We commend the inventors for recognizing that phase-transfer catalysis excels in performing specialty esterifications. We further commend the inventors for recognizing that solid-liquid PTC conditions are most likely to provide good results for the reaction shown in the diagram.

PTC esterifications are often performed at temperatures significantly higher than room temperature and one of the techniques to reduce the temperature is to use PTC-iodide co-catalysis. The inventors chose tetrabutylammonium iodide as the phase-transfer catalyst and this is a very reasonable choice that was likely crucial to achieve high conversion at room temperature.

However, if this reaction would progress to scale up, we would change a few of the process parameters chosen.

First, we would not choose acetonitrile as the solvent. We would choose a less polar solvent that is immiscible with water to facilitate workup on a large scale.

Secondly, we would choose to use a phase-transfer catalyst that is much less expensive than tetrabutylammonium iodide, such as tetrabutylammonium bromide and combine it with a small amount of potassium iodide. The combination of TBAB/KI is usually much less expensive than purchasing TBAI itself and this combination functions just as well as TBAI due to the much higher affinity of quat cations for iodide versus bromide, usually by more than an order of magnitude. We teach this in the 2-day course “Industrial Phase-Transfer Catalysis.” Has your company brought this course in-house in the last decade? If not, click here.

Thirdly, we expect that optimization studies would show that the amount of TBAB/KI could be greatly reduced from 10 mole% catalyst loading, perhaps down to 0.5 mole% to 2 mole%.

Now contact Marc Halpern of PTC Organics when you need to achieve the highest performance of your PTC process while minimizing your process R&D development time and cost.

Tetrabutylammonium iodide is used to catalyze the C-alkylation of a substituted cyclohexanone shown in the diagram.

It is reasonable to assume that the role of the iodide is to form in situ the more reactive 3-iodo-1,1-dimethoxypropane from the bromo derivative.

It is also reasonable to assume that t-butoxide was chosen as the base to avoid hydrolysis of the ester if a base such as NaOH would have been used. The pKa of the methylene alpha to the carbonyl being deprotonated should be within the range of 16-23 for which PTC-NaOH reactions excel. This is taught in the 2-day course “Industrial Phase-Transfer Catalysis.”

Since the reaction is performed in t-butanol, it is likely that the tetrabutyl ammonium iodide is simply a source of soluble iodide and not an actual phase-transfer catalyst from a mechanistic standpoint, since the reactants are likely soluble in t-butanol.

One interesting aspect of the procedure is that the cyclohexanone substrate, the t-butoxide in t-butanol and the tetrabutylammonium iodide were mixed for hours with heating before starting to add the 3-bromo-1,1-dimethoxypropane. This is curious since the acid-base neutralization should be instantaneous and there would be no need for the tetrabutylammonium iodide to be present for the neutralization.

In fact, the more that the tetrabutylammonium cation is needlessly exposed to strong base and heat, the higher the probability of experiencing Hofmann Elimination that decomposes the quat cation. Then again, the reaction appears to proceed in the presence of only 1.3% quat iodide. So, maybe the quat survives this heat history.

We do not know if the 51.5% isolated yield is due to taking a high quality distillation cut or if the conversion was low. If the conversion was low, it would be worthwhile to observe whether the quat cation decomposed during the exposure to the butoxide base which doesn’t have a readily apparent reason for being present during the 4 hours of heat history.

A celebration was held in Ponca City, Oklahoma for the 90th birthday of Charles Starks and his wife Virginia Starks. I (Marc Halpern) interviewed Dr. Starks in his home and he shared many interesting perspectives on the history of phase-transfer catalysis.

As many of you know, Dr. Starks is the inventor of the classical extraction mechanism that serves as the basis for understanding PTC applications and predicting the kinetics for most PTC reactions.

The interview was conducted in the Starks’ garden outdoors, so you will hear in the audio recording sounds of birds and insects. Please do not be distracted by these sounds.

Surprising fact disclosed in this interview: If scientists in the early 1960’s didn’t believe that the world would run out of food, Dr. Starks may not have embarked on the path to find an alternative to oils that served as the basis for soaps that may have been needed to feed people, that eventually led to the discovery of phase-transfer catalysis. The details are fascinating including the objections reviewers had to the original classical 1971 PTC publication.

Following are the intro and questions in this interview.

I have the amazing honor and privilege to be in Ponca City, OK to celebrate the 90th birthday of Dr. Charles Starks, the inventor of the extraction mechanism and the man who coined the term phase-transfer catalysis. Thank you for hosting me in your home.

I’m 70 years old and I fell in love with PTC 48 years ago, the moment I read your landmark publication 5 years after it was published in 1971. I want to thank you for your personal mentorship and more importantly I want to thank you on behalf of the scientific community for the immeasurable positive impact you made on achieving low-cost high-performance green chemistry for thousands of commercial processes.

I would like to ask a few questions for historical perspective.

• How did you come up with the extraction mechanism? Was it driven by your need to understand a specific reaction? Did it come to you in a dream? How did you figure it out?
• Did your bosses want to keep the extraction mechanism of PTC a secret or did they readily agree to patent it?
• Several years passed between your landmark initial publication of PTC and the issuance of your landmark broad scope patent in 1976. Do you recall the objections of the patent office?
• When you coined the term phase-transfer catalysis, how long did it take to realize that it would revolutionize cost reductions, environmental performance, process safety and other extraordinary benefits to the chemical industry?
• Today, PTC is being used in an amazingly wide array of segments of the chemical industry including polymers, monomers, pharmaceuticals, agrochemicals, petrochemicals, flavors & fragrances, dyes & pigments, solvents, explosives, medicine devices, surfactants and other commodity, specialty and fine organic chemicals? Do you recall which industries did PTC affect first and how it caught on?
• What were the barriers to faster and more widespread adoption of PTC? Resistance to change?
• Are you surprised that new PTC applications continue to be developed 53 years after you coined the term phase-transfer catalysis?
• What do you think was the biggest global impact of phase-transfer catalysis on the chemical industry and the world? Positive environmental impact through emissions reduction, reducing excess reactants, replacing hard to recover solvents such as DMSO? Safety by reducing hazardous materials such as phosgene, cyanide and hydrogen generation when producing alkoxides?
• You’re a humble man. How did the breakthrough discovery of PTC not go to your head?
• What did you enjoy more, achieving breakthroughs, managing people who achieved breakthroughs or something else?
• What was the #1 lesson you learned from your experiences from process chemist to senior executive in the chemical industry?
• What advice would you give to chemists starting their career?

As you know, PTC has been my full-time entrepreneurial business since 1995, soon to be 30 years.

When you and Charles Liotta accepted me as your junior collaborator in 1987, you totally changed my life for decades. There are no words to express the depth of gratitude I feel toward you and Charles Liotta for accepting me and mentoring me at the most crucial fork in my career path.

We came across a condensation reaction this month that uses TBAB (tetrabutylammonium bromide) as a catalyst at a loading of 3.1 mole%. The reaction is shown in the diagram.

However, it appears that either there is a missing reactant, such as a base to promote one of the condensation steps, or it is not clear what role TBAB could be playing in this reaction.

What do you think?

The reaction was performed in two steps. First the three reactants were mixed and heated at 70 deg C in ethanol for 2 hours. Then the TBAB was added to complete with additional 0.5 hour at 90 deg C and overnight at r.t.

One possibility is that heating in ethanol facilitates a condensation reaction between the p-diethylaminosalicylaldehyde and the thioamide, resulting in the formation of an intermediate such as that shown in the next diagram. Another possibility is the formation of an imine from the aldehyde and the nucleophilic thioamide, though it is not clear how that would lead to the reported structure of the product.

If we assume that the intermediate is that shown in the second diagram, then TBAB could possibly catalyze a condensation induced by attack on the aldehyde by an anion formed by deprotonation of the methylene group in the beta diketone-thioketone IF a base was present, such as NaOH or potassium carbonate. PTC excels in the formation and nucleophilic attack of such anions. If this PTC catalyzed attack of the carbanion/enolate on the aldehyde, that would form the chromenone ring.

However, if base was not present, it is not clear what role the TBAB plays in these reactions. That is why we speculate that the addition of base was inadvertently omitted from the procedure.

At some point, the formation of a thiazole ring is likely driven by a nucleophilic attack on the carbonyl carbon of ethyl 3-chloro-2-oxobutanoate by an intermediate formed earlier. The sulfur atom in the thioamide participates in the cyclization, leading to the formation of a thiazole ring structure.

The isolated yield after crystallization is 85%.

Why do you think is happening in this reaction system?

We came across a condensation reaction this month that uses TBAB (tetrabutylammonium bromide) as a catalyst at a loading of 3.1 mole%. The reaction is shown in the diagram.

However, it appears that either there is a missing reactant, such as a base to promote one of the condensation steps, or it is not clear what role TBAB could be playing in this reaction.

What do you think?

The reaction was performed in two steps. First the three reactants were mixed and heated at 70 deg C in ethanol for 2 hours. Then the TBAB was added to complete with additional 0.5 hour at 90 deg C and overnight at r.t.

One possibility is that heating in ethanol facilitates a condensation reaction between the p-diethylaminosalicylaldehyde and the thioamide, resulting in the formation of an intermediate such as that shown in the next diagram. Another possibility is the formation of an imine from the aldehyde and the nucleophilic thioamide, though it is not clear how that would lead to the reported structure of the product.

If we assume that the intermediate is that shown in the second diagram, then TBAB could possibly catalyze a condensation induced by attack on the aldehyde by an anion formed by deprotonation of the methylene group in the beta diketone-thioketone IF a base was present, such as NaOH or potassium carbonate. PTC-base conditions excel in the formation and nucleophilic attack of such anions. If this PTC catalyzed attack of the carbanion/enolate on the aldehyde is part of the pathway, that would form the chromenone ring.

However, if base was not present, it is not clear what role the TBAB plays in these reactions. That is why we speculate that the addition of base was inadvertently omitted from the procedure.

At some point, the formation of a thiazole ring is likely driven by a nucleophilic attack on the carbonyl carbon of ethyl 3-chloro-2-oxobutanoate by an intermediate formed earlier. The sulfur atom in the thioamide participates in the cyclization, leading to the formation of a thiazole ring structure.

The isolated yield after crystallization is 85%.

Why do you think is happening in this reaction system?

Ten different quat salts, tertiary ammonium salts and phosphazenium salts, mostly acetates and other carboxylates (succinate, citrate, betaine) were screened and found to be effective initiators for the polymerization of β-propiolactone to poly-3-hydroxypropionate.

Tetramethylammonium acetate (TMA OAc) showed greater control over the molar mass compared to longer chains such as tetrabutylammonium. TMA OAc also showed full beta-lactone conversion in less than 6 hours in both THF and MTBE as solvents. This was achieved with molar ratios of beta-lactone to TMA OAc of 500:1 and even 2,000:1.

Beta-propiolactone is a highly reactive chemical and reactions are performed in solvent to mitigate potential intense exotherms from the enthalpy of ring opening of the 4-membered ring ester monomer.

It is thought that acetate mitigates side reactions and this is evidenced by huge differences in molar mass when using DBUH OAc versus DBU at high monomer to initiator levels.

This polymerization in THF is likely not phase-transfer catalysis since TMA OAc is likely soluble in the THF-monomer mixture. It is not clear if TMA OAc is soluble in the MTBE-monomer system. The poly-3-hydroxypropionate polymer precipitates from the reaction solution, so the system is heterogeneous.

The preparation of specialty quat carboxylates is described in this month’s PTC Catalyst of the Month. The procedure was reported by the inventors at BASF who used the quat carboxylates to catalyze the reaction of TXMDI diisocyanate to polycarbodiimide.

It is reasonable to assume that quat carboxylates were chosen in order to enhance the solubility of the carboxylate in the isocyanate phase. Three quat carboxylate salts were prepared and used for the reaction. They were tetrabutylammonium 2-ethylhexanoate, tetramethylammonium 2-ethylhexanoate and methyl tributyl ammonium 2-ethylhexanoate. We are guessing (but don’t know), that the combination of availability and cost of methyl tributyl ammonium chloride as the starting material for the quat 2-ethylhexanoate salt plus the 13 carbon atoms of this quat versus only four carbon atoms for tetramethyl ammonium might be a good compromise for effective catalytic properties. Tetrabutylammonium chloride is a more expensive starting material, whereas tetrabutylammonium bromide would be 10 times more difficult to be used for the ion exchange to the carboxylate (see explanation in this month’s PTC Catalyst of the Month).

The carboxylate-catalyzed conversion of isocyanate to carbodiimide involves the following mechanism:

Nucleophilic Attack: The carboxylate anion acts as a nucleophile and attacks the carbon atom of the isocyanate group forming a tetrahedral intermediate. This intermediate has a negatively charged oxygen atom and a positively charged nitrogen atom.

Rearrangement and Elimination: The intermediate undergoes rearrangement. The negatively charged oxygen atom pushes back to reform the carbonyl group, leading to the elimination of a molecule of carbon dioxide and forming an isocyanate anion intermediate.

Formation of Carbodiimide: The isocyanate anion intermediate then undergoes rearrangement. The lone pair on the nitrogen attacks the carbon of the original isocyanate group, leading to the formation of carbodiimide.

In summary, the carboxylate anion acts as a catalyst by first attacking the isocyanate to form a reactive intermediate. A quat carboxylate is a better candidate to solubilize the carboxylate in the isocyanate phase than an alkali metal carboxylate. The reactive intermediate then loses carbon dioxide and rearranges to form the carbodiimide product. The catalytic cycle is completed with the regeneration of the carboxylate anion.

Quat bromides are often used as a source of organic-soluble bromide to catalytically open epoxides for the purpose of attack by alcohols. In the reaction shown in the diagram, the quat bromide is used to catalyze the ring opening of an epoxide for the purpose of esterification. This esterification reaction with an epoxide catalyzed by TBAB is not commonly seen in the literature.

We wonder about the mechanism of this esterification. One possibility is that bromide of tetrabutylammonium bromide (TBAB) attacks the epoxide to open the ring and form a 1-bromo-2-alkoxy anion (bromohydrin anion). The basic alkoxy anion could deprotonate the acidic carboxylic acid of the 2,2-bishydroxylmethyl propionic acid to form the substituted propionate anion. This carboxylate anion could  displace the bromide to form the ester and regenerate the free bromide anion for another catalytic cycle. The high temperature of 120 deg C is likely sufficient to induce a successful attack of the carboxylate anion on the C-Br. During the time that the bromide is covalently bound to the carbon, the quat would be free to pair with the carboxylate to perform a classical PTC esterification.

Is this a plausible mechanism, especially in the absence of a base? Do you have any better ideas of how this reaction is catalyzed by TBAB?

Tetrabutylphosphonium bromide (TBPB) was used to catalyze several polyesterifications of 3,3’ dithiopropionic acid with four different diepoxides and using gallic acid to terminate the polymer/oligomer.

We speculate that TBPB was chosen for several reasons. The first is that TBPB provides an organic- soluble source of bromide (not classical PTC) that initiates the ring opening of the epoxide that facilitates the esterification with the acid. A second reason is that the reaction undergoes significant heat history at 105 deg C over 24 hours in all four polyesterifications and quaternary ammonium salts, such as TBAB, are not as stable as quaternary phosphonium salts such as TBPB. Of course, “P-quats” are more expensive then “N-quats”, so it is beneficial to choose a P-quat that is not overly expensive. TBPB has a lower molecular weight than other P-quats, so the cost per mole of P-quat might be acceptable.

The polymers appear to have weight average molecular weights that represent 4-6 repeat units, so these may be considered to be oligomers depending on how you define oligomers versus polymers.

These polyesters are useful in protective films for the lithography process in the production of semiconductor chips.

Peter Wuts (https://petergmwuts.com), André Stoller and Bryce Assink helped us understand this reaction sequence that looks as if it is a deoxygenation reaction. Peter, André and Bryce are long time loyal readers of the PTC Tip of the Month newsletter who participated in our 2-day course “Industrial Phase-Transfer Catalysis” in the early 2000’s.

Tetrabutylammonium bromide is used as the phase-transfer catalyst to “deoxygenate” in very high yield a [1,3]oxathiol-2-one using dibromomethane (also used as solvent) and base.

Our loyal readers pointed out that of the [1,3]oxathiol-2-one is a cyclic monothiocarbonate and as such it is sensitive to hydrolysis, especially in the presence of base. Once the carbonyl is attacked and the ring  opened, the sulfide anion reacts with dibromomethane to form the bromomethyl thioether. After decarboxylation of the newly formed carbonate anion, the remaining phenoxide oxygen attacks the bromomethyl group to close the ring.

In other words, the ring is not directly “deoxygenated.” In fact, the methylene carbon in the 1,3-oxathiolane ring is sourced from the dibromomethane.

Please be aware that when PTC-NaOH conditions are used in the presence of dichloromethane, formaldehyde can be formed which is a safety concern. Under such conditions, dichloromethane is hydrolyzed to chloromethanol that liberates HCl to form formaldehyde. In this case, since 5M NaOH was used as base, it likely was not strong enough to form formaldehyde from dibromomethane.