Richard Fox and Jun Qiu of Bristol-Myers Squibb Company just published a truly landmark publication that will be of great practical benefit to PTC process development chemists and engineers from now and forever. This crucial reference provides massive data for the partitioning of 67 quaternary ammonium and phosphonium salts between water and 12 organic solvents. The quat salts chosen include almost all of the most widely used phase-transfer catalysts in commercial PTC applications. This historical publication was published on December 27, 2019 in the journal Organic Process Research and Development and is referenced at https://dx.doi.org/10.1021/acs.oprd.9b00496.
The ramifications of this work are of huge importance for a variety of purposes.
Environmental
We can use the data in this landmark publication to estimate the number of water washes that may be required to effectively separate a water-soluble phase-transfer catalyst from the product dissolved in any of the solvents studied.
Quality and Purity
We can use the data in this publication to estimate or achieve a defined maximum level of residual phase-transfer catalyst in a product dissolved in one of the solvents studied, as a function of the number of water washes during workup.
Choice of Solvent, Phase-Transfer Catalyst and Leaving Group in PTC Systems
The data in this historical publication give the most information ever reported for toluene which is one of the most common solvents used in PTC reactions in the lab and in the plant. When you look at the partitioning data in Table 2, you may wonder how PTC ever works in toluene since most quat salts partition into water MUCH more than into toluene (often hardly at all into toluene). The answer is that PTC reactions are typically performed with much salt in the aqueous phase or even under solid-liquid conditions. In these cases, the partitioning of the quat salts is between the solvent and high ionic strength aqueous phase (experiencing salting out of quat salt), not between the solvent and pure water. The good news is that after the first phase separation that removes the majority of the water-soluble byproduct salts after the reaction is finished, the phase-transfer catalyst will wash out into fresh water (little to no ionic strength) very readily, as suggested by the reported data.
Most PTC process development chemists screen tetrabutylammonium salts at some point during each development program (even though tetrabutylammonium salts are often not optimal). While it is known that softer more polarizable anions pair more strongly with quat cation, this publication provides quantitative data for 18 tetrabutylammonium salts that enable to predict the competition between reacting anions and leaving group that may be controlled by choice of solvent for desirable partitioning. The data quantitatively confirm how much more tetrabutylammonium iodide, for example, may distribute into a given solvent relative to 17 other anions paired with tetrabutylammonium. Iodide is a know PTC catalyst poison, though not in systems that involve anionic reactants that contain many carbon atoms.
As we teach in our 2-day course “Industrial Phase-Transfer Catalysis”, it is preferable to use a mesylate leaving group than a tosylate leaving group from the standpoint of catalyst poisoning (or partial catalyst poisoning that can slow down a reaction) and this publication provides the data to support the notion that tetrabutylammonium tosylate partitions into certain solvents while tetrabutylammonium mesylate partitions much more into water. Of course, you can perform the desired reactions with high ionic strength in the aqueous phase that will salt out the tetrabutylammonium salts into the organic reaction phase, but the publication shows that it will be much easier (i.e., less costly) to wash the quat mesylate salt into water than the quat tosylate salt when the reaction is finished.
The data in the table confirm that if you are performing a nucleophilic substitution with thiocyanate for example, the quat thiocyanate will partition to a much greater extent into certain organic solvents relative to the corresponding quat bromide. This is important to know since if you are using a small excess of thiocyanate to save money and you are using a bromide leaving group, the small amount of quat thiocyanate remaining at high conversion will continue to partition into the well-chosen organic solvent reaction phase and not remain in the water where it will not react with the organic-soluble substrate.
“Third-Phase” PTC
As we teach in our 2-day course “Industrial Phase-Transfer Catalysis”, when you are able to create a third phase in PTC systems, you often observe extremely high reactivity. This happens when the simultaneous hydrophobicity and organophobicity of certain quat salts are such that the quat salt does not dissolve in either phase. The publication cites some of these salts, though they do not mention whether a third liquid phase is formed.
While this publication is extremely appreciated by PTC experts, one catalyst that we would have liked to see is methyl tributyl ammonium chloride, simply because it is used in large commercial quantities (more than 100 metric tons in single applications) and excels for PTC T-Reactions.
This brief review is just a small sample of the MANY other ramifications this landmark article provides to real world PTC process development chemists and engineers. You must read the article in its entirety to learn of the MANY structure-activity relationships and other scientific conclusions explicitly reported by the authors that are not mentioned here. The authors pulled back the curtain on MANY facts previously hidden from our knowledge and we owe a debt of gratitude to these authors.
It is a sure thing that we will definitely incorporate this crucial reference in all future sessions of the 2-day course “Industrial Phase-Transfer Catalysis.”
On behalf of the entire current and future PTC community, we would like to thank Richard Fox and Jun Qiu for their extremely important contribution to PTC process development and recognize their historic impact on the purity, quality, safety, process cost reduction and environmental performance of the products and processes that will implement phase-transfer catalysis in production in the future!
