- Near-critical Water (NCW),
- which offers organic solubilities and the potential for reversible acid/base catalysis.
- Organic/Aqueous Tunable Solvents (OATS),
- or water-soluble catalysts (including both aqueous organometallic complexes and enzymatic biocatalysts) that can perform difficult transformations on highly hydrophobic substrates.
Near-critical Water (NCW), maintained at 200-300 °C, offers an alternative to liquid water, which is a poor solvent choice for many nonpolar chemicals. It also offers an alternative to organic solvents, since it is able to dissolve both organics and salts. NCW also acts as a self-neutralizing acid and base, so that no catalysts need be added for certain reactions, eliminating post-reaction neutralization and greatly reducing salt waste.
NCW offers substantial cost savings in separation reactions, which, in typical processes, account for 60-80% of the capital and operating costs. With organic reactions in NCW, the separation can be as simple as mere cooling and decanting. The utility of this medium has been demonstrated for a diverse group of organic syntheses, including acylations , alkylations , and condensation reactions .
Self-neutralizing alkylcarbonic acids have also been used for acid-catalyzed synthesis. Alkylcarbonic acids are formed by CO2 addition to primary alcohols — for example, methylcarbonic acid from methanol as shown in Figure 2 (below) (b), by the same mechanism as carbonic acid in carbonated water, as shown in 2(a).
This provides in-situ acid formation which is easily neutralized without the addition of base . Alkylcarbonic acids combine good organic solubility with simple neutralization via depressurization. The use of in-situ acid completely eliminates the solid wastes associated with many acid processes. We have compared the reaction rates of several alkylcarbonic acids, the effect of CO2, and demonstrated the use of alkylcarbonic acids for acetal formation  and the hydrolysis of β-pinene . In specific cases, the necessary methylcarbonic acid is formed by simply bubbling CO2 into the methanol solution. This is shown in Figure 3 (below), where the protonation of Reichardt’s dye results in a distinct color change.
As mentioned, tunable solvents are proving useful in novel homogeneous catalysts. Homogeneous catalysts typically offer higher activities and selectivities than heterogeneous catalysts, but it is very difficult to separate these complexes from reaction products. In addition, they are extremely expensive and toxic, particularly asymmetric types, so their recovery and re-use are imperative.
Separating these catalysts becomes even more important, and difficult, in pharmaceutical manufacturing processes, since even trace levels of metallic contamination are unacceptable in product. The use of recoverable homogeneous catalysts enables the development of highly active organometallic complexes that can be easily removed from the product stream, yielding pure products and recyclable catalytic complexes.
|Figure 4. Illustrative example of the OATS concept for phase separation. The picture on the left is a 50:50 mixture of tetrahydrofuran (THF) and water. After exposure to 15 bar CO2 pressure (right), the mixture splits into two phases. The top phase contains an organic dye (methyl yellow) while the bottom phase contains an aqueous dye (Blue #1).
Figure 4 (at right) demonstrates this “miscibility switch” with a mixture of water and a water-miscible organic solvent (THF). The high-pressure sapphire tube assembly contains an organic soluble pharmaceutical analog (methyl yellow) and a water soluble catalyst analog (Blue Dye #1). At ambient conditions, the two phases are completely miscible, as shown by the green color. With the addition of 15 bar of CO2, the THF organic phase is expanded, tuning the solvent properties, inducing a complete phase separation shown by the distinct yellow and blue phases.
This approach represents an interdisciplinary effort aimed at designing solvent and catalytic systems whereby a reversible stimulus induces a change in the system’s phase behavior, enabling easy recovery of the homogeneous catalysts through simple separation techniques, such as filtering and extraction, which are normally applied to heterogeneous or biphasic catalytic systems. Specific examples include the application of gaseous CO2as a benign agent in GXLs to induce catalytic recycle of:
- Miscible water/organic systems,
- where a catalyst is modified for aqueous solubility;
- Miscible poly(ethylene glycol)/organic systems,
- where a catalyst is modified for PEG solubility;