Usually in PTC etherification of diols, much more diether is formed than monoether, even when the amount of alkylating agent is limited to enough to alkylate just one hydroxyl. The reason is that the quaternary ammonium cation prefers to pair with more organophilic anions. Since the monoether is usually more organophilic than the starting diol, then the ion pair [Q+ R’ORO-] is preferred over [Q+ HORO-]. Since the quat delivers the alkoxide to the alkylating agent (propargyl chloride in this case) in the organic phase and the quat delivers more monoether anion than diol anion, we expect more diether. We teach this in our 2-day course “Industrial Phase-Transfer Catalysis.”

In the reaction shown, the inventor increased the probability of monoetherification by adding the alkylating agent slowly in a controlled manner that kept a high ratio of free diol to monoether in the early stages of the reaction. Performing the reaction at room temperature likely helped selectivity for controlled etherification (avoiding chaotic collisions that are not statistical). The reason that PTC was chosen for this reaction may have been to reduce the energy of activation enough to be able to perform the reaction at room temperature instead of at higher temperatures often used in etherifications of secondary alcohols.

However, it is possible that diether dominated in the reaction shown and that the inventor separated out and isolated the monoether formed in a lesser amount by chromatography. That would be consistent with what we usually observe in PTC etherification of diols, even when only 1 equiv of alkylating agent is used (1.2 equiv were used in this reaction). Since the amount of isolated product was not reported, we don’t know the actual selectivity of the etherification of this diol.

This monoetherification was performed with other reactants including a polyglycol.

The question mark in the title of this post is due to concern that the monooether may not be the dominant product but was successfully isolated for the synthetic purposes of the inventor. We think it is important to highlight the thought process that PTC etherification of diols favors diether formation over monoether formation, so when we see a PTC monoetherification of a diol, we should not conclude that PTC favors monoetherification.

Contact Marc Halpern of PTC Organics to achieve low-cost high-performance green processes for strong base reactions, usually using inexpensive inorganic bases and phase-transfer catalysis.

Improve Polymer Performance for Epoxy Resins

US Patent 9,868,751 shows that when using a variety of curing catalysts containing tetraphenyl phosphonium salts of anilide anions (salicylanilide derivative for example) for polymerizing epoxy resins with curing agents (phenolics such as novolacs) at 95 deg C, for encapsulating semiconductor devices, much better performance is obtained than when using non-phosphonium curing agents such as triphenyl phosphine.

The better performance includes higher flowability, higher stability, lower shrinkage and higher curing rates at lower temperatures, achieved in shorter curing times.

Although not addressed in the patent, the higher performance may be related to the combination of having an anionic curing agent paired with a thermally stable quaternary phosphonium cation.

Kim, M.; Kwon, K.; Lee, D.; Chung, J.; Cheon, J.; Choi, J.; (Samsung SDI CO., LTD.) US Patent 9,868,751, 16-Jan-2018

Improve Polymer Performance for Nitrile Rubber

US Patent 9,868,806 describes technology for producing nitrile rubber that is vulcanized without using sulfur. The rubber is a butadiene (58.5 parts)-acrylonitrile (35.5 parts) polymer containing glycidyl methacrylate (6 parts) for crosslinking. When using tetrabutylammonium bromide (4 parts), without the addition of heavy metal compounds, it is possible to achieve a high elongation at break and tensile strength.

Although not addressed in the patent, it is possible that the mechanism is ring opening of the epoxide by the bromide of TBAB followed by continued reaction of the resulting epoxide (addition reaction to an unsaturated bond).

Brandau, S.; Klimpel, M.; Magg, H.; Welle, A.; (Arlanxeo Deutschland GmbH) US Patent 9,868,806, 16-Jan-2018

Contact Marc Halpern of PTC Organics to integrate your expertise and commercial goals with PTC Organics’ highly specialized expertise in industrial phase-transfer catalysis to achieve higher process performance.

Pat O’Neill of Pfizer provided the following answer to last month’s challenge.

“I would say that this proceeds via acid catalysed hydrolysis of the enamine to the arylacetaldehyde, followed by alpha chlorination (very activated CH bonds). Finally, the alpha,alpha-dichloroarylacetaldehyde undergoes a facile hydrolysis (like a haloform reaction) to formic acid and the gem-dichloro compound. Alternatively, the dichloroarylacetaldehyde could undergo oxidation by HOCl to the arylacetic acid, which would decarboxylate readily to the same compound.”

This is the second challenge this year for which Pat O’Neill provided the first high quality answers. Thank you, Pat!

Phase-transfer catalysis is known to transfer and activate acids such as HCl, HBr, HI, HNO3 and others from the aqueous phase into the organic phase through hydrogen bonding of the acid proton to the halide of a quat salt such as TBAB. So, it is a pretty good idea to apply PTC conditions to transfer HClO into a nonpolar organic solvent and react it under mild conditions.

HClO is well known to add to alkenes to form chlorohydrins. I am not familiar with the reaction that would continue to convert the chlorohydrin or otherwise cleave the alkene then wind up with the benzal group (dichloromethyl).

Earlier this year, our audience helped us identify a reaction with which I was not familiar. Can you help me again this month? Please contact Marc Halpern at PTC Organics with your answer and specify if you authorize us to publish your name and company affiliation in next month’s PTC Tip of the Month.

An exhibit at the 2017 Specialty & Agro Chemical trade show displayed a system by FLEXIM based on measuring changes in the speed of sound in a liquid that can be calibrated to determine conversion of chemical reaction that we think may be particularly useful for solvent-free phase-transfer catalysis reactions or in PTC systems that use solvent and are not overly dilute.

The advantage of the system is that no samples need to be taken and conversion can be monitored continuously after a calibration curve is established.

The principle is based on the fact that the speed of sound transmitted through a liquid is different as the density changes. The system uses a sound wave generator and a sound wave frequency detector, both attached externally to the outside walls of the reactor (shown on the left side in the picture). The reactor can be made of just about anything…glass, metal, plastic, etc. the system is quite sensitive and can discern between 10.0% aqueous NaCl and 10.1% aqueous NaCl, for example.

In Starks’ original solvent-free PTC reaction reported in 1971 in which octyl chloride was converted into octyl nitrile, the difference in densities between these two materials could be used to determine the relative compositions of the two materials, thereby determining conversion.

The main application of FLEXIM’s technology is non-invasive ultrasonic flow measurement.

PTC Organics would be happy to work with your company and the manufacturer of this system to evaluate the applicability of this system to continuously determining conversion of your PTC application without sampling, by integrating our highly specialized expertise in industrial phase-transfer catalysis with your company’s needs and the expertise of the manufacturer of the unit. Now contact Marc Halpern of PTC Organics to explore custom developing a solution for your solvent-free PTC application (or concentrated PTC system).

An exhibit at the 2017 Specialty & Agro Chemical trade show in Charleston, South Carolina (just before Hurricane Irma hit the city) displayed a continuous feeder-mixer by Readco-Kurimoto that, in our opinion, may be useful for certain types of solid-liquid phase-transfer catalysis reactions. We speculate that PTC I-Reactions (in which the rate determining step is NOT transfer) that use two different solids such as NaOH and potassium carbonate and do not require vigorous mixing between the solids and liquids, may benefit from this system.

The unit starts with a screw feeder that delivers solids into a series of rotating blades that can be made of a variety of materials of construction and in a variety of geometries. There are two sets of blades, each on a shaft, that rotate with little clearance between them. This results in mixing and even mild grinding if solids are present. Liquids can be introduced at various locations along the axes of rotation. The unit can be enclosed for temperature control. The speed of the blades can be controlled. The diameter of the blades can be up to 24 inches.

One can envision the use of this system for a continuous process for a solid-liquid PTC reaction. The solids are fed continuously and moved down the length of the unit first by the screw feeder then by the rotating blades where the liquid is introduced and mixed with the solids, all the while being moved forward.

The manufacturer of the unit is willing to test applications in their facility and apply their expertise to the selection of blade geometry and other operating parameters.

PTC Organics would be happy to explore working with your company and Readco-Kurimoto to evaluate the feasibility of this system by integrating PTC Organics’ highly specialized expertise in industrial phase-transfer catalysis with your company’s needs and the expertise of the manufacturer of the unit. Now contact Marc Halpern of PTC Organics to explore custom developing a solution for your solid-liquid PTC application.

I “fell in love” with phase-transfer catalysis at first sight 41 years ago as a second year undergraduate student when I saw that you can replace expensive alkoxides with NaOH. It still bothers me after all these years when I see people wasting money. If you are a process chemist, you probably feel the same way and the reaction choices shown in the diagram probably bother you right now.

Do you know anyone who thinks they need cesium carbonate to deprotonate a thiophenol? We wouldn’t even use potassium carbonate for this reaction, we would just use 1.00 equiv of aqueous NaOH to form the sodium salt and we may even use enough water to fully solubilize the thiophenoxide. This is done in MANY PTC-thiophenoxide applications. The inventors knew enough about PTC to use a tetrabutylammonium salt for this reaction, so they must have seen at least one PTC S-alkylation in the literature.

Do you know anyone who thinks they need a full equivalent (or more!) of a phase-transfer catalyst to perform a simple S-alkylation of the highly nucleophilic thiophenoxide, an anion that has been studied extensively as a model reaction for nucleophilic substitutions to study PTC conditions and mechanisms starting in the 1970’s? I would be embarrassed to use as much as 10 mole% of a phase-transfer catalyst for this application, even during the screening stage of such a reaction.

Do you know anyone who thinks they need to use the most expensive tetrabutylammonium salt (TBAI) to do this reaction?

Do you know anyone who thinks they need to use ethyl iodide for this reaction, when ethyl bromide works well? The first PTC S-ethylation of thiophenoxide was reported in 1975 as one of the early classic publications (by Herriott and Picker). The yield using ethyl bromide was 93% in 15 minutes at room temperature and used 6% NaOH as base with 6 mole% phase-transfer catalyst…in the days before anyone knew how to optimize choice of phase-transfer catalyst.

I can understand that maybe the inventors didn’t want the ethyl bromide to evaporate (b.p. 38 C), but these reactions are fast at room temperature and don’t need a pressure vessel. Maybe there is competition from N-ethylation of the amino group, though I doubt it if we deprotonate the thiol, especially in the presence of water that would hydrogen bond to the amino group.

Do you know anyone who knows about PTC who feels they must use DMF as a solvent for a room temperature reaction when using a phase-transfer catalyst? Wouldn’t you just use toluene? Even Herriott and Picker used benzene back in the days when that was an acceptable choice of solvent.

I know that not everyone is a process chemist and that many chemists need to just make the compound with a high probability of success the first time to meet their project deadline. I understand that.

But such reports still bother me. Maybe I should see a psychotherapist. Maybe you and I will go together and get a group rate.

Now contact Marc Halpern of PTC Organics if you strongly prefer to develop low-cost high performance green chemistry processes using phase-transfer catalysis instead of seeing a psychotherapist.

Have you heard of the Bargellini Reaction? I didn’t until last month when it was pointed out by Dr. Pat O’Neill of Pfizer, Dr. Reinhard Sommerlade of BASF Switzerland, Dr. Joe Schwab of Hybrid Plastics, Dr. Dan Henton (formerly of Dow Chemical), Dr. Klaus Buescher of Novartis and Dr. Thomas Zierke of BASF.

This reaction, first reported by Guido Bargellini in 1906, is the answer to the question posed in last month’s PTC Tip of the Month to explain the sequence of phase-transfer catalysis reactions shown in the figure.

Dr. Sommerlade of BASF Switzerland AG explained the reaction sequence best: “Once the trithiocarbonate anion is formed, it will readily react with 2,2-dichloro-3,3-dimethyloxirane, a product formed in situ from acetone and dichlorocarbene (addition to the C=O bond), which in turn is formed from chloroform under alkaline conditions. The thioanion opens the epoxide and the intermediate product is saponified to give the product shown in the scheme.”

Again, we thank Pat O’Neill, Reinhard Sommerlade, Joe Schwab, Dan Henton, Klaus Buescher and Thomas Zierke for enlightening us about a reaction that has been around for more than a century.

The diagram shows what appears to be consecutive PTC reactions with a good outcome. However, not all of the chemistry is obvious to this reviewer and we need your help to explain how these reactants lead to this product.

Please read the procedure shown below (provided in this patent) in order to figure out which, if any, of the PTC reactions shown below may be at work in this sequence, then contact Marc Halpern writing in the comments section your explanation of the reactions and source of each carbon atom. Thank you in advance for your help.

25 g NaOH (50 wt %) was added dropwise to a solution of ethanethiol (18.9 g), Aliquat 336 (4.9 g) and 150 mL acetone at 0 deg C. over 20 minutes. The reaction was then stirred for a further 10 minutes before adding carbon disulfide (18 mL) and the mixture was then diluted with 30 mL acetone dropwise over 20 minutes. After stirring for another 10 minutes, chloroform was added in one portion and then 120 mL NaOH (50 wt %) was added dropwise over 20 minutes. The resulting solution was then stirred at 0 deg C for 24 hours. Purification was performed by removing acetone, redissolving in 200 mL water and then adding 300 mL concentrated HCl(aq) while stirring rapidly in an ice bath. The sample was extracted with PET spirit then washed with water three times. The PET phase was collected and dried with magnesium sulphate (MgSO4). The solution was then filtered and concentrated by rotary evaporation. The product was recrystallized from PET spirit three times, resulting in bright yellow crystals. (91.2%) 1H NMR (400 MHz, CDCl3): δ=3.30 (q, 2H), 1.73 (s, 6H). 1.33 (t, 3H). 13C NMR (400 MHz, CDCl3): δ=207.18 (C=S), 177.35 (COOH), 55.49 (SCCH3), 31.26 (SCH2), 25.22 (CCH3), 12.85 (CH2CH3).

Phase-transfer catalysis excels in many nucleophilic substitutions and strong base reactions. The procedure provided is Example 2.2 in the patent and appears to start with one of PTC ‘s strengths which is the transfer and reaction of thiolates. In the first step, ethyl mercaptide is easily formed by neutralization with base and should easily react with carbon disulfide in acetone, aided by Aliquat 336 to produce the first intermediate that we assume is ethyl trithiocarbonate sodium salt. It is possible that this reaction works without PTC and that Aliquat 336 possibly reduces the energy of activation enough to keep the temperature low enough to avoid/minimize the ignition of carbon disulfide.

The next reactions are the ones in question. When looking at the placement of the carbon atoms, one may be able to suggest that the electron rich S-anion attacks the electron deficient carbonyl carbon of acetone. But, if so, then what? Is it possible that dehydration happens under basic conditions? Even if it is possible, then what?

PTC excels in carbene reactions in which dichlorocarbene is formed from chloroform and NaOH and adds to electrophiles. If the electrophilic dichlorocarbene is the active species, would it add to the double bond if the intermediate from the reaction of the S-anion with acetone dehydrated? If so, can the dichlorocyclopropane somehow be ring opened and hydrolyzed to the carboxylic acid.

Alternatively, is it possible that when the S-anion attacks acetone to form an O-anion, can the O-anion react with the dichlorocarbene then rearrange before hydrolyzing into the carboxylic acid?

These all seem to be strange speculations.

PTC-NaOH-chloroform is also known to convert alcohols to alkyl chlorides in high yield (with retention of configuration through an SNi mechanism). Can this be somehow involved in this reaction sequence?

Of course, PTC also excels in alkylation of ketones, so acetone could be deprotonated under these PTC-strong base conditions. But then what?

It is also possible that the structure of the product is drawn incorrectly. The structure drawn is consistent with another structure shown later in the patent and is also consistent with the compound name.

Your challenge is to figure out what reactions are happening here with which reactants and confirm or refute the structure of the product shown. While it is embarrassing to admit not understanding the chemistry in this sequence, I am not embarrassed to ask for help from smarter organic chemists. We understand phase-transfer catalysis extremely well, but we need your help to understand the chemistry.

Please submit your understanding of this chemistry using the comments section of the contact form and next month we will publish the best explanations and name the contributors. If you don’t want your name published, please let us know.

Over the past decade, we have written several times about the potential to achieve outstanding processes by combining the strengths of liquid-liquid PTC systems for high reactivity in continuous processes with the strengths of microreactors to conduct fast reactions with excellent heat transfer and low heat history in continuous processes.

Corning is a leader in the production of microreactors made of glass or silicon carbide that can endure reaction conditions up to 18 bar and 200 C.

At Informex 2017, we were able to take these pictures of microreactors. The large unit shown contains an array of microreactors with a production capacity of up to about 2,000 tons of product per year.

At PTC Organics, we have always known that phase-transfer catalysis is a solution looking for a problem. Similarly, Corning knows that microreactor technology is a solution looking for a problem.

We believe that there is great opportunity to make a lot of money, even for a small company or startup, by LEVERAGING THE COMBINATION OF:

[1] the greatly reduced CHEMICAL energy of activation of phase-transfer catalysis in liquid-liquid PTC systems in 30 broad reaction categories with

[2] the greatly enhanced heat transfer, controlled agitation and other PHYSICAL characteristics provided by microreactors.

The potential to make money is limited only by the creativity of our readers to identify “problems” in search of the solution that is the combination of PTC with microreactors. This challenge requires knowledge of chemical market opportunities, highly specialized PTC expertise and engineering expertise in microreactors.

Please contact Marc Halpern of PTC Organics if you are aware of a chemical challenge, especially one that requires high selectivity or high productivity or short heat history and is a strong base reaction, nucleophilic substitution, oxidation or reduction. We will be happy to sign a CDA and explore development and commercialization.

Closeup picture of several microreactors: