The Industrial Phase-Transfer Catalysis Experts

PTC Tip of the Month E-Newsletter

PTC Reaction of the Month - October 2023

PTC Esterification with a Twist in a 3-Reaction Sequence

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

The 3-reaction sequence shown in the diagram starts with an N-alkylation that does not appear to be catalyzed by TBAB. In fact, the N-alkylation in the presence of TBAB is somewhat puzzling. The amount of base added was 2.15 equivalents. The first equivalent obviously neutralizes the carboxylic acid to form the sodium carboxylate salt. If the second equivalent of base would deprotonate the N-H of the piperidine ring, then the N-anion would be a stronger nucleophile than the O-anion of the carboxylate. But I don’t expect the pKa of the piperidine N-H to be low enough to be deprotonated by 32% NaOH. If so, then I would expect the O-anion of the carboxylate to be more nucleophilic than the non-bonding electrons on the nitrogen atom of the non-deprotonated N-H. It is puzzling to me that the acid chloride reacts at the neutral nitrogen atom and not at the O-anion of the carboxylate. Then again, I must accept the reality that the acid chloride reacts at the nitrogen atom despite the formation of the carboxylate anion before adding the acid chloride last.

The second reaction in the sequence is the esterification of the carboxylate with a phenacyl chloride and that reaction makes total sense for phase-transfer catalysis by tetrabutylammonium.

The removal of water by azeotropic distillation very likely enhances the reactivity of the carboxylate anion which very likely reduces the combination of time and temperature to achieve complete conversion.

In the third reaction, the ammonium acetate apparently serves as a source of ammonia that provides the nitrogen atoms for the formation of the imidazole. The mechanism of this reaction is not immediately obvious (at least to me it is not obvious). In a somewhat similar reaction, though with significant differences, the synthesis of imidazole derivatives in the presence of ammonium acetate is described in this reference: M. Adib, S. Ansari, S. Feizi, J. A. Damavandi, P. Mirzaei, Synlett2009, 3263-3266. A mechanism is proposed that may possibly be adapted to the reaction shown above. It may require a lot of rearrangement of atoms to rationalize the mechanism for the third reaction shown in the diagram.

In the reaction reported by Adib et al, “a one-pot, four-component synthesis of 1,2,4-trisubstituted 1H-imidazoles was achieved in very good yields by heating a mixture of a 2-bromoacetophenone, an aldehyde, a primary amine and ammonium acetate.”

This 3-reaction sequence is an example of why we find organic chemistry to be interesting, even after decades of experience.

What else is interesting AND PRACTICAL? The 2-day course “Industrial Phase-Transfer Catalysis“! Now is the best time to plan your 2024 training budget and schedule this course in-house at your company site, presented by 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!).

One thought on “PTC Esterification with a Twist in a 3-Reaction Sequence

  1. Jeff Marra

    Hi Mark,

    Just thinking out loud…
    In the first reaction, the piperidine carboxylate would probably be in the aqueous layer, and therefore extremely hydrogen bonded so that the negative charge would be dispersed and effectively rendered non reactive.
    The acid chloride must be in the organic phase or it would be hydrolyzed; does the TBAB then help bring the acid chloride into the aqueous layer in a organic solvent sphere so it can find the piperidine N and react?

    Organic Chemistry hand waving at it’s best, making up stuff to explain what actually happened!

    Hope all is well, my friend.

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