The highest performing phase-transfer catalysis reaction is etherification and PTC is usually the best choice for etherifications except for commodity ethers such as lower symmetrical dialkyl ethers such as diethyl ether that are made by dehydration of the alcohols.
In this patent, the inventor performed etherifications using methyl iodide and deuterated methyl iodide on scale from 10 g to 200 g.
As we have been highlighting in the past few months in the PTC Tip of the Month newsletter, a lot of inventors have been using water-miscible solvents such as acetonitrile and acetone for PTC reactions, when they probably could have been using water-immiscible solvents and PTC that usually simplify workup. In this case, the inventor used mostly acetone.
The workup started with a filtration, evaporating the solvent, then partitioning the product and salts between water and methylene chloride followed by water washes. If a water-immiscible solvent would have been used, the filtration and solvent strip could probably have been eliminated and handling losses would likely have been avoided.
When using 2.2 equivalents of methyl iodide to dietherify a catechol derivative using 3 equivalents of potassium carbonate as the base and acetone as the solvent, a yield of 72.9% was achieved without PTC after 36 hours at 38-40 C. In other words, PTC is not needed for the reaction to proceed. Adding 1 mole% TBAB improved the reaction a bit to 76.3%. Increasing the TBAB to 5 mole% increasing the yield to 86.6%. In other words, PTC does have a positive effect.
Interestingly, the use of 10 mole% 18-crown-6 resulted in 81% yield which was not as effective as 5 mole% TBAB. Quantitative yield (100%) was achieved with 5 mole% 18-crown-6 by increasing the methyl iodide amount to 3.0 equivalents.
The use of 5 mole% tetrabutylammonium iodide with 2.2 equivalents methyl iodide in acetone gave 79.8% yield. We speculate that the inventor might have screened TBAI in order to assess whether the bromide of TBAB was forming the less reactive and more volatile methyl bromide which might have ben responsible for less than quantitative yield. We do not know if that was the rationale but it is interesting to speculate.
One attempt was made using acetonitrile with 5 mole% TBAB and the yield was only 75% even though the methyl iodide was used in the larger excess of 3 equivalents.
We would have liked to see how high the yield would have been with a water-immiscible solvent since that would have eliminated the filtration and solvent evaporation and eliminating the filtration might have avoided handling losses.
When your company needs to develop the lowest-cost highest-performance green chemistry processes for etherifications, now contact Marc Halpern of PTC Organics to explore integrating highly specialized expertise in industrial PTC etherifications with your development and/or optimization program and achieve both higher profit and high R&D efficiency.
