One of the most practical advantages when using phase-transfer catalysis is the ability to streamline processes. In our 2-day course “Industrial Phase-Transfer Catalysis,” we highlight multiple examples of leveraging the advantage of PTC to use almost any organic liquid as a solvent in order to eliminate solvent exchanges between steps of a reaction sequence.
The benefits of choosing the same solvent for a PTC reaction to be the same as the solvent used in either a previous step or next step include reducing process cycle time, minimizing or eliminating handling losses, minimizing solvent recovery/recycle/storage tanks and in one classic notable case, significant environmental emissions.
The reaction shown in the diagram does the opposite. The starting material is a phenol derivative that is brought into the process dissolved in toluene as a 13.3% solution. This solution was the product of the previous step that produced the isopropyl methoxy phenol used in this current step. Toluene has been used successfully in hundreds of PTC etherifications including etherifications of phenols. However, the inventors chose to concentrate the solution of starting material in toluene and replace the toluene with acetonitrile as the solvent. This appears to “unstreamline” the process.
The other PTC reaction conditions chosen were quite reasonable using 1.1 mole% tetrabutylammonium hydrogen sulfate, potassium carbonate as the base and a temperature of 40 C. For scale up, we would probably have chosen tetrabutyl ammonium bromide which is less expensive than the hydrogen sulfate and the bromide would likely co-catalyze the reaction by forming in-situ the more active bromoacetonitrile as the alkylating agent. Then again, the reaction time was only 4 hours (likely not optimized), so unless the process scale was very large or if the reactor time is at a premium in a multi-purpose reactor train, there might not be a significant advantage to reducing the reaction time.
During workup, the reaction mixture was treated with water (presumably to dissolve the NaCl byproduct and possibly to start removing the tetrabutylammonium catalyst) and the phases separated. But then the organic phase was washed with 10% aqueous NaCl (instead of just water), perhaps to avoid handling losses of the cyanoether product to acetonitrile that may distribute into water if water was used with no ionic strength. At that point, the inventors switch the solvent back to toluene (under vacuum) before filtration and concentration to provide a 58% solution of the ether in toluene. The cyanoether was introduced into the next step as a solution in toluene.
It is puzzling to understand why the inventors chose to replace the toluene from the previous step with acetonitrile when toluene would have likely been effective for the PTC O-alkylation. Their choice of acetonitrile as the reaction solvent seems non-optimal since their workup involved treatment with water and separation from the aqueous phase which would obviously entrain some acetonitrile at low ionic strength. This solvent exchange is further puzzling since the inventors actually replaced the acetonitrile with toluene after the reaction and workup.
It would appear obvious to use toluene as the reaction solvent for this etherification as avoid the effort, handling of another solvent and extra time for solvent exchange, while avoiding problems associated with the miscibility of acetonitrile and water, then avoid the replacement of the acetonitrile back to toluene, which was used in the next step anyway. This appears to be “unstreamlining” of the process.
If any of our readers would like to offer the rationale for the solvent exchange toluene to acetonitrile and back to toluene, we would be curious to hear it. It should be noted that the inventors reported the same O-alkylation without PTC and they chose NMP as the solvent and NaOH as the base. In that case, they similarly replaced the toluene at the outset of the reaction with NMP and switched back to toluene at the end of the workup in preparation for the next step.
If your company is developing a commercial O-alkylation, explore integrating the extensive highly specialized expertise of PTC Organics in PTC etherifications with your process R&D program to achieve streamlined low-cost high-performance green chemistry for such O-alkylations. Now contact Marc Halpern of PTC Organics.
