Hexaalkylguanidinium salts are used as thermally stable phase-transfer catalysts. While the guanidinium salts shown in the diagram are not a hexaalkylguanidinium salt, it caught our attention because these compounds have an unusual and surprisingly high affinity for sulfate over chloride.

This is a big deal both in concept and in practice.

Following are two excerpts from the patent Williams; N., Custelcean; R., Seipp; C., Moyer; B., Ellis; R., Abney; C. (UT-Battelle) US Patent 11,001,554, 11-May-2021: “The above described DIG [di-iminoguanidinium] receptor is remarkable in both the unparalleled high selectivity for sulfate over chloride as well as the unique ability to solubilize the superhydrophilic ion pairs in the aliphatic hydrocarbon solvent.” Another statement about the utility of this discovery is “The removal of superhydrophilic anions, such as sulfate and phosphate, from brines, agricultural runoff, and industrial waste continues to be an ongoing challenge.”

The inventors compared these lipophilic di-imino-guanidinium [“DIG”] salts to Aliquat 336 in terms of their abilities to extract sulfate from an aqueous stream. The DIG’s were able to extract 4-5 orders of magnitude more of sulfate into dichloroethane than Aliquat 336 and an additional 1-3 orders of magnitude into hydrocarbons.

Similarly, the lipophilic DIG’s were about 1,000 times more selective toward sulfate than chloride versus Aliquat 336 (dichloroethane as solvent). In hydrocarbons, lipophilic DIG’s were about 1,000-5,000 times more selective for sulfate than chloride. This is very unusual behavior for PTC experts used to opposite behavior for quaternary ammonium cations. Classical phase-transfer catalysts greatly prefer monoanions over dianions and trianions.

It should be noted that the DIG’s for which data were presented apparently have alkyl groups on the aromatic rings that have between 4 and 12 carbon atoms. These extra carbon atoms (Rnx) impart the added lipophilicity to the guanidinium salts. It is not clear what are the exact structures of the DIG’s for which data are shown in the figures.

The patent addresses the thermodynamic factors that are relevant to the classical understanding of why hydration of sulfate versus hydration of chloride makes it so hard to extract sulfate from aqueous solution in the presence of chloride. This is an interesting and surprising patent to those few of us who have been teaching quat-anion affinities for decades.

Tetralkyl ammonium salts are typically prepared by reacting a trialkylamine with an alkyl bromide. The reason is that when reacting trialkylamines with alkyl chlorides that have 2 or more carbon atoms (ethyl halide and higher), the amine usually acts primarily as a base that dehydrochlorinates the alkyl chloride to form an alkene and the amine hydrochloride. For example, while it is easy to prepare tetrabutyl ammonium bromide from tributylamine and butyl bromide in acetonitrile, one cannot prepare tetrabutyl ammonium chloride from tributylamine and butyl chloride since dehydrochlorination of butyl chloride dominates over substitution.

A patent was issued recently [Anbanandam; P. (Agency for Science, Technology and Research) US Patent 10,995,220, 04-May-2021] that successfully prepares hydroxyethyl quat salts from ethanolamine derivatives and alkyl chlorides or alkyl dichlorides such as 1-chlorododecane, 1,10-dichlorodecane and 1,4-dichlorobutane. All of these alkyl chlorides contain beta-hydrogen atoms and could undergo elimination in principle, but they appear to quaternize instead of dehydrochlorinate.

N-methyldiethanolamine was quaternized with 1.02 equiv 1-chlorododecane at 100 C for 42 hours in the absence of solvent to afford N,N-bis(2-hydroxyethyl)-N-methyl dodecyl ammonium chloride in 88% yield as a waxy solid.

N,N-dimethylaminoethanol was reacted with 1,10-dichlorodecane at 80 C for 4 hours in the absence of solvent to afford the corresponding bis-quat salt in 64% yield.

N,N-dimethylaminoethanol was reacted with 1,4-dichlorobutane at 80 C for 30 minutes in the absence of solvent to afford the corresponding bis-quat salt in 69% yield.

In all cases, quaternization did not occur at room temperature and proceeded well at 80 C-100 C

The inventors did not prepare these quat salts to be used as phase-transfer catalysts. These hydroxyethyl quat salts and bis-quat salts, including quats with benzyl groups, were reacted with diisocyanates to form polyurethanes that were in turn found to be effective as anti-fouling agents for marine applications. The quat groups impart biocidal properties to the polyurethanes, especially those containing benzyl groups.

The reason that we highlight here the alkyl chloride alkylating agents and not the benzyl chlorides is the surprising avoidance of dehydrochlorination that is not possible with the benzyl halides.

Scott Sherwood, a highly creative scientist who attended our 2-day course “Industrial Phase-Transfer Catalysis,” solved a problem that usually renders anion exchange resins as impractical for using them as polymer-bound phase-transfer catalysts. Scott’s innovation is as described in Sherwood; S. (Eagle US 2 LLC) US Patent 10,968,153, 06-Apr-2021.

As many of you are aware, the most common “strong base anion exchange resins” are quaternary ammonium salts that are bound to crosslinked polystyrene that are produced by chloromethylating crosslinked polystyrene followed by amination using a tertiary amine (most commonly trimethylamine).

As a loyal reader of the PTC Tip of the Month newsletter, you are well aware that the most common class of phase-transfer catalysts. Also as a loyal reader of the PTC Tip of the Month newsletter, you are aware that separation of quaternary ammonium phase-transfer catalysts from the product is an important requirement that is sometimes challenging.

For that reason, strong base anion exchange resins that are essentially polymer-bound quaternary ammonium salts, have been studied as phase-transfer catalysts since the early days of PTC in the 1970’s since such these insoluble solid resins provide the automatic benefit of separation of the quaternary ammonium phase-transfer catalyst from the product when the product is liquid or dissolved in a liquid organic solvent.

As we discuss in the course “Industrial Phase-Transfer Catalysis”, one of the major challenges of using commercial strong base anion exchange resins as phase-transfer catalysts has to do with the hydrophilic-lipophilic balance inside of the resin matrix.

Even though the polymer backbone of the anion exchange resin is hydrophobic crosslinked polystyrene, the polymer-bound benzyl trimethyl ammonium functional group is quite hydrophilic. The characteristics of strong base anion exchange resins include a high water content (“water retention”) wherein water typically constitutes 30 weight% or more of the total weight of the resin.

This high water-content is a barrier for non-polar organic solvents to penetrate (“swell”) the anion exchange resin, especially “gel” resins.  Common organic solvents used in PTC systems such as toluene, do not penetrate the interior of the resin bead and therefore most of the anions paired with the quaternary ammonium cations in the interior of the bead are not available for reaction with reactant dissolved in the toluene. Even more polar solvents that are immiscible with water, such as chlorinated hydrocarbons, do not penetrate into the interior of the bead due to the high water content.

As we teach in our course “Industrial Phase-Transfer Catalysis,” macroporous strong base anion exchange resins with low ring substitution (e.g., only 40% of the benzene rings of the polystyrene are chloromethylated and quaternized) can be effective polymer-bound phase-transfer catalysts (see for example Arrad, O.; Sasson, Y.; J. Org. Chem., 1989, 54, 4993). The problem with low ring substitution is that the “capacity” (density of quaternary ammonium groups per unit volume) is low and a lot of resin is required for a small amount of conversion.

The reason that strong base macroporous anion exchange resins work better than strong base gel resins for phase-transfer catalysis is that the pores/channels in the macroporous resins for liquid to penetrate the interior of the bead are much wider and enable access to the internal quaternary ammonium sites.

In Scott Sherwood’s patent, he reported the use of Purolite PPA 500PLUS for the replacement of bromide with chloride, for example to remove bromide from 1-bromo-2-chloroethane by converting it into 1,2-dichloroethane. PPA 500PLUS is a strong base macroporous anion exchange resins with a reasonably high capacity (1.15 eq/L). The classical problem of using string base anion exchange resins as polymer-bound phase-transfer catalysts is present when using PPA 500PLUS since its water content is typically 57%-63% water by weight.

The inventor solved this problem was by removing the water either by adding methanol to the resin then azeotroping off the water to achieve a water content of 3% or so, or by purging the resin with an inert gas (nitrogen) to reduce the water content.

When the water content was reduced to 3%, the bromide content was reduced by 97.5% after 1 hour at 90 C using the dried PPA 500PLUS (using a mixture of tetrachloroethylene and trichloroethane as solvent) and 98.5% after 22 hours. When the resin was not dried (used as-is) with 54% water content, the bromide content was reduced by only 5% after 1 hour at 90 C and only 64% after 22 hours. Clearly, the drying of the resin made a huge difference in the efficacy of the commercial macroporous strong base anion resin as a polymer-bound phase-transfer catalyst.

Scott Sherwood demonstrated the use of this method in both flask batch and fixed-bed column configurations. The fixed-bed column system was operated at 60 C and achieved 90%-92% conversion consistently in 5 samples taken from 53 hours to 118 hours of operation.

This is a patent worth studying.

If you too would like to benefit from the same high quality PTC training that Scott Sherwood enjoyed, now contact Marc Halpern of PTC Organics to inquire about bring the 2- day course “Industrial Phase-Transfer Catalysis” to your company, either in person at your location or by videoconference.

As we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” benzyl trimethyl ammonium chloride, BTMAC, was one of the first phase-transfer catalysts used in large scale commodity chemicals. BTMAC has been used in quantities of more than 500 metric tons per year since the 1980’s in the manufacture of aryl glycidyl ethers (such as bisphenol A diglycidyl ether) for epoxy resins. When I spoke with the chief scientist of an epoxy resin manufacturer in 1987 and I noted that BTMAC is likely not the optimal catalyst for such glycidyl etherifications, he said that they knew that however, it would be impractical to requalify the epoxy resin products used by thousands of customers just to optimize the structure of the phase-transfer catalyst.

BTMAC is extremely easy and inexpensive to produce. Simply mix an aqueous solution of trimethylamine with benzyl chloride and after a sufficient reaction time and temperature, distill off the water to meet the specification and ship what’s left in the reactor.

Last week, a patent was issued that cited BTMAC as the catalyst to produce the triglycidyl ether of 1,2,3-trihydroxybenzene. Unlike the early Dow Chemical patents using BTMAC for the reaction of bisphenol A (deprotonated with NaOH) with epichlorohydrin (long since expired), the reaction shown in the diagram used the chloride of BTMAC to catalyze the formation of the ring opened chlorohydrin followed by a separate reaction using NaOH to perform the ring closing. The 2-step process of ring opening of epichlorohydrin by a nucleophile followed by ring closing to the epoxide using base, is used for aliphatic glycidyl ethers.

Phosphonium salts are used as phase-transfer catalysts to build molecular weight of epoxy resins. In other words, two different phase-transfer catalysts are used in the epoxy resin industry.

If your company needs to develop optimized low-cost high-performance green chemistry processes for the manufacture of epoxy resins or for any nucleophilic substitutions, now contact Marc Halpern of PTC Organics to integrate 4.5 decades of highly specialized expertise in industrial phase-transfer catalysis with your commercial goals.

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.

The patent cited here uses a tetrabutylammonium salt in stoichiometric quantity to dissolve a compound in a reaction solvent for the purpose of deptrotection.

Stoichiometric quat salts are often used either to diagnose the feasibility of a PTC application before screening catalytic quat salt or in cases such as the one described in this patent which is to quantitatively solubilize an anion in a solvent for effective reaction.

In this case, an amino oxoazetidine needed to be functionalized with benzyloxycarbonyl at the amino nitrogen and not the azetidine nitrogen. The azetidine nitrogen was functionalized with a sulfonic acid before the reaction with benzyloxycarbonyl N-succinimide. Then the quat salt shown was formed by mixing tetrabutylammonium hydroxide with (2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-methyl-4-oxoazetidine-1-sulfonic acid to form the tetrabutylammonium salt shown in the diagram. In the next step, the quat sulfonate salt was dissolved in THF and treated with trifluoroacetic acid, then aqueous NaOH to yield the deprotected compound with a free N-H on the azetidine, benzyl ((2S,3S)-2-methyl-4-oxoazetidin-3-yl)carbamate.

This patent also mentioned the use of tetrabutylammonium azide in the reaction shown below.

N-ethyl pyridinium iodide was used as an ionic liquid solvent and promoter for the hydrocarboxylation reaction of olefins with carbon monoxide to produce carboxylic acids (adding one carbon atom). This is a continuous process and one may assume that the rhodium catalyst and the ethyl pyridinium iodide are recyclable. Other ionic liquids, including imidazolium salts and phosphonium salts were also shown in the examples to work well as solvents/promoters for this reaction.

When using N-ethyl pyridinium iodide, there is no need to use corrosive acids or alkyl halides that generate corrosive acids. This process also avoids the need for extreme temperature (> 270 deg C) and extreme pressure (> 2700 psig).

There are many different alkyl triphenyl phosphonium salts that are used as phase-transfer catalysts for high temperature reactions and for the second step of producing epoxy resins to build molecular weight. One attempt to use methyl triphenyl phosphonium bromide is described in this month’s PTC Reaction of the Month for a Fluoride-Halex Reaction.

A patent was issued this month (Watanabe, T.; Miyake, Y.; Kinsho, T.; (Shin-Etsu Chemical) US Patent 10,737,999, 11-Aug-2020) describing the preparation of pentyltriphenylphosphonium bromide. Even though this was for a Wittig reaction for an agrochemical intermediate and not as a phase-transfer catalyst, we are highlighting here how simple it is to synthesize these salts.

The synthesis is simply: To a reactor were charged 1-bromopentane (185 g, 1.20 mol), triphenylphosphine (321 g, 1.20 mol) and N,N-dimethylformamide (225 g), and the resulting mixture was stirred at 110 C to 115 C for 6 hours to prepare pentyltriphenylphosphonium bromide.

Tetrabutylammonium acrylate was used as an initiator at 0.5 wt% in the polymerization of the cyclic compound beta-propiolactone in the presence of carbon monoxide. The conversion of bPL to poly-beta-propiolactane was 89% after 36 minutes.

Tetrabutylammonium acrylate is a less expensive alternative to more thermally stable phosphazenium phase-transfer catalysts (described in Brunelle’s 2010 US Patent 7,705,190 and in our 2-day course “Industrial Phase-Transfer Catalysis”) such as hexaphenyl phosphazenium acrylate described in Novomer’s previous 2013 patent WO 2013/126375.

Polypropiolactone itself is a biodegradable polymer that can be used in many packaging and thermoplastic applications. beta-Propiolactone is made from ethylene oxide and carbon monoxide. Pyrolysis of poly-beta-propiolactone produces high purity glacial acrylic acid. In other words, this reaction sequence has several multibillion dollar products.

As reported in the October 2019 PTC Catalyst of the Month, tribenzyloxybenzyl quininium chloride worked better than 15 other chiral PTC quats screened for the reaction shown in the figure. A new patent was just issued that focuses on obtaining the desired polymorph of the product (S)-afoxolaner by recrystallization. In order to conduct this study, the inventors needed significant amounts of the product, so they successfully scaled up the chiral PTC addition of hydroxylamine to the substrate on a 1 kg scale.

Comparing the procedures from the two patents, it is apparent that some process improvement was performed, including reducing the amount of hydroxylamine from 3.0 equiv to 1.1 equiv and reducing the amount of solvent used from 30X to 9X.

If your company wants to improve performance by choosing the best phase-transfer catalyst for reactivity, selectivity, minimizing waste and achieving effective separation of the phase-transfer catalyst from the product, now contact Marc Halpern of PTC Organics.