The Industrial Phase-Transfer Catalysis Experts

PTC Tip of the Month E-Newsletter

PTC Reaction of the Month - October 2022

PTC C-Alkylation of Malonate

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

It is always nice to report an effective PTC reaction performed by one of our long-time loyal readers of the PTC Tip of the Month. Dr. Zofia Komsta is one of the inventors on this patent that uses phase-transfer catalysis to perform a C-alkylation of dimethyl malonate.

The pKa of the methylene group of dimethyl malonate is about 13. The first pKa of carbonic acid (base strength of potassium carbonate) is 10.3. PTC conditions activate the basicity of bases such as hydroxide and carbonate, especially in the presence of non-polar solvents, such as toluene chosen for this C-alkylation. Therefore, potassium carbonate was an effective base in this reaction.

In addition, potassium carbonate serves as a desiccant in case water is present in the system or is generated during deprotonation (in this case KHCO3 is the byproduct of deprotonation, not water). So, the use of potassium carbonate was a good choice for basicity, to activate the enolate due to no hydration and to minimize potential hydrolysis if water would be present.

We are somewhat surprised by the very long reaction time, but that was likely due to the fact that these reaction conditions were chosen for a single attempt and the process was not at all optimized. Dr. Komsta also suggested that there might have been some steric hindrance at work even though the bromide is secondary since the bromoalkyl group is near a multi-ring steroid.

It is very reasonable to assume that if this reaction was to be optimized for a commercial process, the mole ratios would be significantly reduced for the dimethyl malonate, potassium carbonate and the phase-transfer catalyst, relative to the bromoalkyl steroid.

It is noteworthy that Dr. Komsta performed her graduate research under Professor Makosza who was a pioneer of he use of quaternary ammonium catalysts for C-alkylations, first published in 1966, as we teach in our 2-day course “Industrial Phase-Transfer Catalysis.”

When your company needs to develop low-cost high-performance green chemistry reactions using base, now contact Marc Halpern of PTC Organics for PTC-base consulting. Dr. Halpern has been performing PTC C-alkylations since 1976.


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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