The good news in this patent is that the inventors reported that the use of catalytic TBAI reduces reaction time for complete conversion from 60 hours to 24 hours (81% conversion in 3 hours). We assume that the 2 mole% iodide forms ethyl iodide in in-situ that speeds up the reaction. That’s great. But why do they use t-butoxide as base when hydroxide can probably be used with the same phase-transfer catalyst? The pKa pf the N-H group is under 23 which means that PTC-NaOH should work well for both the deprotonation as well as the N-alkylation.
Since the inventors used THF as the solvent, perhaps they were not performing phase-transfer catalysis at all. They may have just been using the TBAI as an organic-soluble source of iodide. That would be consistent with using sodium t-butoxide as base that would be soluble in THF together with the acetamide starting material.
If this was our reaction for development, we would screen the use of an accessible quaternary ammonium phase-transfer catalyst with a q-value well above 1 and NaOH as the base. In fact, we would start with butyl triethylammonium bromide, that has a q-value of 1.75, since this is likely a PTC T-Reaction and if the phase-transfer catalyst decomposed by nucleophilic attack of the N-anion, it would actually generate the desired product! If the reaction turns out to be a PTC I-Reaction, we would add 1 mole% KI to the reaction mixture as well.
In any case, we would start this development program intending to replace the t-butoxide with PTC and hydroxide to save cost and facilitate handling.
If your company has any commercial strong base reactions that use t-butoxide, now contact Marc Halpern of PTC Organics Inc. to explore major savings by replacing the expensive hard-to-handle t-butoxide with inexpensive hydroxide that generates water as by product instead of t-butanol.
About Marc Halpern
Dr. Halpern is founder and president of PTC Organics, Inc., the only company dedicated exclusively to developing low-cost high-performance green chemistry processes for the manufacture of organic chemicals using Phase Transfer Catalysis. Dr. Halpern has innovated PTC breakthroughs for pharmaceuticals, agrochemicals, petrochemicals, monomers, polymers, flavors & fragrances, dyes & pigments and solvents. Dr. Halpern has provided PTC services on-site at more than 260 industrial process R&D departments in 37 countries and has helped chemical companies save > $200 million. Dr. Halpern co-authored five books including the best-selling “Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives” and has presented the 2-day course “Practical Phase-Transfer Catalysis” at 50 locations in the US, Europe and Asia.
Dr. Halpern founded the journal “Industrial Phase-Transfer Catalysis” and “The PTC Tip of the Month” enjoyed by 2,100 qualified subscribers, now beyond 130 issues. In 2014, Dr. Halpern is celebrating his 30th year in the chemical industry, including serving as a process chemist at Dow Chemical, a supervisor of process chemistry at ICI, Director of R&D at Sybron Chemicals and founder and president of PTC Organics Inc. (15 years) and PTC Communications Inc. (20 years). Dr. Halpern also co-founded PTC Interface Inc. in 1989 and PTC Value Recovery Inc. in 1999. His academic breakthroughs include the PTC pKa Guidelines, the q-value for quat accessibility and he has achieved industrial PTC breakthroughs for a dozen strong base reactions as well as esterifications, transesterifications, epoxidations and chloromethylations plus contributed to more than 100 other industrial PTC process development projects.
Dr. Halpern has dedicated his adult life to his family and to phase-transfer catalysis (in that order!).
