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
