The Industrial Phase-Transfer Catalysis Experts

PTC Tip of the Month E-Newsletter

PTC Reaction of the Month - November 2017

PTC Nucleophilic Aromatic Substitution with Mercaptide

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

Nucleophilic aromatic substitutions are often performed at “high” temperature (60 C – 180 C) depending on the activity of the nucleophile and on the activation of the leaving group on the ring by electron withdrawing substituents. Mercaptides are good nucleophiles and require lower temperatures. Phase-transfer catalysis conditions further activate the reactivity of nucleophiles, though have limited effect on the inherent activity of the ring being attacked. PTC activates the already nucleophilic ethyl mercaptide anion to perform the reaction shown in the diagram at a very mild temperature, which is also useful to avoid hydrolysis of the thioester in the presence of aqueous base.

Interestingly, similar results were obtained by starting with the acid chloride (3,6-dichloropyridine-2-carbonyl chloride) as the starting material, also using TBAB as the phase-transfer catalyst. One equivalent of ethyl mercpatan made the thioester and the second equivalent of ethyl mercaptan performed the nucleophilic aromatic substitution. The inventors also attempted a non-PTC reaction using sodium hydride and the PTC-NaOH reaction worked better.

PTC Organics has helped companies achieve low-cost high-performance nucleophilic aromatic substitutions using phase-transfer catalysis. Now contact Marc Halpern of PTC Organics to improve you process performance and R&D efficiency when developing commercial nucleophilic aromatic substitutions and nucleophilic aliphatic substitutions.


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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