The choices of catalyst and solvent for this reaction are interesting, especially upon scale up.
Phase-transfer catalysis excels in a wide variety of N-alkylations, including heterocycles such as pyrazole that is easily deprotonated by weak base such as potassium carbonate. Once the pyrazolide anion is formed, most standard phase-transfer catalysts with sufficient organophilicity can transfer the N-anion into almost any organic solvent.
In this case, the inventors chose ethyl acetate as the solvent for this reaction on a 20 g scale. This is a reasonable choice since PTC systems are easier to handle during workup with solvents that form two phases with water. This is due to the ease of dissolving the KCl and KHCO3 salt byproducts in water and then separating the two phases to remove the salt from the product.
18-crown-6 is certainly an effective phase-transfer catalyst but it is also much more expensive than common quaternary ammonium phase-transfer catalysts. The inventors clearly knew about PTC as evidenced by their knowledge of crown ethers. So it is not clear why they chose the expensive crown ether. Using 20 g grams of dimethyl pyrazole, they used 11 grams of 18-crown-6. That is a strange choice.
The inventors scaled up the reaction to 400 g of dimethylpyrazole. At that point, they probably realized that using 20 mole% 18-crown-6 was overkill and very expensive so they reduced the loading to 3.6 mole% 18-crown-6 which was 40 grams. That is still a lot. We wonder why they didn’t at least screen much less expensive readily available quaternary ammonium phase-transfer catalysts.
In addition, upon scale up to 400 grams, the inventors changed the solvent to acetonitrile. Since the product was isolated by distillation, they may not have needed to dissolve the salt byproducts, but the workup still included dissolution of salts in water and two subsequent washes with aqueous NaCl.
In the end, the isolated yields for both sets of reaction conditions were in the 90’s. So, the results were good. However, we expect that if the reaction needed to be scaled up further, there would be better choices of solvent and phase-transfer catalyst to minimize both cost and the amount of aqueous waste.
In our 2-day course “Industrial Phase-Transfer Catalysis,” we teach how to choose phase-transfer catalyst, solvent, base, hydration, agitation and other process parameters to optimize performance, cost and green chemistry. Your company should now inquire about conducting this valuable PTC in-house at your site.
