per liter. Others are preferred for ease of removal in the isolation and purification of the product. Usually, this is because it is too high boiling/viscous for the work-up or makes drying tedious. Whatever it is, because solvent choice is a discrete variable, (if binary mixtures are off limits) there is a widespread tendency to quickly settle for one of those ‘old faithfuls’ and then systematically work with the continuous variables to ‘optimize’.
It is true that if
- the substrate and reagent (A and B) are both soluble in a solvent and
- that solvent has already been successfully used in an example in the literature
your chance of successfully adapting it is substantially increased;
however, there are cases where benefits can accrue by looking beyond the ‘old faithful’ solvents. Those benefits are most likely to be realized
(a) if there is plenty of room to improve the reaction’s yield
(b) if a good ‘in situ’ assay for the desired product is available, and
(c) if one knows how to conduct an efficient search.
On the other hand, there are good reasons for not considering these less-utilized solvents.
Reactions that cannot be totally quenched deteriorate during solvent switching. For example, if the substrate can over-react with excess of a reagent but excess reagent is necessary to give the required conversion, then tacking on a solvent switching operation to get rid of a higher-boiling reaction solvent, will most likely lead to overreaction and extra byproduct formation. Similarly, if the desired reaction product is thermally unstable, the extra heat input and time spent for solvent switching may prove deleterious.
But if any excess reagent can be first completely destroyed or otherwise disabled, solvent switching to separate a higher boiling reaction solvent can still be considered.
It is not necessary to demonstrate the separation from a higher boiling reaction solvent unless such solvent actually seems to be delivering the required improvement in reaction yield. At this scouting stage in an ‘optimization’, improvement only needs to be hinted at by an improved assay for the desired product in the completed reaction mixture. This is why having a dependable product assay needs to be in hand before looking for a less-common reaction solvent.
Switching from High-boiling Reaction Solvents for Work-up
A reaction solvent can be removed by distilling it away from an even higher-boiling solvent called the chaser solvent. I will consider five different chaser solvents: Acetic anhydride, Quinoline, Triethanolamine, PEG 400 (liquid polyethylene glycol), Glycerin, and Paraffin.
Each of these chasers has some unique feature that allows it to be in turn easily exchanged for something low-boiling to continue the isolation and purification.
Acetic anhydride can only chase solvents of boiling point less than 140 C. It works because it can be converted to an aqueous acetic acid-water mixture that will be immiscible with many low-boiling, classic organic solvents that may be preferable for separation, purification, and isolation.
Quinoline is high boiling. It can be removed by steam distillation, even under vacuum for greater stability of the solutes. Trace residues can be removed by extraction with acidic water since quinoline is mildly basic.
Triethanolamine is very high boiling and can be a chaser for even rather high-boiling solvents. It is miscible with water. Traces that are carried over to a new lower boiling solvent can be extracted with aqueous acid.
PEG 400 is essentially nonvolatile. It can be a chaser for any organic solvent. It can be precipitated with diethyl ether.
Glycerin, although very viscous, can occupy the minimum stirrable volume in a reactor and allow another lower boiler to be distilled away. Glycerin is immiscible with a wide variety of regularly used organic solvents. Glycerin will keep polar solutes in solution.
Paraffin is the opposite polarity extreme to glycerin. It is essentially non-volatile straight-chain saturated hydrocarbons. It can occupy the minimum stirrable volume in a reactor allowing a reaction solvent to be completely replaced. Because paraffin is made up of long-chain hydrocarbons, it is immiscible with regular solvents which are themselves immiscible with hexane, heptane, cyclohexane, etc. Traces of paraffin, because they are straight chains in structure, can be removed as urea inclusion complexes that crystallize from methanol.
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