A phase-transfer catalyzed nucleophilic aromatic etherification was described in the March 2021 patent cited in the reaction diagram. There are several interesting points about the reaction conditions.
The first item that stands out is that this reaction was performed at room temperature. Most PTC nucleophilic aromatic substitutions are performed at temperatures of 60 C to 220 C, depending on the nucleophilicity of the nucleophile and the reactivity of the aromatic ring carbon. For example, mercpatides are strong nucleophiles can work at lower temperatures, phenoxides are weaker nucleophiles and require higher temperatures including using thermally stable phase-transfer catalysts.
The nucleophilic aromatic etherification shown in the diagram uses an aliphatic secondary alkoxide attached to a ring. Aliphatic alkoxides are strong nucleophiles. The steric hinderance of the secondary alkoxide that increases the energy of activation is apparently counteracted by the loose [Q+OR-] ion pair that enjoys reduced hydrogen bonding in the bulk organic phase and reduces the energy of activation. The ability of phase-transfer catalysis to reduce energy of activation of nucleophilic substitutions is a common compelling benefit of PTC.
Another interesting aspect of this reaction is the choice of methylene chloride as the solvent in the presence of NaOH with no added water. The combination PTC-NaOH-methylene chloride forms some amount of formaldehyde and this is usually not advisable for a commercial process.
In addition, methylene chloride can act as an alkylating agent forming “methylene bridged” byproducts (acetals in this case). Although methylene chloride is an excellent solvent for most phase-transfer catalysts, it is usually best to consider alternative solvents that are more inert and more environmentally acceptable.
This reaction also uses a remarkably low excess of NaOH (20 mole% relative to the alcohol; 25 mole% relative to the dichlorophthalazine). The procedure notes that the reaction was run until the “termination of the reaction was confirmed by TLC”. It is not clear if that means that the reaction stalled or proceeded to complete conversion.
The t-butyl ester likely made the reactant resistant to hydrolysis even in the presence of strong non-hydrated NaOH.
The high catalyst loading of 30 mole% TBAB may have been due to small scale or perhaps the bromide suppressed hydroxide availability due to affinity of tetrabutylammonium to bromide over hydroxide. If the latter was in effect, then, as we teach in our 2-day course “Industrial Phase-Transfer Catalysis” the use of TBA HSO4 would likely have resulted in a lower requirement for phase-transfer catalyst loading.
When you need to choose PTC-NaOH conditions like an expert to achieve low-cost high-performance green chemistry, now contact Marc Halpern of PTC Organics to explore integrating our highly specialized expertise in strong base PTC reactions with your company’s commercial goals.
