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.
There are two important points regarding the choices for the reaction conditions for the second reaction shown in the diagram which is obviously a PTC nucleophilic substitution. In this etherification, 1.5 equiv o-nitrobenzyl alcohol were reacted with N,N-dimethyl chlorouracil in the presence of 5 equiv NaOH diluted to 5% in water, methylene chloride as the solvent and 10 mole% benzyl tributylammonium chloride as the phase-transfer catalyst. The yield over two steps was 70% and the yield of the second step was 78% (based on the N,N-dimethyl barbituric acid).
One point is that when benzyl quats are used as phase-transfer catalysts in nucleophilic substitutions, the benzyl quat competes as an alkylating agent with the intended electrophilic substrate being attacked. In other words, whenever using a quat such as benzyl triethyl ammonium or benzyl tributyl ammonium, you must consider whether you will unintentionally form benzylated side products from the nucleophile.
We speculate that in this case, the avoidance of high temperature was keeping the benzylation of the nitrobenzyl alcohol low. The nitrobenzyl alcohol is used in excess and perhaps that masks some of the benzyl ether formation. Working at room temperature may be the cause for the long reaction time.
We usually prefer to avoid using benzyl quats in PTC nucleophilic substitutions. We discuss this in more detail in our 2-day course “Industrial Phase-Transfer Catalysis.”
A second point is that phase-transfer catalysis enhances the reaction between methylene chloride and NaOH to produce formaldehyde. We speculate that the high dilution of the NaOH may have been chosen to minimize formaldehyde formation and possibly also hydrolysis of the chlorouracil. We are somewhat surprised that the dilution of 4 g NaOH in 80 mL water afforded a base strong enough to perform the desired etherification, but the high yield is proof that these reaction conditions work.
A patent application was published this month (Myers, J. (Blue Chip IP) US Patent Application Publication 2024/0018073, 18-Jan-2024) that uses PTC for dehydrochlorination. As will be explained below, we speculate that Aliquat 336 (trademark of BASF) was chosen as the phase-transfer catalyst for two reasons: [1] since Aliquat 336 has negligible partitioning into the aqueous phase with high ionic strength, this particular phase-transfer catalyst will not contaminate aqueous waste streams and will be removed with heavy distillation fractions for incineration and [2] since Aliquat 336 is very effective for PTC dehydrochlorination, it is effective at low levels such as 0.4-0.6 weight% as described in the examples.
First, let’s discuss the background for this PTC dehydrochlorination.
Chloroalkenes are useful intermediates in pharmaceuticals, agrochemicals and other organic chemicals. They are produced by dehydrochlorination of chloroalkanes. Polychloropropenes are particularly useful and produced by dehydrochlorination of polychloropropanes that in turn are produced by a telomerization process between carbon tetrachloride and ethylene that uses metal catalysts such as ferric chloride and promoters such as tributyl phosphate.
During separation of the various polychloropropane isomers after the telomerization process, there are light fractions and heavy fractions. The ferric chloride metal catalyst and the tributyl phosphate promoter are carried forward in the heavy fractions. However, the heavy fractions still contain valuable polychloropropanes, especially 1,1,1,3-tetrachloropentane (HCC-250fb) or 1,1,1,3,3-pentachloropropane (“HCC-240fa”) that together comprise more than 80% by weight of the heavy fractions.
The heavy fraction is dehydrochlorinated in the presence of 0.4-0.6 wt% Aliquat 336 (relative to the total weight of the heavy fraction) in the presence of 13.7% aqueous NaOH for 3.7 hours at 62-68 deg C. The trichloropropenes and tetrachloropropenes can be separated by distillation leaving the final heavies that contain the metal catalyst, the promoter and the Aliquat 336. This final heavy fraction is then sent to incineration.
We speculate that lower molecular weight quat salts such as methyl tributyl ammonium chloride or tetrabutyl ammonium chloride (formed from tetrabutyl ammonium bromide that would cause bromide contamination of the product) would distribute to some degree into the aqueous waste stream and require additional costly waste treatment.
The inventors wanted to prove that the Aliquat 336 was an effective phase-transfer catalyst. They subjected pure 1,1,1,3,3-pentachloropropane to 19.4% aqueous NaOH for 1.5 hours at 66 deg C without PTC and observed 1.3% dehydrochlorination. They then added 0.64 weight% Aliquat 336 to the mixture and after 3 hours at 65 deg C, they observed more than 60% conversion.
This patent application reinforces what we teach in our 2-day course “Industrial Phase-Transfer Catalysis” which is that Aliquat 336 is chosen for PTC reactions that need a combination of high reactivity and separation by certain methods including distilling the product, recrystallizing the product, extracting the product into water and other separation methods that require the phase-transfer catalyst to avoid significant distribution into an aqueous waste stream.
PTC has been reported for several oxidations using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical). In such oxidations, TEMPO is used catalytically and the phase-transfer catalyst is used to transfer the stoichiometric oxidant to regenerate the active TEMPO oxidant. In this case, the oxidant is hypochlorite used in 21.5 mole% excess. The reaction was performed until full conversion of starting material was observed by HPLC (in-process control).
The inventors also reported the use of silica-supported TEMPO and polystyrene-supported TEMPO.
The mechanism for TEMPO oxidation: https://www.organic-chemistry.org/chemicals/oxidations/tempo-2,2,6,6-tetramethylpiperidinyloxy.shtm
The purpose of synthesizing the ketone was to serve as a starting material for the asymmetric transfer hydrogenation of the substituted bicyclic pyridine ketone in presence of a chiral ruthenium catalyst.
In the past, we described PTC oxidations with TEMPO in the following examples.
http://phasetransfercatalysis.com/ptc_tip/ptc-oxidation-with-hypochlorite-and-hydroxy-tempo/
http://phasetransfercatalysis.com/ptc_tip/ptc-tempo-hypochlorite-oxidation/
http://phasetransfercatalysis.com/ptc_tip/combining-ptc-with-high-shear/
The second reaction shown in the diagram uses crown ether presumably to transfer potassium peroxide to the organic phase by complexation. The crown ether is not catalytic and is used in large quantities, apparently to match the large loading of the potassium peroxide.
In the first step, the alcohol is converted into the mesylate. In the second step, the peroxide appears to attack the mesylate by a nucleophilic substitution based on the inversion of configuration. At the same the, the acetate is hydrolyzed to the alcohol (obviously with retention of configuration).
We would be curious to learn if our readers have encountered using peroxide as a nucleophile in this manner.
Whenever we see the use of sodium hydride with a quat salt, especially for a simple etherification reaction, PTC experts cringe. After all, phase-transfer catalysis using NaOH is almost always the slam-dunk best option to produce non-commodity ethers through Williamson ether synthesis.
However, this month we saw a reaction that might likely be the first example we have seen that may justify the use of NaH instead of PTC-NaOH for a Williamson ether synthesis.
The reaction involves a diol derivative of trans-cyclooctene (“TCO”). The twisted strained TCO molecule is thermodynamically unfavored relative to the much more stable cis-cyclooctene. In fact, TCO is formed from cis-cyclooctene by high-energy photochemistry that is described in this patent application publication.
The many reactions described in the patent application publication are performed at room temperature or lower and reaction times are minimized. This is done presumably to minimize the heat history of these compounds and minimize isomerization back to the less strained cis isomers.
It is possible that PTC-NaOH conditions could be used to perform the O-alkylation on the primary alcohol with propargyl bromide shown in the diagram. However, it is likely that the reaction temperature and reaction time with PTC-NaOH would be longer which could potentially jeopardize the strained trans configuration staying intact.
For this reason alone, we support the choice of NaH as the base and the use of the polar solvent THF that results in very high yield in just 1 hour at room temperature. We suspect that the reason for adding the tetrabutylammonium iodide is to form the propargyl iodide in-situ to further reduce the energy of activation and minimize heat history.
It is also obvious that the primary alcohol is more reactive than the secondary alcohol. In fact, the secondary alcohol is also axial which makes it even less available for attack. So, selectivity for etherification of the primary alcohol is very high.
In summary, in contrast to what we teach for almost all Williamson ether synthesis applications in our 2-day course “Industrial Phase-Transfer Catalysis,” the specific etherification shown in this patent application publication justifies the use of sodium hydride.
A patent was issued this month that reminds us that phase-transfer catalysis facilitates various coupling reactions catalyzed by transition metal complexes such as those containing palladium.
More than a dozen coupling reactions catalyzed by tetrabutylammonium bromide or chloride and tetrakis(triphenylphosphine)palladium were described in detail. Some of the coupling reactions were Suzuki. The diagram shows two examples. The ratio between the quaternary ammonium phase-transfer catalyst and the tetrakis(triphenylphosphine)palladium catalyst, varies from application to application.
We are not aware of reports that definitively elucidate the role of the quaternary ammonium phase-transfer catalyst in reactions catalyzed by palladium. However, Dr. Peter Wuts has offered input about the co-catalytic effect of quat salts and palladium complexes in Suzuki reactions that contain water. You can read Dr. Wuts’ input at http://phasetransfercatalysis.com/ptc_tip/alternative-explanation-for-ptc-suzuki/.
The second reaction shown in the diagram is an oxidation of a sulfide to a sulfone using Oxone® (registered trademark of Lanxess Deutschland). Oxone® is a mixture of salts including the active potassium peroxymonosulfate, which is more stable than potassium peroxymonosulfate by itself.
As we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” from an industrial standpoint on a large scale, PTC can preferably be used with hydrogen peroxide to perform the oxidation of sulfides to sulfones. See for example Shintaku, T.; Katsura, T.; Itaya, N. (Sumika Fine Chemicals) 2004, US Patent 6,740,770 or Gargano, G.; Halpern, M.; (Ultraclean Fuel Pty Ltd) US Patent 10,214,697, 26-Feb-2019.
Also as we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” PTC has been used in several oxidations using Oxone® including another oxidation of a sulfide to a sulfone, epoxidation of alkenes and a chiral oxidation (using a chiral auxiliary) shown in the April 2012 PTC Reaction of the Month.
Additional details for this oxidation can be found in the August 2021 PTC Tip of the Month. This includes a discussion that PTC should have been used (or at least considered) for the base-promoted first reaction.
Tetraphenyl phosphonium salts are stable at high temperature and have been reported for several PTC reactions including fluoride halex reactions and polymerizations based on nucleophilic aromatic substitution. Alkyl triphenyl phosphonium salts are used to build molecular weight for epoxy resins after benzyl trimethyl ammonium chloride is used to form bisphenol A diglycidyl ether (“BAGDE”).
The reaction shown in the diagram is not a phase-transfer catalysis reaction, it’s a reaction catalyzed by organic soluble chloride or bromide. The halide opens the epoxide rings of BADGE and the resulting alkoxide attacks the isocyanate (MDI) that ring closes to the oxazolidone, liberating the halide for another cycle. In a second step, molecular weight is built by adding more MDI. A monofunctional epoxide, para-t-butyl phenyl glycidyl ether is used to cap (terminate) the polymer, performed in two steps.
The reaction conditions described in the patent application publication provides several advantages. This catalyst system produces a polyoxazolidinone product with low polydispersity, and high chemical selectivity. In particular it reduces the amount of unwanted side products like isocyanurates (formed from isocyanates) that cause unwanted cross-linking of the reaction product and negatively impact the thermoplastic properties.
