The Industrial Phase-Transfer Catalysis Experts

PTC Tip of the Month E-Newsletter

PTC Reaction of the Month - February 2019

PTC Addition of Alcohol to Nitrile in the Presence of an Ester

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

The reaction shown in the diagram has several interesting aspects. First, some may find it surprising that the addition of the secondary alcohol to the carbon atom of an electron deficient nitrile proceeds well without being overwhelmed by hydrolysis of the ester. The pKa of the alcohol is such that the alkoxide is formed in relatively small concentration by the deprotonation equilibrium. That would appear to give plenty of opportunity for the aqueous hydroxide to hydrolyze the ester. We do not know the extent of hydrolysis due to the 45% isolated yield after chromatography.

Phase-transfer catalysis provides several factors that protect the ester from hydrolysis. The first is that the cyclopentanol ester is dissolved in the methylene chloride phase and the phase boundary between the organic phase and the aqueous phase provides some protection to the ester from hydrolysis by attack of the hydroxide located in the aqueous phase. Of course, interfacial hydrolysis is possible. That is one reason that it is important to avoid over-agitation that would cause hydrolysis and instead allow the phase-transfer catalyst do its job to bring the alkoxide in contact with the nitrile. We also speculate that the inventors wisely chose to work at sub-ambient temperature to minimize hydrolysis among other reasons.

If we were designing the experiments for the development of this reaction, we would have minimized the presence of water, possibly using solid KOH and maybe even adding some potassium carbonate to further control hydration. As noted above, we would recommend avoiding over-agitation. The choice of tetrabutylammonium hydrogen sulfate by the inventors was good as was the choice to work at low to ambient temperature.

We speculate that 10 equiv of KOH was overkill. In fact, it is known that when using excess hydroxide in the presence of methylene chloride, formaldehyde is formed and we avoid such conditions whenever possible.

Note that we do not know the extent of hydrolysis since the 45% isolated yield after chromatography might be due to handling losses or might be due to hydrolysis or other side reactions. It is possible that the reaction was very selective for the desired product. We just don’t know.

If you are developing a strong base reaction, you should now contact Marc Halpern of PTC Organics to benefit from integrating our four decades of highly specialized expertise in industrial PTC strong base reactions


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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