Why do process chemists regularly optimize a chemical step using only a single reaction solvent? Neal G. Anderson in his valuable text, Practical Process Research & Development, dedicates an entire chapter to solvent selection; however, all that he says about using mixtures of solvents is “Sometimes a mixture of solvents will dissolve a compound much better than any one solvent .....” Rather obliquely, regarding the goal of solvent selection, he writes, “[Other] important considerations are to decrease waste and allow for efficient solvent recovery and reuse.”
Although purifying and recycling solvent is almost certainly easier if it is a single substance; generally, in the fine chemical industries, including making pharmaceuticals and pharmaceutical intermediates, solvents are not reused. The exception would be some product that achieves a massive volume. Thus, it might make sense for the owner of a composition of matter patent for a major pharmaceutical to use a single-component solvent so that solvent recovery would be simpler if that product became a blockbuster drug.
The reason recycling is rare is economic. In a multipurpose plant, batch sizes are too small and the number of different solvents used is too many to make it worthwhile accumulating and storing used solvents for delivery to a solvent recycling specialist. As for purifying solvents themselves, the reactors in a multipurpose plant are too costly to be used for solvent recycling. Finally, recycling solvent within a fine chemical facility would only be acceptable so long as the same strict specifications could be met for recycled solvent as for other input reactants and this testing brings its own costly analytical burden.
My conclusion: most of the time using mixtures of solvents as the reaction medium is just as practical as using a single solvent. That is despite the almost universal traditional practice of using a single component solvent without asking the reason why it must be so.
Let us examine some of the reasons solvent mixtures could be advantageous.
Throughput
A solvent mixture may well dissolve more substrate per liter than any single component medium can. Getting more substrate dissolved homogeneously in a reactor can improve the economics by increasing throughput, especially in early process steps which need to be run multiple times. (Solubility is the single advantage that Neal Anderson did mention.)
Cost
One particular solvent may possess a specially advantageous property while, at the same time, being prohibitively expensive. Using a mixture of this expensive solvent and a cheaper cosolvent may adequately preserve the special property while reducing the overall cost.
Increasing the Heat Capacity
The preferred solvent for yield optimization may be one that boils substantially above the best reaction temperature. Adding a co-solvent that boils at the desired reaction temperature can increase the heat capacity of the medium at the reaction temperature. The lower boiling solvent’s vaporization into the condenser and the returning condensate will stabilize the reactor temperature. Consequently, the addition rates of reactants can be higher without overshooting the optimum reaction temperature.
Changing a Phase’s Density
Some solvents are more dense, and some less dense than water. In work-ups with water, sometimes having the product-containing liquid phase more or less dense than water can have an advantage. There can be fewer transfers between vessels. The number of large vessels needed to execute a process step may depend upon it. Processing times can be reduced and throughput increased. Fewer vessels mean less cleaning and a smaller burden on plant facilities.
Reducing the Solubility of a Product or Co-product
Decreasing the solubility of a product or co-product can cause it to precipitate as the reaction proceeds. This can drive an equilibrium towards completion, simplify isolation or raise the overall yield.
Making Telescoping Reactions Easier
Sometimes it is not useful to isolate a process intermediate but the solvents appropriate for the present and subsequent process steps are not the same. A solvent switch is required. Evaporation to dryness is not possible at scale. It would be advantageous if the second step in the telescoped pair was optimized in a solvent mixture consisting of a minor amount of the first solvent and a majority of the second solvent. If this were done it would not be required to substantially remove the first solvent. This might save substantial time and substantially reduce waste.
Because the Solvent Mixture Selected is a Constant Boiling Azeotrope
A constant boiling azeotrope has a fixed composition and it boils at a constant boiling point. In these respects, it is the same as a pure single molecular species. It can usually be purified by simple distillation. However, many azeotropes have the advantage that by changing the pressure-usually by reducing the pressure- the azeotrope can be split into its component substances for distillation. This distillation at a different pressure can potentially remove the better solvent and lead to the precipitation or crystallization of a solute.
To Reduce Solvent Viscosity
Viscous solvents are often usefully high boiling but their viscosity is a problem for stirring and for heat conduction. Mixing with another solvent can reduce the viscosity of the reaction medium.
To Provide a Distillation Chaser
Adding a higher boiling solvent into a reaction solvent mixture can provide a chaser for reaction mixtures that are subsequently worked up by distillation. In ordinary distillation, sometimes a substantial amount of product is lost in the still pot and the distillation column. A solvent component that can act as a chaser can eliminate this loss. Of course, such a chaser could also be added after the reaction is over but before the distillation step.
Drying Simplicity
Drying solvents at scale with inorganic salts followed by filtration of the inorganic salt hydrates uses labor, equipment, and time inefficiently. It is greatly disfavoured for work at scale. The preferred method for solvent drying selects a solvent that forms an azeotrope with water and distills a portion of the solvent as the azeotrope. Such a solvent may usefully be part of the original reaction solvent liquid.
Raising the Freezing Point
At what temperature does the solvent that is being considered solidify or become highly viscous? The freezing point can limit the range of temperatures that can be used in the optimization. Lowering the temperature is often the best option for increasing the selectivity of the desired reaction versus competing reactions that produce by-products. If low temperatures create vicious reaction mixtures, these can result in hot spots during reagent additions. Inadequate mixing leads to incorrect stoichiometry, creating in turn by-products, and poor crystallization control. For example, DMSO when diluted with a small amount of toluene is more resistant to freezing and so can be cooled to a lower reaction temperature.
