Before reading this patent, please be aware that PTC Organics developed PTC etherification technology using epichlorohydrin that is more selective than that reported here and in other PTC glycidyl etherification literature. PTC Organics maintains this technology under trade secret status. Contact Marc Halpern of PTC Organics to inquire about licensing PTC etherification technology using epichlorohydrin.
One of the largest scale early commercial applications of phase-transfer catalysis was the reaction of bisphenol A with epichlorohydrin to for the bisphenol A-diglycidyl ether (DGEBA), a monomer used in epoxy resins. The inventors note that isosorbide diglycidyl ether may be a suitable substitute for DGEBA which has raised concerns about carcinogenicity even though there are no data that support human carcinogenicity. This patent describes the use of PTC for the etherification of isosorbide (derived from a natural product) with epichlorohydrin.
The challenge is to selectively produce the diglycidyl ether while minimizing both residual monoglycidyl ether and higher oligomers that result from hydrolysis of the epoxide and subsequent oligomerization. The inventors found that using 1 wt% tetraethylammonium bromide or tetrabutylammonium iodide maximizes the desired digylcidyl ether.
The inventors used 5 equiv epichlorohydrin. This level of excess is common in reports of other glycidyl etherifications. The excess epichlorohydrin also provides extra fluidity since no additional solvent is used.
50% NaOH (2.0 equiv) was added over time with continuous azeotropic drying to minimize hydrolysis, to neutralize the 2 hydroxyls without excess hydroxide.
The reaction was performed at 80 C. This is also a common temperature used in the literature foe etherifications using epichlorohydrin.
The attention to detail in reporting by the writers and examiners of the patent is poor. In all the examples, the identity of the phase-transfer catalyst quat is referred to as triethylammonium instead of tetraethylammonium and the abbreviations for the quats in the table are amazingly: TBAI = triethylammonium iodide, TEAC = triethylammonium chloride and TEAB = triethylammonium bromide. Look it up if you have a hard time believing that such errors would make it through all the reviews. We know that the real catalysts are tetraalkyl quats based on the claims, which apparently were actually read before issuing the patent.
If your company has a commercial application that can greatly benefit from selective PTC etherification technology, especially using epichlorohydrin, now contact Marc Halpern of PTC Organics to explore business opportunity under secrecy agreement.
One of the major advantages of phase-transfer catalysis is the ability to replace expensive anhydrous bases with PTC and common inexpensive bases. There are countless examples of reports in which chemists use t-butoxide when they could and should use PTC-NaOH or PTC-potassium carbonate.
However, there are few examples when chemists are clever enough to think about using PTC but continue to use t-butoxide in cases that don’t require deprotonation of high pKa substrates. This patent is such an example.
In fact, the reactant being deprotonated is a phenol which is so acidic that it doesn’t even need NaOH, let alone t-butoxide. Potassium carbonate by itself is basic enough to deprotonate the phenol. Potassium carbonate can also serve as a desiccant to “hide” any water in the system. This is important because nucleophilic aromatic substitutions usually need significant energy of activation and we don’t want to add energy of activation due to hydration of the attacking phenoxide anion.
Moreover, I would be concerned using excess t-butoxide that can cause Hofmann Elimination of the TBAB that decomposes the phase-transfer catalyst, especially at 80-85 C. Who knows…maybe that is why the inventors used such a high catalyst loading of 20 mole%, to overcome catalyst decomposition.
It is always possible that the inventors tried PTC with just carbonate (no t-butoxide) and it didn’t work. However, I would be surprised if that was the case.
If your company is using t-butoxide or any other expensive, anhydrous and/or hazardous base, now contact Marc Halpern of PTC Organics to reduce your cost of manufacture, reduce your development time and improve process performance by integrating PTC Organics’ highly specialized expertise in industrial phase-transfer catalysis with your process development and commercial goals.
In the October 2018 PTC Reaction of the Month, we asked for suggestions to explain the mechanism for the tetramethylammonium chloride catalyzed esterification of methacrylic acid with epichlorohydrin. Peter Kapferer, a process chemist at a well-known manufacturer in Switzerland, proposed the following mechanism that is quite plausible.
Peter wrote: Opening of the epoxide by the Quat-chloride would, in the absence of any inorganic cations, lead to Quat-1,3-dichloro-2-propanolate, a strong base. This could take the proton from methacrylic acid, and then Quat-methacrylate reacts with Quat-1,3-dichloro-2-propanol to form the ester and Quat-Cl, closing the catalytic cycle. There are a few examples in the literature where tertiary amines and an epoxide form strong alkoxide bases. The advantage of the two-stage process could thus be to carry out the esterification under more or less neutral conditions (with only traces of a base formed in-situ), avoiding the formation of oligomers by repeated addition of epichlorohydrin. As the ester forms, the base “disappears”.
We thank Dr. Kapferer for this contribution and continued interest in the PTC Tip of the Month for more than a decade.
We also corrected the name of the inhibitor shown in the diagram in the October 2018 PTC Reaction of the Month,
As we teach in our 2-day PTC course “Industrial Phase-Transfer Catalysis,” the method of separation of the phase-transfer catalyst from the product is usually determined by the difference in polarity between the catalyst and product and include extraction of the catalyst into water (most common), recrystallization of product, adsorption onto a solid support (clay, silica, alumina) and extraction of the phase-transfer catalyst into a non-polar solvent in which the product is not soluble.
In some cases, phase-transfer catalyst separation is feasible by distilling the product away from the catalyst. This method is used in many commercial PTC processes for the manufacture of fragrances, low molecular weight monomers and halocarbons.
In this patent, the CFC mixture is added to aqueous NaOH and phase-transfer catalyst at 35 C-42 C (near its boiling point), then heated to 70 C. The boiling point of the product (hexafluoro-2-butyne) is -25 C and can be taken overhead as it is formed (collected in a cooling trap, hopefully with low handling losses). PTC enables performing this dehydrochlorination at a low enough temperature to avoid polymerizarion of the alkyne product.
If the organophilic quats tetraoctylammonium or Aliquat 336 would be used for this reaction, one should be able to recycle the phase-transfer catalyst easily. If tetrabutylammonium is used, it may be lost in the aqueous phase during workup. So, if phase-transfer catalyst recycle is required to meet economic targets, we would avoid the use of TBAB.
The patent does not address the recycle of the phase-transfer catalyst and we each this in our 2-day course “Industrial Phase-Transfer Catalysis.”
The patent also mentions the possible addition of NaCl to the reaction mixture, even though NaCl is a byproduct. The inventors note that the alkali metal halide might be stabilizing the phase-transfer catalyst. However, as we teach in our 2-day PTC course “Industrial Phase-Transfer Catalysis,” the addition of NaCl to certain PTC processes is used to salt out phase-transfer catalysts into the organic reaction phase (such as tetrabutylammonium that are not as organophilic as Aliquat 336 or TOAB) which in turn enhances reactivity since the rate determining step is likely to take place in the organic phase according to the Halpern pKa Guidelines (taught in our 2-day PTC course “Industrial Phase-Transfer Catalysis) as applied to PTC dehydrohalogenation.
If your company wants to achieve the lowest cost highest performance green chemistry processes using phase-transfer catalysis, now contact Dr. Marc Halpern of PTC Organics, the industrial phase-transfer catalysis experts.
This patent describes the synthesis of derivatives of propane diyl dicinnamate. The inventor used phase-transfer catalysis to perform an esterification of a cinnamate derivative (e.g., potassium cinnamate, sodium dimethoxycinnamate) with epichlorohydrin, that serves as both reactant and solvent in great excess. The esterifications to the glycidyl cinnamate derivative are typically performed for an hour at temperatures of about 65C of 100C. The resulting glycidyl esters are then isolated and reacted with the salt of a second cinnamate derivative, in DMSO as the solvent to form a dicinnamate ester of 2-propanol.
The inventor is to be commended for thinking to use PTC to perform the esterification with epichlorohydrin and also for the thought to use solvent-free PTC conditions. However, there are several additional thoughts that could have likely been used to streamline this 2-step process.
First, the excess of epichlorohydrin is very large. It is so large that it would be worthwhile to consider using an inert solvent such as toluene (with a very similar boiling point to epichlorohydrin) and cut down the excess epichlorohydrin to a minimum.
Once toluene is used for the first esterification, it could be used for the second esterification as well if we leave the phase-transfer catalyst in the system. This could be easily done since the inventor simply filtered off the KCl formed after the first esterification. It is possible that the KCl doesn’t need to be filtered off from the first esterification before simply adding the second cinnamate salt on top of the crude reaction mixture from the first esterification. Reducing unit operations could streamline the process.
Moreover, the inventor recovered the DMSO by distilling it off under reduced pressure. If toluene would be used as the solvent for both steps, while avoiding the isolation of the intermediate, we would achieve less unit operations as well as being able to distill away a much lower boiling solvent of toluene instead of DMSO.
When using toluene as the solvent for both steps, the salt byproducts and the phase-transfer catalyst could be separated from the dicinnamate ester product by dissolving them in water and separating the phases.
In all these concepts could be successfully implemented, advantages would include benefitting from the presence of the phase-transfer catalyst for two esterifications, reducing the excess epichlorohydrin by at least 90%, avoiding isolation of an intermediate, replacing a high boiling solvent with a lower boiling solvent and achieving easy separation of the salts and phase-transfer catalyst from the product.
We might be able to further speed up the reaction by the addition of 1 mole% iodide which might be able to be leveraged to reduce the reaction temperature and/or time. Temperature reduction might be good for stability.
Now contact Marc Halpern of PTC Organics to achieve low-cost high-performance green chemistry by integrating our highly specialized expertise in industrial phase-transfer catalysis with your commercial goals, especially to streamline PTC esterifications and other nucleophilic substitutions.
A patent issued this month cites the use of catalytic tetrabutylammonium bromide (TBAB) in the ring opening esterification of glycidyl ethers using acrylic acid and methacrylic acid (see Example 7). In PTC esterifications, we typically expect the presence of a base to form the carboxylate salt from the acid then the quat acrylate would be more reactive as a looser ion pair than say sodium acrylate, even assuming that all components are fully soluble in acetonitrile.
However, the procedure in this patent does not report the use of any base. It is possible that the acid protonates the epoxide which makes it susceptible to attack by the bromide to form the bromohydrin which may be more reactive than the closed epoxide.
We find it surprising that the inventors did not titrate the acrylic acid/methacrylic acid with a weak base that is also a desiccant which would enable the loose quat-acrylate ion pair to be more effective.
If any of our readers have a better explanation of how the quat bromide is catalyzing this reaction, please contact Marc Halpern with your input.
By the way, sometimes quat bromides are known to catalyze reactions of epoxides by having the bromide attack an epoxide to form a bromoalkoxide that reacts further. However, in this case it is not clear that this would help form the desired product.
Tetrabutylammonium nitrate-trifluoroacetic anhydride, TBAN-TFAA, is a known nitrating agent for addition of NO2 to double bonds (J. Org. Chem., 2013, 78, 8442) and aromatic rings (Fieser and Fieser Reagents for Organic Synthesis, 2006).
A patent was issued last week (US Patent 10,028,962) that used TBAN-TFAA for the nitration 3-methylpyridine-2-carbonitrile that used 1.10 equiv TBAN and 1.12 equiv TFAA. This was a small scale reaction.
If this reaction would be considered for large scale, it may be worthwhile to consider using catalytic tetrabutylammonium salt (with a non-nucleophilic anion) and sodium nitrate in order to save the cost of the tetrabutylammonium salt. If any of you are aware if this has been tried and can disclose, please contact Marc Halpern of PTC Organics.
Tetrabutylammonium nitrate is made by ion exchange from an alkali nitrate with tetrabutylammonium chloride, bromide or hydrogen sulfate. Each of these quat salts has advantages and disadvantages from the standpoint of cost and thermodynamics, but the ion exchange unit operation costs money in all cases. A possible way to save money for a nitration using TBAN-TFAA would be to use a catalytic amount of tetrabutylammonium hydrogen sulfate and neutralize the proton with a non-aqueous base, then add stoichiometric sodium nitrate to the reaction (maybe potassium nitrate if the sodium salt doesn’t work due to lattice energy/structure).
As we teach in our 2-day course “Industrial Phase-Transfer Catalysis”, the affinity of a quaternary ammonium cation toward nitrate is about 1,000 times greater than for sulfate. That means that if we used, for example, 1 mole% tetrabutylammonium “sulfate” (neutralized hydrogen sulfate) and 1.1 equiv alkali metal nitrate, most of the tetrabutylammonium salt would be paired with nitrate and not with sulfate, even if the molar ratio of nitrate to sulfate were reversed at 1:100.
This is the basis for our speculation that the use of catalytic tetrabutylammonium hydrogen sulfate with just enough non-aqueous base to neutralize the proton (that will generate non-nucleophilic sulfate), plus the use of stoichiometric inorganic nitrate (with a cation that enables the nitrate anion to be physically available to the quat cation) has a good chance of forming tetrabutylammonium nitrate in situ under conditions that may not interfere with the trifluoroacetic anhydride.
If your company is continuously seeking ways to save money in commercial processes, now contact Marc Halpern of PTC Organics to explore opportunities to leverage highly specialized expertise in industrial phase-transfer catalysis with your internal company expertise to achieve low-cost high-performance green chemistry.
Phase-transfer catalysis excels in the selective mild oxidation of primary alcohols to aldehydes without overoxidation to the carboxylic acids as first reported by Lee and Freedman in the 1970’s as we teach in our 2-day course “Industrial Phase-Transfer Catalysis” (soon to be conducted in Philadelphia in October). TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl radical) is a well known catalyst for oxidant that is used in catalytic quantities, due to its high cost, in conjunction with other less expensive oxidizing agents. Hydroxy-TEMPO (HO-TEMPO) can be used in many cases in which TEMPO is used since it is readily made from less expensive starting materials.
This patent shows that careful choice of PTC reaction conditions using hypochlorite and HO-TEMPO results in a very rapid and selective oxidation of alcohols to the aldehydes. Similar to the Lee and Freedman publication, the reaction must be stopped at the right time to minimize over-oxidation. In this case, the reaction time needs to be stopped at 8 minutes to achieve the highest amount of desired product.
Tetrabutylammonium hydrogen sulfate is usually used as the phase-transfer catalyst in PTC hypochlorite oxidations (quat hydrogen sulfates are also used for hydrogen peroxide oxidations). TBAB can make hypobromite in-situ and cause further complications.
A high shear Silverson mixer was used in this patent. PTC reactions that use sensitive reactants and products are sometimes better performed with lower agitation efficiency in order to minimize non-catalyzed interfacial side reactions. It is often better to let the phase-transfer catalyst control the contact between the reactants instead of the less controlled brute force of high shear agitation. It is not known if less agitation would be beneficial in this case but it is worthwhile to consider this concept in the future for compounds that are sensitive to water, oxidants, etc.
When you need to control selectivity to achieve the highest performance for your commercial process in development or in production, contact Marc Halpern of PTC Organics to integrate highly specialized expertise in industrial phase-transfer catalysis with your commercial needs.
Sometimes, we don’t choose a phase-transfer catalyst based on how much reactivity it will induce, but rather based on how efficiently we can recycle the catalyst and at minimal cost.
In a PTC dehydrofluorination patent that issued this month, Aliquat 336 was chosen to selectively produce 1-chloro-2,3,3-trifluoropropene from 3-chloro-1,1,2,2-tetrafluoropropane with only 5% byproducts. The base was aqueous KOH.
We speculate, but do not know, that the reason for choosing Aliquat 336 instead of TBAB for example, was that Aliquat 336 is so hydrophobic that it will not distribute significantly into the aqueous phase, even during workup which usually involves dilute aqueous solutions. TBAB distributes into dilute aqueous solution and would likely be lost to the aqueous waste stream during workup. The losses of Aliquat 336 into the aqueous waste stream in such systems are often negligible.
If you want to learn how to choose PTC conditions like an expert, including how to simultaneously optimize reactivity and catalyst separation from product, bring the course “Industrial Phase-Transfer Catalysis” to your department in-house or register for a public PTC course. The next public PTC course will be conducted in Philadelphia in October 2018.
We appreciate the input of expert process chemist, Peter Wuts, who pointed out that there is a better alternative explanation for the mode of action of the phase-transfer catalyst in the PTC-Suzuki reaction reported last month at http://phasetransfercatalysis.com/ptc_tip/ptc-suzuki-for-polymers/. Following is Dr. Wuts’ input.
“It is generally well accepted that boronates, in order to transfer to the Pd complex, require a nucleophile like water to add to the empty orbital on boron. It seems that these substrates are so “greasy” that the only way to accomplish this is with PTC and maybe the greasier and bigger catalyst is more effective. I don’t believe the quats have any influence on the palladium. The first thing that needs to happen in these reactions is the reduction of Pd(II) to LnPd(0). In this case it is probably the phosphine ligand (Ln) which is used in excess that reduces the Pd(II). Once this is accomplished, Pd(0) does oxidative addition with the bromide and then the Ar group from the boronate-nucleophile complex is transferred and then reductive elimination returns the Pd(0) which cannot react with a quat. The cycle starts over until all bromide is consumed. The [Q+ PdCl3-] complex is not relevant to the case at hand because we need to get into the Pd(0) manifold for the Suzuki to work.”
We would like to add that it may be possible that the role of the catalyst may be to deliver the required water to the reaction site by hydrogen bonding to the counteranion of the organophilic quat cation.
Peter Wuts of Wuts Chemistry Consulting (http://www.petergmwuts.com/) is one of the leading process chemists in the industry and is the author of the authoritative book “Protecting Groups: Effects on Chemical Reactivity.”
