Most of the common quaternary ammonium phase-transfer catalysts are made by reacting a trialkylamine with an alkyl halide. However, sometimes specialty quat salts are required that have anions other than halides. The most common method for making quat salts that are not halides, is by liquid-liquid ion exchange by mixing a solution of a quat halide with an aqueous solution of a sodium or potassium salt of the “new” anion.
However, as we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” different anions have different affinities toward quat cations. The relative affinities between quat cations and anions are determined by thermodynamics. As a general guideline, lower charge density anions have a higher affinity toward quat cations than higher charge density anions. Thus, the affinity of halides toward quat cations such as tetrabutylammonium or methyl trioctyl ammonium follows the order I > Br > Cl > F. Tosylate has a much higher affinity toward quat cations than mesylate due to the delocalization of the single negative charge over many more atoms.
A patent was issued last week that provides insight into the relative affinities of bromide and tosylate toward a specific quat. The salts glycopyrronium bromide and glycopyrronium tosylate are biologically active compounds that are used to treat of a variety of medical conditions. The structures are shown in the figure.
It is interesting that the inventors used a 1:1 ratio of tosylate:bromide (instead of an excess of tosylate used in other similar ion exchange transformations) and that gave 70.6% tosylate 1.6% bromide after extraction and treatment with cyclohexane to precipitate the product. Further dissolution, precipitation and cooling reduced the bromide content to 0.1% bromide. A third and final crystallization resulted ion 53% yield of the tosylate that was essentially free of bromide.
The important lesson from these results is that, consistent with what we teach about the affinities of tosylate and bromide toward quat cations, there is a strong preference for quat cations to pair with tosylate over bromide.
For reasons that are not totally clear (possibly pair with the bromide?), the inventors added TBAB, CTAB (cetyl trimethyl ammonium bromide) , Aliquat 336 and even 18-crown-6 in catalytic quantities and obtained similar results. Aliquat 336 gave the best result at 72.6% yield with only 0.04% bromide. We can speculate that the chloride of Aliquat 336 more readily exchanged with bromide than the other non-chloride phase-transfer catalysts.
One puzzling aspect of this patent is that the key claims 1 and 2 include the presence of a phase-transfer catalyst, however Example 2 that is performed in the absence of a phase-transfer catalyst appears to produce glycopyrronium tosylate that meets the low-bromide specification.
If you want to learn more about achieving the best performance for anything related to phase-transfer catalysts or phase-transfer catalysis, now contact Marc Halpern of PTC Organics.
