Cetyl Trimethyl Ammonium Bromide (CTAB) is a quaternary ammonium salt that is usually used as a surfactant, sometimes as a phase-transfer catalyst and sometimes as both.
In the application shown in the diagram, CTAB is reported to be used for a “micelle catalyzed Diels-Alder reaction that enhances reaction yields and shortens reaction times.”
Even though the diagram on page 4 of the patent application publication explicitly shows “PTC” to represent CTAB, there is obviously no possibility for phase-transfer catalysis in this Diels-Alder reaction. However, it is always useful to examine the workup after a reaction using CTAB to see if there appears to be a challenge with emulsions during workup or if a clean phase separation is observed.
In this case, the reaction used a lot of water (~15X versus the combined mass of the freshly prepared cyclopentadiene and methyl naphthoquinone) and no organic solvent. The workup started with extraction of the organic product (adduct) into ether. No mention was made of emulsions during workup and the 86% yield after recrystallization suggests that there was little to no handling loss due to emulsions.
We have seen commercial applications emulsify unintentionally during workup when using quaternary ammonium salts as phase-transfer catalysts and care is not taken to avoid critical micelle concentration.
When this happens, there can be significant economic losses if the product cannot be recovered easily. Addition of salt can sometimes break the emulsion, but it is not a desirable situation.
Therefore, we are always on the lookout for applications that use alkyl trimethyl ammonium quats like CTAB that are performed without issues during workup.
This publication also described PTC reactions that used tetrabutylammonium bromide for nucleophilic substitutions and a dithionite reaction.
Quaternary ammonium phase-transfer catalysts can and do decompose by Hofmann Elimination in the presence of base and nucleophilic attack in the presence of anions that can be nucleophilic. Tetrabutylammonium is used in many PTC applications and when it decomposes, it produces some amount of tributylamine, by both decomposition mechanisms.
While the tributylamine byproduct is adequately removed during workup after most PTC applications using TBAB, some applications are so sensitive to the presence of amine, that non-detectable levels of tributylamine must be achieved.
In the Patent Application Publication shown here, it was required that tributylamine be removed to non-detectable levels.
This publication describes methods for reducing tributylamine levels from polysulfane-silanes produced using tetrabutylammonium bromide.
- Carrier vapor distillation of bis(triethoxysilylpropyl)tetrasulfane produced using TBAB reduced tributylamine from 0.33% to < 0.01%
- Ozone treatment of bis(triethoxysilylpropyl)tetrasulfane produced using TBAB reduced tributylamine from 0.15% to < 0.01%
- Thin film evaporation of bis(triethoxysilylpropyl)tetrasulfane produced using TBAB reduced tributylamine from 0.15% to < 0.01%
- Activated charcoal treatment of bis(triethoxysilylpropyl)tetrasulfane that was previously treated by carrier vapor distillation that still had 0.01% tributylamine reduced the tributylamine to < 0.01%
The choices of catalyst and solvent for this reaction are interesting, especially upon scale up.
Phase-transfer catalysis excels in a wide variety of N-alkylations, including heterocycles such as pyrazole that is easily deprotonated by weak base such as potassium carbonate. Once the pyrazolide anion is formed, most standard phase-transfer catalysts with sufficient organophilicity can transfer the N-anion into almost any organic solvent.
In this case, the inventors chose ethyl acetate as the solvent for this reaction on a 20 g scale. This is a reasonable choice since PTC systems are easier to handle during workup with solvents that form two phases with water. This is due to the ease of dissolving the KCl and KHCO3 salt byproducts in water and then separating the two phases to remove the salt from the product.
18-crown-6 is certainly an effective phase-transfer catalyst but it is also much more expensive than common quaternary ammonium phase-transfer catalysts. The inventors clearly knew about PTC as evidenced by their knowledge of crown ethers. So it is not clear why they chose the expensive crown ether. Using 20 g grams of dimethyl pyrazole, they used 11 grams of 18-crown-6. That is a strange choice.
The inventors scaled up the reaction to 400 g of dimethylpyrazole. At that point, they probably realized that using 20 mole% 18-crown-6 was overkill and very expensive so they reduced the loading to 3.6 mole% 18-crown-6 which was 40 grams. That is still a lot. We wonder why they didn’t at least screen much less expensive readily available quaternary ammonium phase-transfer catalysts.
In addition, upon scale up to 400 grams, the inventors changed the solvent to acetonitrile. Since the product was isolated by distillation, they may not have needed to dissolve the salt byproducts, but the workup still included dissolution of salts in water and two subsequent washes with aqueous NaCl.
In the end, the isolated yields for both sets of reaction conditions were in the 90’s. So, the results were good. However, we expect that if the reaction needed to be scaled up further, there would be better choices of solvent and phase-transfer catalyst to minimize both cost and the amount of aqueous waste.
In our 2-day course “Industrial Phase-Transfer Catalysis,” we teach how to choose phase-transfer catalyst, solvent, base, hydration, agitation and other process parameters to optimize performance, cost and green chemistry. Your company should now inquire about conducting this valuable PTC in-house at your site.
A patent was issued this month [Storz, C.; (Huntsman Advanced Materials) US Patent 11,518,846, 06-Dec-2022] that reports an accelerator system for curing thermosets based on polyfunctional isocyanates with mono- or polyfunctional epoxy resins. The challenge is to achieve a rapid cure time at moderate temperatures without building up viscosity too quickly that results in flawed product.
The inventors found a surprising behavior that achieves the desired goals. When they used a classical accelerator such as a complex of boron trichloride-dimethyloctyl amine, curing was too slow. When they used benzyltriethyl ammonium chloride as the accelerator, curing was very fast but the viscosity build was too fast as well. For reasons not explained, when the inventors used an accelerator that was a mixture of these two materials (using the same quantities of each component as in the control runs), the curing and building of viscosity was intermediate between the two and not additive. The desired performance was achieved.
The inventors screened several quat salts as co-accelerators to modify the performance of boron trichloride-dimethyloctyl amine including benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl phosphonium chloride and tetrabutyl phosphonium bromide. In all cases, the quat salts without the BCl3-amine complex were too fast but when the quat salts and BCl3-amne complex were used together, viscosity build up and gelation time were slowed down to an acceptable level. It is unclear why the BCl3-amine complex would reduce the activity of the quat salt, but the reality is that these systems work.
Alkyl triphenyl phosphonium salts are used as phase-transfer catalysts to build the molecular weight of epoxy resins. In US Patent 11,492,457 [Mitchell, M.; Anderson, B.; Dahlke, G.; Fukushi, T.; (3M Innovative Properties Company) US Patent 11,492,457, 08-Nov-2022], benzyl triphenyl phosphonium chloride was reported as being used for the curing and crosslinking of a variety of fluoropolymers produced by the reaction of perfluoroalkenes, polyhydroxy compounds and phthalonitrile compounds.
It is not clear why benzyl triphenyl phosphonium chloride was chosen out of the 24 quaternary ammonium and phosphonium salts cited in the teachings in the patent. The inventors even specify that phenolate is the preferred anion for both quaternary ammonium and phosphonium salts but benzyl triphenyl phosphonium chloride was chosen anyway. We speculate that the choice may have been based on the least expensive phosphonium quat which is made from triphenylphosphine and benzyl chloride.
Tetrabutylammonium tribromide (TBATB) is used as a source of bromine that is convenient for weighing as a solid instead of liquid bromide that could spill and cause safety and environmental consequences.
The procedure to perform the reaction shown in the diagram is extremely easy and straightforward by just mixing the reactants.
The inventors did not report the selectivity of the bromination site. The downstream isomer products were separated by chromatography after two additional steps of fluoride-bromide exchange and oxidation. Judging by the mass of isolated isomers after two chromatography separations, the ratio of the two products was very roughly 1.5:1 for 7-fluoro-6-methoxy to 5-fluoro-6-methoxy.
The process development group at Ono Pharmaceuticals used TBATB for the ring bromination of 3-ethyl phenol as described in the July 2013 PTC Catalyst of the Month. See http://phasetransfercatalysis.com/ptc_catalyst/tetrabutyl-ammonium-tribromide/
The reaction shown in the diagram is a reminder that phase-transfer catalysis works well when combined with a variety of transition metal catalysts such as palladium tetrakis-triphenylphosphine for the Suzuki reaction. Catalyst loading seems very high though this was not intended to be a process for scale up.
As we teach in the 2-day course “Industrial Phase-Transfer Catalysis”, quaternary ammonium phase-transfer catalyst are very effective for transition metal catalysts including inorganic and organometallic catalysts containing palladium, platinum, rhodium, ruthenium, cobalt, nickel, copper, zinc and others.
Remember that you can save a lot of money when you reduce the usage of very expensive catalysts based on precious metals by combining them with inexpensive quaternary ammonium phase-transfer catalysts.
Carbon disulfide is a nonpolar liquid, similar to supercritical carbon dioxide. When a polar inorganic anion reacts with carbon disulfide, an organophilic quaternary ammonium phase-transfer catalyst often helps.
In the first reaction shown in the diagram, 50% aqueous cyanamide is reacted with 2 equiv 50% NaOH added at a rate to maintain the temperature under 10 C. This neutralization (no excess NaOH) forms sodium cyanamide, Na2CN2 (calcium cyanamide, CaCN2, is a commercial salt that is used to prepare cyanamide by hydrolysis). The quaternary ammonium chloride is then added followed by carbon disulfide in one portion. It is reasonable to assume that the quat cation pairs with the cyanamide anion and transfers it to the CS2 phase for the nucleophilic attack to form the disodium salt “disodium N-cyanodithioiminocarbonate”.
In Example 1 in the patent, methyl tributyl ammonium chloride (MTBAC) is used as the phase-transfer catalyst. MTBAC has 13 carbon atoms which is likely enough to be effective to transfer the cyanamide anion into the nonpolar carbon disulfide. Example 1 also uses 95 g of water which is about 1.5X the combined mass of the starting materials (neutral aqueous cyanamide and 50% NaOH). The reaction to form disodium N-cyanodithioiminocarbonate is stirred overnight at room temperature.
In Example 2, the inventors chose to use a more organophilic quat, Aliquat 336 with an average of 27 carbon atoms. Although the reason is not explained, one can assume that the 27-cabon quat may be better than the 13-carbon quat for transfer of an anion into the nonpolar carbon disulfide phase. Perhaps more importantly, the inventors also chose to greatly reduce the water content which is known to enhance reactivity solid-liquid PTC systems. The then followed the reaction by GC and determined that the reaction was complete in 7 hours when using Aliquat 336 and reduced water. This is consistent with the typical behavior of solid-liquid PTC I-Reactions that we teach in our 2-day course “Industrial Phase-Transfer Catalysis.”
In the second step, S-methlyation is performed using dimethyl sulfate to form “sodium methyl N-cyanodithioiminocarbonate.” The entire reaction mixture (both phases) is used in the second step that starts with a pH adjustment. Toluene is added and the mixture is cooled. Dimethyl sulfate us added at a rate to maintain the reaction mixture at a temperature below 15 C.
Since the phases were not separated after the first step, the phase-transfer catalyst is still present during the S-methylation step.
Again, the more organophilic quat of Aliquat 336 is expected to transfer more anion to the toluene phase than the less organophilic MTBA cation. In addition, the added water in the MTBAC system should suppress some of the transfer of the reacting anion into the toluene since MTBA quat salts are usually very water-soluble and preferably distribute into the aqueous phase if the aqueous phase has low ionic strength. In comparison, salts of Aliquat 336 are typically only slightly soluble in water. A comparison of the distribution of Aliquat 336 and MTBAC between water and various organic solvents was reported by Grinstein and Halpern 25 years ago as shown at http://www.phasetransfer.com/catsep.pdf.
The effects of both quat structure and water in this system are predictable based on the content we teach in our 2-day course “Industrial Phase-Transfer Catalysis.”
If you have not yet conducted the course “Industrial Phase-Transfer Catalysis” at your company, the time has come that you do so in 2022 or 2023 so you can develop higher performance PTC processes in shorter development times and stop wasting precious constrained process R&D resources. Now contact Marc Halpern of PTC Organics to schedule this extremely valuable PTC course in-house at your company.
As we teach in the 2-day course “Industrial Phase-Transfer Catalysis,” quaternary ammonium and phosphonium salts used as phase-transfer catalysts sometimes contain hydroxy alkyl groups, including hydroxymethyl, 2-hydroxyethyl and 2-hydroxypropyl groups. One of the practical challenges when using quat salts is analytical detection of residual quat salt in the product or aqueous waste stream.
A patent was issued this month (Zhu; X., Moniee; M., Al-Saleh; M. (Saudi Arabian Oil Company) US Patent 11,385,171, 12-Jul-2022) that describes the analytical determination of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) in the range of 2-500 ppm. The analytical method described in this patent may be applicable to other quat salts that contain hydroxyalkyl groups and that is why we chose to highlight this patent in our monthly newsletter.
The method involves reacting the hydroxymethyl phosphonium quat with potassium permanganate and measuring the reduced intensity of the absorption measured at a wavelength of 525 nm due to permanganate consumption. The measured intensity is normalized by subtracting a background intensity at a wavelength of 650 nm. The presence and concentration of THPS in the water sample can then be determined by comparing the normalized intensity with intensity values of the absorption in calibration samples comprising potassium permanganate and known THPS concentrations.
Quaternary phosphonium salts are used as phase-transfer catalysts, biocides, ionic liquids, surfactants or flame retardants. In this patent, THPS is cited for its use as a biocide. Again, the value of this patent to PTC chemists is likely to be when developing analytical methods for hydroxyalkyl quats used as phase-transfer catalysts.
A very interesting and useful patent was issued this month that describes the use and recycle of the phase-transfer catalyst methyl tributyl ammonium chloride (MTBAC, C# = 13, q-value = 1.75).
As we teach in the 2-day course “Industrial Phase-Transfer Catalysis”, careful choice of phase-transfer catalyst, non-polar solvent and high ionic strength of the aqueous phase, can result in the formation of three liquid phases, in which a small volume middle liquid phase is formed that typically consists 30%-70% of phase-transfer catalyst that has two major benefits: (1) greatly enhanced reactivity versus a non-three liquid phase system and (2) suitable for economically advantageous recovery and recycle of the phase-transfer catalyst.
In this patent, the inventors added water to the reaction mixture during workup to expand the volume of what we think is a three liquid phase PTC system. The water in the workup will be discussed later in this review.
Prior to workup during the reaction, there was little free water in the system available for hydration to form an “omega phase” (thin film of saturated aqueous solution of the reacting nucleophile; term coined by Dr. Charles Liotta of Georgia Tech) since the source of water was 50% NaOH that can act as a desiccant for the organic phase due to the high hydrophilicity of sodium and hydroxide ions that are converted to chloride ions as the reaction progresses. The reactivity of such PTC systems are often sensitive to small changes in the water available to form the omega phase which in turn affects the ability of the quat cation to act as an effective phase-transfer catalyst.
We do not know if the reactivity of this particular system was so sensitive to small changes in the amount of water in the system, but hydration level is often be a consideration when optimizing such PTC applications. We show several examples of optimizing water levels in PTC systems in our 2-day course “Industrial Phase-Transfer Catalysis.”
The inventors discuss that one key for the recovery and recycle of the MTBAC was choosing just the right amount of water during workup. That amount of water should be enough to dissolve the NaCl byproduct but not add so much water that the MTBAC, normally soluble in water with low ionic strength, will dissolve in the aqueous phase that would make the MTBAC difficult to recover and recycle. The inventors impressively achieved 84% recovery of the MTBAC by simply separating the middle phase that was well designed for the workup.
The inventors compared various phase-transfer catalysts and they found that 75% methyl tributyl ammonium chloride in water (MTBAC, C# = 13, q-value = 1.75), greatly outperformed the following phase-transfer catalysts used in solid form: benzyl trimethyl ammonium chloride C# = 10, q-value = 3.1; tetraethyl ammonium chloride C# = 8, q-value = 2.0; and tetrapropyl ammonium bromide C# = 12, q-value = 1.33.
As we teach in the 2-day course “Industrial Phase-Transfer Catalysis,” MTBAC is often an optimal phase-transfer catalyst for reactivity and cost for PTC-hydroxide “T-Reactions” (transfer rate limited) with substrates that have a pKa in the range of 16-23 according to the Halpern pKa Guidelines for the evaluation and optimization of PTC applications. The pKa of propargyl alcohol is 13.6. According to the Halpern pKa Guidelines, quat cations with higher C# should work better for PTC reactions of substrates with pKa’s below 16. This is consistent with the order of reactivity of quat salts shown in the patent.
Toluene was used as the non-polar organic solvent. As we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” aromatic and aliphatic hydrocarbons, such as toluene and decane, have been have been studied in detail as solvents to form 3-liquid phase PTC systems.
MTBAC is also one of the lowest cost per mole phase-transfer catalysts used commercially in volumes of more than 100 metric tons per year in a single process.
When your company requires optimization of choice of phase-transfer catalyst for simultaneous high reactivity, low cost, and effective catalyst separation, now contact Marc Halpern of PTC Organics to integrate highly specialized expertise in industrial phase-transfer catalysis with your commercial goals.
