The inventors had good intentions by using phase-transfer catalysis for an O-acylation of a phenol with acetyl chloride, stoichiometric NaOH and no added water.
One major problem is that they used 0.5 equivalents of tetrabutylammonium hydrogen sulfate. Since hydrogen sulfate (pKa ~2) is 100 million times more acidic than phenol (pKa ~ 10), it is very likely that half (50 mole%) of the phenoxide ion deprotonated the hydrogen sulfate to form sulfate and the neutral phenol which in turn limited the maximum theoretical yield to 50%. The idea of neutralizing the phenol with exactly one equivalent of NaOH was a good idea to avoid free hydroxide that could potentially hydrolyze the acetyl chloride. It’s a shame that half of that NaOH had to deprotonate the HSO4. They should have used a quat chloride (or bromide, though the in-situ formation of acetyl bromide could be either good or bad, depending on whether it enhances hydrolysis more than acylation)
In addition, one equivalent of water was generated by the deprotonation of the phenol with NaOH (assuming that the inventors would have avoided a hydrogen sulfate quat). Since dioxane was used as the solvent and is miscible with water, that guaranteed that the water will come in contact with the acetyl chloride and cause some hydrolysis
Hydrolysis could have been avoided by using potassium carbonate as the base and desiccant and/or using a solvent such as toluene that rejects water instead of dioxane that attracts water. After all, the job of the phase-transfer catalyst is to bring the phenoxide anion into the organic phase for reaction with the acetyl chloride. Let the quat do the heavy lifting of the reacting anion instead of the solvent.
It is not surprising that the yield was less than 50% due to the combination of using a large amount of a hydrogen sulfate quat that could be deprotonated (accounting for 50% yield reduction) plus using a solvent that readily dissolves water and brings it into contact with the water-sensitive acetyl chloride further reducing the yield to 32%.
It would have been interesting to observe the results if a water-immiscible solvent was used (such as toluene) with a base that is a desiccant and a phase-transfer catalyst that did not contain a deprotonatable hydrogen (such as a quat chloride or bromide). The large catalyst loading was also unnecessary (50 mole% was way too much).
One would hope that most of our readers would not make these obviously bad choices but there are other situations in which poor choices are not so obvious. In those cases, you should really contact Marc Halpern of PTC Organics to integrate highly specialized expertise to properly choose, base, phase-transfer catalyst, solvent and other PTC parameters to achieve low-cost high-performance green chemistry for industrial PTC applications.
