In the November 2016 PTC Catalyst of the Month, we suggested that tetrabutylammonium oxone can be replaced by tetrabutylammonium hydrogen sulfate and Oxone (TM). A patent was issued this month used that combination to convert a thioether to the corresponding sulfone shown in the diagram.

Oxone (registered trademark of DuPont) is a commercial oxidizing agent that is a triple salt mixture of 2KHSO5·KHSO4·K2SO4. This mixture has a higher stability than the potassium peroxymonosulfate by itself. Under PTC conditions, the quat cation transfers the HSO5- anion, a peroxy oxidizing agent, into the organic phase to perform efficient oxidation.

Note that one equivalent of Oxone contains two equivalents of KHSO5. Therefore, 775 mmol of Oxone contains 1,550 mmol of active peroxy oxidizing equivalents. Since 516 mmol of sulfide requires 1,032 mmol active oxygen, there is a 50 mole% excess of oxidizing agent to form the sulfone.

Even though the inventors chose to use PTC only for the oxidation of the sulfide to the sulfone, all three reactions in the sequence shown in the diagram should have been PTC candidates. As we teach in our 2-day course “Practical Phase-Transfer Catalysis”, PTC excels in transferring ethoxide into toluene and PTC excels even more in transferring and activating mercaptide anions in thioetherifications.

In other words, one could choose a single phase-transfer catalyst that would continue with the toluene phase and perform all three reactions using PTC in a streamlined process.

Then again, with 87% overall yield for the three steps, all three reactions must be quite good as reported. We are always looking for ways to minimize unit operations to streamline processes.

If your company can benefit from streamlining processes by performing multiple consecutive PTC reactions using a single solvent and a single phase-transfer catalyst, now contact Marc Halpern of PTC Organics and/or complete the form at www.phasetransfer.com/projectform.pdf to obtain a free estimate of the probability of success for using PTC to meet your performance targets.

The process described in Allemand; P. (Cambrios Film Solutions Corporation) US Patent 11,020,802, 01-Jun-2021, is not a phase-transfer catalysis process but it is interesting because of the use of tetrabutylammonium chloride (TBAC) to reproducibly produce silver nanowires from silver nitrate when the absence of TBAC resulted in nanoparticles that were not nanowires.

The presence of 1 mole% tetrabutylammonium chloride (TBAC) was able to selectively and reproducibly convert silver nitrate into a silver nanowire on a 50 g scale, instead of producing a mixture of silver nanoparticles of various structures. The solvent and “reducing agent” (Ag [1] to Ag[0]) was ethylene glycol (3000 mL). One equivalent of PVP (polyvinyl pyrrolidone) served as a plastic flexible sheet upon which the silver is deposited. The PVP was dispersed in 1 L of ethylene glycol with a high shear mixture prior to the addition to the reaction flask. The mixture was heated to 140 C for 30 minutes. The length of the silver nanowires was 14 +/- 8 micrometers and the width was 83 +/- 22 nanometers.

We would appreciate input from our readers as to how ethylene glycol serves as a reducing agent for the ionic silver to silver metal.

The inventors had good intentions by using phase-transfer catalysis for an O-acylation of a phenol with acetyl chloride, stoichiometric NaOH and no added water.

One major problem is that they used 0.5 equivalents of tetrabutylammonium hydrogen sulfate. Since hydrogen sulfate (pKa ~2) is 100 million times more acidic than phenol (pKa ~ 10), it is very likely that half (50 mole%) of the phenoxide ion deprotonated the hydrogen sulfate to form sulfate and the neutral phenol which in turn limited the maximum theoretical yield to 50%. The idea of neutralizing the phenol with exactly one equivalent of NaOH was a good idea to avoid free hydroxide that could potentially hydrolyze the acetyl chloride. It’s a shame that half of that NaOH had to deprotonate the HSO4. They should have used a quat chloride (or bromide, though the in-situ formation of acetyl bromide could be either good or bad, depending on whether it enhances hydrolysis more than acylation)

In addition, one equivalent of water was generated by the deprotonation of the phenol with NaOH (assuming that the inventors would have avoided a hydrogen sulfate quat). Since dioxane was used as the solvent and is miscible with water, that guaranteed that the water will come in contact with the acetyl chloride and cause some hydrolysis

Hydrolysis could have been avoided by using potassium carbonate as the base and desiccant and/or using a solvent such as toluene that rejects water instead of dioxane that attracts water. After all, the job of the phase-transfer catalyst is to bring the phenoxide anion into the organic phase for reaction with the acetyl chloride. Let the quat do the heavy lifting of the reacting anion instead of the solvent.

It is not surprising that the yield was less than 50% due to the combination of using a large amount of a hydrogen sulfate quat that could be deprotonated (accounting for 50% yield reduction) plus using a solvent that readily dissolves water and brings it into contact with the water-sensitive acetyl chloride further reducing the yield to 32%.

It would have been interesting to observe the results if a water-immiscible solvent was used (such as toluene) with a base that is a desiccant and a phase-transfer catalyst that did not contain a deprotonatable hydrogen (such as a quat chloride or bromide). The large catalyst loading was also unnecessary (50 mole% was way too much).

One would hope that most of our readers would not make these obviously bad choices but there are other situations in which poor choices are not so obvious. In those cases, you should really contact Marc Halpern of PTC Organics to integrate highly specialized expertise to properly choose, base, phase-transfer catalyst, solvent and other PTC parameters to achieve low-cost high-performance green chemistry for industrial PTC applications.

This patent describes the synthesis of the compound mesitrione. The fifth step of six chemical steps is the PTC acylation of the sodium salt of cyclohexanedione. The cyclohexanedione anion reacts at the enol oxygen with a water-sensitive benzoyl chloride.

Acyl chlorides are sensitive to hydrolysis and the inventors note that they worked at low temperature between 0 C and 15 C to avoid hydrolysis. They describe three different sets of conditions that give 92%-94% yield.

The inventors do not highlight the advantage of PTC in this system which is the use of the phase boundary to protect the acyl chloride from water by dissolving the organic acyl chloride in dichloroethane that is immiscible with water. The phase-transfer quat cation transfers the cyclohexanedione anion into the bulk organic phase where it reacts with enhanced reactivity with the acyl chloride with little to no hydration and little to no hydrolysis.

We speculate that the inventors chose to add solid sodium salt of cyclohexanedione in the first set of conditions (“Conditions A”) in order to minimize the amount of water in the system and thus minimize hydrolysis. The inventors were even bolder in Conditions B and C by adding the sodium salt of cyclohexanedione as a 28% aqueous solution, first at 2 C, then at 5 C.

The inventors did not describe their agitation system, but we would recommend avoiding over-agitation since that would cause non-catalyzed interfacial hydrolysis.

Further optimization of this PTC acylation should be possible, focused on reducing the excess sodium salt of cyclohexanedione while achieving a yield in the high 90’s. If your company needs to achieve high yield of reactions using water-sensitive compounds in the presence of water, now contact Marc Halpern of PTC Organics to benefit from highly specialized expertise in developing low-cost high-performance green chemistry processes using phase-transfer catalysis, specifically for water-sensitive compounds.

A patent was issued 3 days ago that describes the PTC N-alkylation of imidazole with dichloroethane shown in the diagram. The desired product requires reaction at only one end of the alkylating agent. It is reasonable to assume that the inventors used a very large excess of dichloroethane (34.5 equiv!) as solvent to maximize the probability that the imidazolide anion (formed from imidazole and base) will collide with a dichloroethane molecule rather than a 2-chloroethyl imidazole molecule. Before discussing combining high dilution with the strengths of PTC, let’s talk about the reaction conditions chosen.

The reaction is a solid-liquid PTC system with no added water. In fact, during the workup, the solids were filtered off for separation from the product and consisted of the excess base and KCl byproduct.

Also during workup, the organic phase was washed with water twice, maybe not necessarily to remove residual salts, but probably to begin to separate the tetrabutylammonium salt from the product before purification by chromatography. Tetrabutylammonium salts have a very high affinity for dichloroethane and is quite hard to separate from this solvent by just water washing as I explicitly published in 1998 (http://phasetransfer.com/catsep.pdf). The yield after chromatography was only 41.7%. Since quats have a high affinity to chromatography materials (such as silica), the column undoubtedly removed the phase-transfer catalyst.

I am not totally sure but I think that imidazole is also soluble in dichloroethane. If so, then high dilution is likely even more of a requirement to achieve selectivity of displacement of only one chlorine atom.

It turns out that phase-transfer catalysis provides the opportunity to simulate high dilution in certain systems.

If we assume that the N-alkylation under PTC conditions occurs in the bulk organic phase and not at the interface, then we can control the amount of reactive imidazolide anion in the organic reaction phase by setting the catalyst loading. Let’s say that we use 2 mole% quat, then we can only have no more than 2 mole% imidazolide anion in the reaction phase in the form of [Q+Im-]. If we choose a nonpolar solvent in which imidazole is not very soluble and if we minimize interfacial reaction between imidazolide anion and alkylating agents in the organic phase, then we can create an effective dilution of 100:1 at the outset of the reaction by using 2 mole% quat and 2 equiv of alkylating agent, even though the entire reactor actually contains 1 equiv imidazole and 2 equiv of alkylating agent. The ratio of chloroethylimidazole to dichloroethane will still increase as the reaction progresses, but the ratio of quat imidazolide to alkylating agent IN THE REACTION PHASE will still remain lower throughout the reaction profile than if not using a quat. This improves selectivity.

By the way, the pKa of imidazole is 14.5. Since the pKa of water is 15.7, then when mixing NaOH and imidazole, about 90% of the imidazole will be deprotonated in the imidazolide anion form. So, in order to minimize undesired contact between the imidazolide anion (present to a large extent) and the alkylating agent, we should work at an intermediate rpm and avoid over-agitation.

If your company wants the most highly specialized expertise in industrial phase-transfer catalysis now contact Marc Halpern of PTC Organics to achieve the lowest cost highest performance green chemistry using PTC.

Yes, you read that right… “2020 Qtr 5!” is the morbidly humorous term that some purchasing managers in the chemical industry are using to describe the first quarter of 2021 that ends this week.

As you know, 2020 was an extremely unusual year and that included the prices of chemicals, especially petrochemicals and especially quats.

As you likely know, quaternary ammonium salts which are the most common large scale commercial phase-transfer catalysts, are produced from amines which are produced from alcohols which are produced from alkenes.

For example, butanol is produced by hydroformylation of propylene. Butanol is a raw material for tributylamine which is the starting material for tetrabutylammonium bromide (TBAB) and methyl tributyl ammonium chloride.

The disruptions in the petrochemical markets in 2020 due to COVID-19 were severe and prices fluctuated making supply unpredictable. Those of you who do not work in the purchasing departments of your companies may not be aware that shipping costs increased very dramatically in 2020, sometimes more than 100% and lead times to fulfill chemical orders went from days/weeks to weeks/months!!!

The global demand for surface disinfectants and hand sanitizers experienced a crazy sudden increase and biocidal quats such as didecyl dimethyl ammonium chloride became one of the hottest items in the world. If you look at the bottle of disinfectant concentrate that you couldn’t even buy in April 2020, you will see a list of quaternary ammonium salts as the active ingredients, usually the ONLY active ingredient. If you were using one of those quat salts in your commercial PTC processes, you might have had to shut down your plant!

Several readers of the PTC Tip of the Month reached out to us in mid-2020 asking if we knew of any secret quat suppliers. In one case, a chemist contacted me to ask for his local hospital.

Billions of people around the world were happy to usher in 2021 and forget about the nightmare of 2020. Those of us who lost loved ones to COVID-19 (my uncle succumbed to COVID-19 in March 2020 in a hospital in New York City) will NEVER forget the pandemic. But we somehow have to move on and that included the psychological stress of 2020.

As the revolutionary vaccines are now being distributed in early 2021, there is an expectation that within a few months, markets may start to stabilize. However, oil prices continued to rise from $47/barrel on January 1 to $66 in mid-March. Availability, inflationary pricing and lead times for petrochemical derivatives continued to be tight in early 2021.

And then…the petrochemical industry in Texas quite literally froze during February 10-20. Petrochemical plants in Texas shut down suddenly and unexpectedly and that meant that alkenes were and continue to still be scarce. The shut down of the Suez Canal for nearly a week now in March, delayed 12% of the world’s shipping trade and that certainly didn’t help.

Propylene (PGP = polymer grade propylene) increased in price by 140% from $843 per metric ton on November 20, 2020 to $2,028 per metric ton on February 5, 2021 (data for propylene and butanol shown here) JUST BEFORE the Texas weather crisis shutdown! Butanol prices increased by 167% from April 20, 2020 to January 29, 2021 BEFORE the shut downs in Texas. That is when people started morbidly joking that the first quarter of 2021 was the fifth quarter of 2020.

We do not know when the prices, availability and shipping costs for quaternary ammonium phase-transfer catalysts will return to “normal” (whatever that means). But at least we understand how the various disruptions in the petrochemical markets affected our ability to obtain our catalysts.

A silver lining in this crisis is that COVID-19 forced new manufacturing entrants into the global quat salt supply chain. That means that as demand for disinfectant biocide quats decreases, prices may find a new low, but not too low, as the newly increased capacity is rationalized. Of course, that is a very long term thought since prices, availability and shipping costs are likely to remain tight over the next few quarters.

Most of the subscribers to the PTC Tip of the Month newsletter are process chemists and process engineers. We live in a space of uncertainty as we pursue process chemistry breakthroughs that have never been attempted before. The thoughts shared above demonstrate that the purchasing managers at your companies also live in a space that in the past year has been as uncertain as we experience in breakthrough R&D.

Say thank you to a purchasing manager at your company for keeping the supply chain moving forward since the product that your company sells pays your salary, pays for the flasks, pays for the HPLC and everything else you need to do the remarkable work that you do.

When stoichiometric (or more) TBA HSO4 is used, the question needs to be asked, why? We speculate that iodide poisoning of the phase-transfer catalyst might be at play in the reaction shown in the diagram. Let’s discuss.

As we teach in our 2-day course “Industrial Phase-Transfer Catalysis” (on manual page 76), quaternary ammonium cations have a higher affinity for larger softer polarizable anions with low charge density. Iodide is a rather large soft polarizable anion and is also a very good leaving group.

Quats are soft cations and their affinities for soft anions are higher than for hard anions with high charge density.

For that reason, iodide and even tosylate can sometimes be a catalyst poison for quaternary ammonium phase-transfer catalysts. It depends on the relative affinities toward the quat cation of the competing anions: iodide and the desired nucleophile.

The reaction shown in the diagram was described in a patent that issued a few days ago. The reaction is the O-alkylation of an alcohol that has 12 carbon atoms, one nitrogen and 7 oxygen atoms, so it is not obvious how organophilic the alkoxide might be.

The reason we are discussing catalyst poisoning is that iodide is the leaving group and tetrabutylammonium hydrogen sulfate is used in excess, which is very rare.

We don’t know why the inventors chose to use so much TBA HSO4, but when we are trying to interpret choice of reaction conditions, we must consider the possibility of catalyst poisoning, especially when using iodide as the leaving group.

By the way, the inventors also used PTC for an O-alkylation using propargyl bromide using catalytic tetrabutylammonium iodide, catalytic sodium iodide, THF as the solvent and KOH as the base.

Now contact Marc Halpern of PTC Organics to explore how to leverage PTC Organics’ highly specialized expertise in industrial phase-transfer catalysis to achieve low-cost high-performance green chemistry for your commercial processes and process in development.

Phase-transfer catalysis is often used to improve transition metal catalyzed reactions. We have been reporting a lot of phase-transfer catalyzed Suzuki applications in recent years but not too many hydrogenations, though we teach some in our 2-day course “Industrial Phase-Transfer Catalysis.”

This month, Dr. Schnatterrer’s process R&D department at Bayer, that frequently develops PTC applications, screened nine tetramethyl-, tetraethyl- and tetrabutylammonium salts to enhance hydrogenation using 15 different palladium catalysts. The reaction shown in the diagram uses TBAB with palladium hydroxide on carbon (Noblyst P1071) in methanol. The product was isolated as a 20% solution in methanol. The methanolic solution of the amine product was used in te next step which was a N-benzoylation.

Other PTC palladium co-catalyzed hydrogenations we have seen use Aliquat 336 as the phase-transfer catalyst and toluene as the solvent.

This patent describes the purification of oxydiphthalic anhydride (ODPA; useful as a monomer for polyetherimides engineering thermoplastics) after it is formed by consecutive phase-transfer catalysis reactions shown as one step in the diagram. These PTC displacement reactions require high temperature and require thermally stable phase-transfer catalysts, such as hexaethyl guanidinium chloride (HEG Cl) and tetraphenyl phosphonium bromide (TPPB). The reaction also requires azeotropic drying for both reactivity to minimize side reactions.

Two different procedures were used to synthesize ODPA. ODPA is a solid that is precipitated during workup, then washed with a solvent for purification. The suitability of a particular solvent was based on the solubility of the reactants, byproducts, reaction intermediates and catalyst. The goal was to dissolve the phase-transfer catalyst and the impurities while not dissolving the desired ODPA product.

After measuring solubility of the reactants, byproducts, reaction intermediates and catalyst in 10 different solvents, seven solvents were screened for the washing step of the ODPA solid in the workup. Methanol was clearly shown to be the best solvent to clearly achieve simultaneous high yield (no loss of product during workup) and high purity (separate the phase-transfer catalyst and impurities from the product).

Tetraphenyl phosphonium bromide was found to be an effective catalyst for the PTC reactions. However, its removal from the ODPA during the washing step was not complete and ODPA product purity was only 96.5% to 97.8% after three washes of the solvents screened (isolated yields were 15%-85%). In contrast, when using HEG Cl, removal of HEG Cl from the ODPA by three washes with methanol gave non-detectable residual HEG Cl in the product with overall product purity at 99.48% and 91% isolated yield. HEG Cl appears to be the best catalyst for this application with the well chosen workup.

Effective separation of phase-transfer catalyst from the product is so important that we dedicate a section of our 2-day course “Industrial Phase-Transfer Catalysis” to this topic. Now click here to inquire about conducting this valuable PTC course in-house at your company (by live Zoom video conference or in person when travel is feasible).

One of the recurring practical challenges we face in PTC process development is performing analysis of our products at the end of the PTC reaction to assure that there is no phase-transfer catalyst residue in our products. This is especially true for analyzing samples for the presence of tetraalkyl quaternary ammonium salts since they have no chromophores for typical detector in HPLC and they are not volatile to go through a GC injection port, though they do break down in injector ports tp form trialkylamines that can sometimes be analyzed.

A patent was issued last week that appears to address the issue of analyzing for tetraalkyl quaternary ammonium cations. I must admit that I am not an expert in mass spectrometry. I know just enough about MS to understand that cations are hurled through a magnetic field and are separated by their mass that determines their trajectory on a curve with a radius depending on the mass of the cation.

Tetraalkyl ammonium quats are already cations and don’t need to be bombarded by anything to form cations. Accordingly, the invention described in Cooks, R.; Baird, Z.; Wei, P.; (Purdue Research Foundation) US Patent 10,720,316, 21-Jul-2020, utilizes the concept used in mass spectrometry to analyze for tetraalkyl quaternary ammonium cations. I have read the patent a couple of times and, frankly, I need someone to explain it to me in layman’s terms.

A key concept in the patent is that “the invention provides sample analysis systems that are configured to analyze ions at or above atmospheric pressure and without the use of laminar gas flow.”

The preferred analyzer appears to consist of three curved electrodes separated from each other by a non-conductive spacer and at least one of the three curved electrodes includes an opening through which a probe may be inserted.

A solution of 10 microM each of tetrapropyl-, tetrabutyl-, tetrahexyl-, and tetradodecylammonium bromide in acetonitrile was analyzed by performing separation of the ions in air without the use of a vacuum or a flowing gas. Instead, pulsed voltages were employed with the multi-electrode system as a means to inject ions into the curved ion path and effect a separation of the tetraalkylammonium cations.

The patent contains many diagrams of the analyzer configuration as well as graphs and pictures of the analysis of the tetraalkyl ammonium cations.

If you have faced the challenge of analyzing residual quat in your product, you may want to forward this patent to the creative problem solvers in your analytical department to see if they can utilize this information, or buy a piece of equipment that can perform such analysis.