The Industrial Phase-Transfer Catalysis Experts

PTC Tip of the Month E-Newsletter

PTC Reaction of the Month - October 2017

N-Alkylations Using Catalytic Tetrabutylammonium Iodide

By Marc Halpern, the leading expert in industrial phase-transfer catalysis.

Three N-alkylations were published this month using tetrabutylammonium iodide and each used conditions that were surprising.

N-Ethylation of Acetamide Using TBAI

The inventors used the combination of tetrabutylammonium iodide catalysis to enable the N-ethylation of an acetamide using ethyl bromide that is much less expensive than ethyl iodide. The use of THF as the solvent may have been required in order to solubilize the polar reactant. We are not sure why the inventors chose sodium t-butoxide as base instead of the less expensive and easier to handle sodium hydroxide though the reason may have been solubility in THF. We speculate that a less polar solvent could have been used and form two phases with water during workup in which case PTC-NaOH conditions are known to be effective in alkylations of substrates with a pKa of 23 or less using ethyl bromide.

N-Alkylation of Indazole Using TBAI

N-alkIndazole

TBAI was used to activate methyl chloroacetate in the N-alkylation of an indazole. We are not sure why the inventors used such a polar solvent unless it was really necessary to dissolve the indazole. Again, we speculate that a less polar solvent could have been used and form two phases with water during workup in which case PTC-NaOH conditions are known to be effective in alkylations of substrates with a pKa of 23 or less using methyl chloroacetate.

When reading the procedure, it seems like the inventors initially expected the reaction to be complete by using 1.5 equiv of methyl chloroacetate and potassium carbonate. The extended reaction time was likely due to the multiple additions of alkylating agent and base after every analysis. We too would have expected the reaction to go to completion with the initial charge of 1.5 equiv methyl chloroacetate and potassium carbonate that also serves as a desiccant, when using PTC-iodide co-catalysis and a less polar solvent more convenient for solvent recovery.

The challenge in this reaction appears to be the selectivity of which nitrogen to alkylate.

N-Alkylation of Tetrahydropyrimidinone Using TBAI

N-alkpyrimidinone
In this N-alkylation, sodium hydride may have been needed due to the high pKa of the N-H of the tetrahydropyrimidinone, so PTC-NaOH conditions were probably not feasible and the use of a less polar water immiscible solvent would not have provided advantage. As in the examples above, catalytic TBAI was used as an iodide catalyst to activate the chloromethyl group.

Choose PTC conditions like an expert to improve your N-alkylations! How? Now bring the excellent course “Industrial Phase-Transfer Catalysis” to your company and train your staff to improve numerous processes and increase R&D efficiency. Now contact Marc Halpern of PTC Organics.


About Marc Halpern

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!).

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