Another reminder was reported this month that described how easy it is to form quat salts with organic anions.

In this case, an organic N-sulfate salt dissolved in water was first produced by reacting the hydroxyl amine shown in the diagram with a pyridine-sulfur trioxide complex in methylene chloride, then  was treated with aqueous sodium bicarbonate.

The aqueous solution of the salt was contacted with an organic solution of tetrabutylammonium hydrogen sulfate in chloroform (not our first choice for an industrial process) and was stirred for 10 minutes. Finally, “the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to afford the product (yield 91%).”

As we teach in the 2-day course “Industrial Phase-Transfer Catalysis,” tetrabutylammonium hydrogen sulfate is often used to exchange anions since sulfate, formed from the hydrogen sulfate under  basic conditions, is a dianion that is disfavored for pairing with the tetrabutylammonium cation. In this case, the anion to be paired with the quat, has 13 carbon atoms and therefore has a much higher affinity to the quat than the inorganic sulfate dianion.

In any case, liquid-liquid ion exchange of the anion paired with the quat cation is very often a simple procedure to execute and yield are high…when the anion desired to be paired with the quat at the end is more organophilic than the anion that is being replaced.

A very simple procedure was described for the preparation of tetrabutyl ammonium imidazolate in Pyun; L., Jung; I., Min; B, Lee; J., Jeong; J. (SK Innovation Co. Ltd) US Patent Application Publication 2025/0001390, 02-Jan-2025. This quat salt was used for a carbon dioxide absorbent ionic liquid.

5.00 g (18.0 mmol) of tetrabutylammonium chloride, 1.37 g (18.0 mmol) of sodium imidazolate, and 20 mL of ethanol were added to 100 mL of RBF, and then stirring was performed at room temperature for 2 hours. The produced solid was filtered out of the reactant, and the filtrate was dried under vacuum at 50 deg C. for 15 hours to obtain 5.46 g (98%) of a light yellow oil.

Several tertiary and quaternary ammonium salts were screened for the condensation shown in the diagram.

It appears that the reaction is acid catalyzed and that the role of the catalyst is to provide the availability of the proton in the reaction phase. It also appears that more acidic protons give higher yield and selectivity.

For example, tertiary onium salts of phosphoric acid, such as triethylamine trihydrogen phosphate (also called rather inaccurately “triethylamine phosphate”), bistriethylammonium dihydrogen phosphate and pyridinium trihydrogen phosphate give yields of 91%-92% with selectivities of 92%-94%. In contrast tetrabutyl ammonium hydrogen sulfate gave 41% and 43% selectivity.

TMAOH has been used as a base in organic chemistry in general and in PTC in particular for many years.

Dr. Neal Anderson of Anderson’s Process Solutions, brought to our attention an important reference that is important for the safety of PTC process chemists who use tetramethylammonium hydroxide (TMAOH) as a base.

It is strongly recommended that before using TMAOH, or even considering using TMAOH, please read the information sheet shown here: https://ehs.stanford.edu/wp-content/uploads/21-012-TMAH-Fact-Sheet.pdf.

When you read the Stanford fact sheet, pay close attention to the following excerpts: “The key factor that makes TMAH particularly hazardous is how quickly it acts. Life-threatening symptoms can develop within 20 minutes, unconsciousness within 30, and, in the worst cases, death can occur within an hour.” Other important information is cited here: “It is important to remember, however, that life-threatening symptoms may occur with concentrations as low as 2%.”

We can speculate the the hydrophilic-lipophilic properties that make TMAOH useful as a base in organic reactions in polar solvents may be the same properties that make it toxic to biological systems with affinity to similar hydrophilic-lipophilic properties.

TMAOH has been used as a base in organic chemistry in general and in PTC in particular for many years. Of great commercial importance was the replacement of KOH by TMAOH in chip manufacture several decades ago to increase yield. KOH was used in the early days of chip manufacture but tiny amount of residual ions on the chip rendered them unusable. TMAOH was then used to replace KOH since upon heating, the TMAOH undergoes decomposition by nucleophilic attack to form methanol and trimethylamine, both of which are volatile and evaporate from the surface of the chip, leaving no ionic residue.

The PTC community thanks Dr. Anderson for bringing this important information to our attention. Please visit Dr. Anderson’s website for useful process development tips, consulting and training services.

There is learning value for process and product development chemists in a patent that describes polymerizable quat salts reported as cationic dopants to achieve a balance of physical properties in an adhesive in electro-optic applications. See McCullough, L.; Thomas, M.; Regan, T. (E Ink Corp) US Patent 12,031,065, 09-Jul-2024.

An electro-optic device consists of several layers with adhesive between them. The charge on the quat apparently participates in the electric field aspects of the device. However, if the charge migrates too much due to the electric field, this can cause non-uniform domains that lead to performance problems (see explanation below quoted from the patent).

If I understand correctly, one can achieve the right balance by dialing in certain side chains on the quats with the right polarity, chain length and monomer functional group(s) to enable the cationic dopant to function properly while preventing too much migration of the charge.

In this case, the best polymerizable quat salts were certain di-N-alkylated imidazolium salts.

The learning value for process and product development chemists is that we can achieve higher performance by customizing a specific balance of the physical availability and chemical properties of quat salts to meet specific needs. Since we have four chains on the quat, there are endless possibilities for designing this balance of physical and chemical properties.

Quote from the patent that describes the cationic quat dopants: “Without wishing to be bound by theory, dopants that exist in the adhesive layer as small molecules may diffuse and migrate in the layer and separate in their own phase or domain. This may create an adhesive layer having low and high conductivity domains and increasing the overall volume resistivity of the adhesive layer and, as a result, reducing the electro-optic switching performance of the electro-optic assembly. Such dopant separation is less likely to happen with polymeric dopants, which may be significantly less mobile and less likely to diffuse through the adhesive layer.”

In the patent, Hata, R. (Shin-Etsu Chemical) US Patent 12,030,902, 14-Jul-2024, tetrabutylammonium m-chlorobenzoate was used as an anionic catalyst for a “group transfer polymerization” to form a polymer crosslinking agent that is a (meth)acrylic-based graft silicone. The monomers were a long chain methacrylate (such as stearyl or dodecyl), 2-allyloxyethyl methacrylate, a silicone methacrylate ester and the initiator was dimethylketene methyl trimethylsilyl acetal.

The inventor did not explain why TBA m-chlorobenzoate was chosen as the anionic initiator though it is obvious that its solubility in the reaction mixture with THF as solvent and several liquid monomers ensures a homogeneous reaction mixture, which is critical for efficient polymerization and uniform polymer properties.

The choice of m-chlorobenzoate is not clear and it was used in all 7 examples of polymerization, even though 17 salts were cited in the teachings, including several fluoride salts that are known to be effective anionic catalysts for group transfer polymerizations of this type.

Background: Group transfer polymerization (GTP) is a type of living polymerization technique used primarily for the synthesis of acrylic polymers and copolymers and that is exactly what the inventor was describing. The key feature of GTP is its ability to produce polymers with well-defined molecular weights and narrow molecular weight distributions.

GTP involves the transfer of a silyl ketene acetal to a growing polymer chain. This process is initiated by a catalyst, often a fluoride ion, which facilitates the transfer of the silyl group. GTP is particularly effective for polymerizing methacrylates, acrylates, and other related monomers.

The technology described in this patent is consistent with all of the typical characteristics of GTP, except that m-chlorobenzoate was used instead of the more common fluoride anionic catalyst.

The application was for the cosmetics industry.

Specialty quat salts, such as quat carboxylates, can be prepared from common quat salts, such as commercially available quat bromides and chlorides by ion exchange. However, there are several factors that must be optimized to make this work.

Three factors that must be taken into account are (1) the relative affinities of the quat cation toward the anion being exchanged and the anion of the original commercial quat salt, (2) whether the ion exchange is performed by liquid-liquid extraction or using an ion exchange resin and (3) the physical characteristics of the ion exchange resin.

The first factor is the relative affinities of the quat cation toward the anion being exchanged and the anion of the original commercial quat salt. As we teach on the famous page 76 of the PTC course manual (this has been the same page in the manual for more than 20 years!), quat cations have different affinities for different anions that differ by many orders of magnitude. For example, the methyl trioctyl ammonium prefers to pair with iodide versus hydroxide by more than 100,000 times, bromide versus hydroxide by about 1,000 times and chloride versus hydroxide by about 100 times.

If one wanted to exchange a halide for hydroxide by liquid-liquid ion exchange, that would take a large number of extractions with large excess of hydroxide or an extremely efficient countercurrent system.

In US Patent Application Publication 2024/0182626 published this month, inventors at BASF reported the preparation of the 2-ethylhexanoate salts of tetrabutylammonium, tetramethylammonium and tributylmethylammonium, in two steps.

The first step uses an ion exchange resin to convert the quat chloride into quat hydroxide. In the second step, the quat hydroxide is neutralized with 2-ethylhexanoic acid to form the quat 2-ethylhexanoate salt.

The inventors wisely chose to perform the ion exchange starting with quat chlorides since quat chlorides are commercially available and it is thermodynamically much easier to exchange chloride for hydroxide than from bromide.

The ion exchange resin chosen in “Reference Example 2” was AMBERSEP 900 in the hydroxide form. AMBERSEP (R) 900 OH is a strongly basic, macroreticular (macroporous), Type I, quaternary ammonium anion exchange resin specially sized for use in Ambersep (R) resin systems. The macroporous resin has large pores formed during the polymerization process by the presence of large inert pore former molecules around which the monomer is polymerized and crosslinked. These large pores are essential to allow the large quat salts to enter and exit the ion exchange resin beads for the chloride-hydroxide ion exchange that provides a large surface area as opposed to accessing only the hydroxide sites on the surface of a non-porous gel resin.

The nature of the ion exchange resin column is such that when passing the quat chloride solution through the length of the column, it acts as a countercurrent ion exchange system.

Once the quat hydroxide is formed, the neutralization with the carboxylic acid is easy and instantaneous.

Thus, the benefit of using the ion exchange resin is to form the thermodynamically disfavored quat hydroxide from the quat chloride in an efficient manner that generates less waste.

Thank you to Brian Tarbit for bringing to our attention a very interesting article written by Dr. Johanna Templ and Prof. Michael Schnürch in Chemistry Europe entitled: “Strategies for using Quaternary Ammonium Salts as Alternative Reagents in Alkylations” available at https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202400675?af=R.

An example of this concept is that quaternary ammonium cations can be viewed as alkylated trialkylamines in which the alkyl group can be displaced by a nucleophile to form the alkylated product and liberate trialkylamine as the leaving group. For example, one might replace toxic dimethyl sulfate or methyl iodide with phenyl trimethyl ammonium chloride. One could then perform a methyl etherification, N-methylation or other nucleophilic substitution that would liberate phenyl dimethyl amine as the leaving group instead of methyl sulfate or iodide.

Phenyl trimethyl ammonium chloride is used as a methylating agent for the O-alkylation of alkaloids. For example, dextromethorphan, (9α,13α,14α)-3-methoxy-17-methylmorphinane (23.2.1), is synthesized from (±)-3-hydroxy-N-methylmorphinane by methylating the phenol hydroxyl group using phenyl trimethyl ammonium chloride and sodium methoxide in methanol.

In another example, morphine can be selectively mono-O-alkylated to produce codeine using phenyl trimethyl ammonium chloride as the methylating agent.

In our course “Industrial Phase-Transfer Catalysis,” we teach a PTC application that forms a specialty benzyl quat as a benzylating agent from trimethyl amine and 4-ethyl benzyl bromide. The quat benzylating agent is used for the C-alkylation of a sterically hindered aldehyde.  See http://phasetransfercatalysis.com/ptc_reaction/ptc-c-alkylation-2/.

If you have been following the PTC literature since the 1960’s (like I have since 1976), you may wonder how benzylated quats are widely used for PTC reactions such as the hundred or so reports by Makosza using benzyl triethyl ammonium chloride for a wide variety of C-alkylations.

In fact, on the negative side, when using benzyl quats for PTC nucleophilic substitutions, there is usually observed at least some undesired benzylated side product. About 30 years ago, I was shocked to discover that a pharmaceutical company was using a benzylated quat for a PTC esterification of a penicillin derivative at high temperature and when I suggested that they may be inadvertently forming benzyl ester byproducts, they used LC-MS (that started to be affordable at that time) to detect the byproduct. I made the recommendation to replace the benzylated quat with a different phase-transfer catalyst that would be more stable at that temperature. I usually recommend against using benzylated quats as phase-transfer catalysts for nucleophilic substitutions unless you are purposely trying to benzylate the nucleophile.

In summary, if you are trying to benzylate, allylate or methylate nucleophiles, you can consider using the corresponding quats of those alkylating agents. If not and if you are working at high temperature and want to use such a quat as a phase-transfer catalyst, be aware that you may form undesired byproduct by the attack of the nucleophile on a potentially labile alkyl group on the quat.

This month we seem to have more patent activity than usual in the area of quats with epoxides used in the semiconductor industry.

This publication, Matsuura, Y.; Sato, A.; Yamazawa, T. (Namics Corporation) US Patent Application Publication No 2024/0132714, 25-Apr-2024, describes the use of a variety of quat salts in a system that I will attempt to explain according to my novice understanding that may be incorrect.

If I understand correctly (which might not be the case), the goal of this technology is to ensure that the electrode “bump” of a semiconductor is accessible while protecting the rest of the semiconductor surface. For this purpose, a cured epoxy resin and a “filler” (like silica) is used to coat the semiconductor with the electrode protruding for connection to another component.

The epoxy resin is cured with a curing agent, typically containing an amine.

The patent claims that the presence of an ionic compound (chosen from a group with many quat salts) is crucial to ensure uniform distribution of the epoxy resin and filler but the patent does not explain why the ionic compound works. I speculate that the anion of the ionic compound serves as an initiator for the curing of the epoxy resin by the amine-based curing agent.

Regardless of whether this speculative explanation is correct, the ionic compounds that are explicitly claimed in Claim 8 contain quat cations familiar to us as PTC practitioners and they are:
• Methyltrioctylammonium tosylate
• Methyltrioctylammonium hexafluorophosphate
• Methyltrioctylammonium imidodisulfuryl fluoride
• Methyltrioctylammonium bis(trifluoromethanesulfonyl)imide
• Tributyldodecylphosphonium tosylate
• Tributyldodecylphosphonium dodecylbenzenesulfonate
• Tributylmethylammonium bis(trifluoromethanesulfonyl)imide
• Tetrabutylammonium hexafluorophosphate
• 1-Butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide
• Tributyldodecylphosphonium bis(trifluoromethanesulfonyl)imide
• 1-Hexyl-4-methylpyridinium bis(trifluoromethanesulfonyl)imide
• Trimethylpropylammonium bis(trifluoromethanesulfonyl)imide
• 4-(2-Ethoxyethyl)-4-methylmorpholinium bis(trifluoromethanesulfonyl)imide
• 1-Butyl-3-dodecylimidazolium bis(trifluoromethanesulfonyl)imide
• N-Oleyl-N,N-di(2-hydroxyethyl)-N-methylammonium bis(trifluoromethanesulfonyl)imide
• Tributyl[3-(trimethoxysilyl)propyl]phosphonium 1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide

An interesting two-step sequence was described that uses tetrabutylammonium chloride (TBAC) as catalyst. This sequence was reported in an earlier 2019 patent.

In the first reaction TBAC is a source of catalytic chloride that is soluble in an organic liquid to perform a reaction and in the second step the TBAC, which is not isolated from the first reaction appears to serve as a phase-transfer catalyst to transfer and activate inorganic sulfide as a nucleophile.

In the first reaction, we assume that the chloride from TBAC opens the ring of epichlorohydrin to form mostly 1,3-dichloropropoxide that attacks phosgene to form the intermediate chloroformate in high yield and high regioselectivity. The chloride liberated from the phosgene regenerates TBAC.

The first reaction uses no added solvent and the crude product was used in the next step without isolation. An interesting two-condenser system was used, presumably to contain the phosgene.

Since the reaction mixture from the first step was used without workup in the second step, the tetrabutylammonium phase-transfer catalyst was still present in the second reaction and available to transfer, activate the inorganic sulfide for the nucleophilic displacement of two chlorides to form the 1,3-oxathiolane-2-one ring. As long as the regioselectivity of the first reaction was high, then the ring closure in the second step should afford the right product. One may assume that the use of 1.0 equiv sulfide with no excess avoided further reaction of the final chloromethyl group.

Interestingly, the inventors chose to use tetramethylammonium chloride with DMF as the solvent for the subsequent esterification of the 5-(chloromethyl)-1,3-oxathiolane-2-one with sodium acetate or sodium methacrylate. These esterifications required higher temperatures (100 deg C and 120 deg C), which is common but they gave relatively low conversions (23% and 48% by GC). We wonder if the inventors tried using more organophilic phase-transfer catalysts and less polar solvents, especially with quat bromides or quat iodides that usually reduce the temperature required for PTC esterifications.

When your company needs to optimize process conditions for PTC esterifications, now contact Marc Halpern of PTC Organics to explore collaboration through PTC Process Consulting.