As we teach in the 2-day course “Industrial Phase-Transfer Catalysis,” PTC enables high-performance reactions of water-sensitive compounds in the presence of water when properly choosing PTC conditions. The reaction shown in the diagram is particularly interesting because of the combination of a high pKa substrate that requires strong base for deprotonation and the presence of an ester that may be sensitive to hydrolysis.
The pKa of fluorene is 23 so the pKa of dibromofluorene is no more than 1-2 pKa units lower than that. The pKa of water (the conjugate acid of hydroxide) is 16, so that means that hydroxide must deprotonate the organic substrate to form a fluorenyl anion that is about 1 million times more basic than hydroxide. This requires a strong hydroxide base and the inventors used 12.3 equiv of 50% NaOH.
One might expect that such a large excess of 50% NaOH would hydrolyze the ester starting material and/or the diester product.
Under PTC conditions, when hydroxide has a choice between acting as a nucleophile and acting as a base, hydroxide prefers to act as a base. This does not totally eliminate the potential for ester hydrolysis, but the inventors performed the reaction at room temperature and used toluene as the solvent. Both of these choices likely minimized ester hydrolysis. Toluene rejects water and protects the esters from hydrolysis to some degree as long as non-catalyzed interfacial can be minimized.
Agitation was not described in detail in the procedure but the inventors noted that they used magnetic stirring. Magnetic stirring is often less vigorous than mechanical stirring and that might be an additional reason that minimized interfacial hydrolysis.
We each explicit guidelines for using PTC with water-sensitive compounds in our 2-day course “Industrial Phase-Transfer Catalysis.” Register for the rare public PTC course in Prague in October 2019 by June 30, 2019 and you will enjoy a 15% discount. Alternatively, conduct the PTC course in-house and train up to 30 process chemists how to choose PTC conditions like an expert to achieve low-cost high-performance green chemistry for many current and future processes in development or in production.
Now contact Marc Halpern of PTC Organics to explore the many different ways your company can improve process performance and R&D efficiency using PTC Organics’ highly specialized expertise in industrial phase-transfer catalysis.
