Phase-transfer catalysis excels in a wide variety of N-alkylations, especially those with deprotonatable N-H groups (to form N-anions) sufficiently activated by electron withdrawing groups to have pKa’s of 23 or lower.
Example 63 in this patent describes a solid-liquid PTC N-alkylation of a protected hydrazine with a sufficiently low pKa that produces the substituted hydrazine after deprotection. The KOH was added as a solid and no addition of water.
Since bromide was the leaving group, we would use tetrabutylammonium bromide (TBAB) as the catalyst instead of the more expensive tetrabutylammonium hydrogen sulfate (slightly incorrectly referred to in the patent as tetrabutylammonium sulfate).
The alkylated intermediate was isolated by chromatography before hydrolysis. It is not known if the tetrabutylammonium salts were separated from the intermediate during the chromatography or during the workup since there was only aqueous extraction of the organic phase after the reaction and it had to dissolve the NaBr byproduct. TBAB usually requires aqueous washes with fresh water with no or low ionic strength for effective catalyst separation (see http://www.phasetransfer.com/catsep.pdf).
The inventors note that other alkyl halides were used with this procedure to form other alkylated hydrazine compounds.
If your company has the need to improve N-alkylations, with performance that exceeds that shown in the diagram, now contact Marc Halpern of PTC Organics to explore how we can work together to achieve low-cost high-performance green chemistry, especially for strong base reactions.
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!).
