At the beginning of every new process development project, we first do a literature search to see what similar reaction conditions have been chosen for similar reactions. Sometimes, we encounter procedures that scream out to be replaced by phase-transfer catalysis.
In the reaction shown in the diagram, the role of the catalytic iodide was to activate the alkyl chloride alkylating agent and the role of the phase-transfer catalyst was to transfer the phenoxide from the solid surface of the potassium carbonate and activate the phenoxide for the O-alkylation nucleophilic substitution.
In this case, we wonder why the inventors chose to use DMF as the solvent followed by chromatography for isolation when they clearly already thought of using tetrabutylammonium iodide to catalyze the reaction. The answer is that the inventors were probably not process chemists, they may have just been interested in obtaining material quickly and purifying it without any process development.
The inventors probably could have easily used a water-immiscible solvent and washed the salts away from the organic product before purifying the product and possibly may have avoided handling losses and solvent-entrainment losses which may be at least partially responsible for the 80% yield instead of a higher yield that we would expect from a PTC etherification of a phenol.
In this case, phase-transfer catalysis using a water-immiscible solvent is particularly applicable since the next step is a borohydride reduction and that too should be a PTC reaction.
So, if the inventors wanted to streamline their process and still insist upon doing chromatography after the borohydride reduction to obtain a pure product, they could have performed both the O-alkylation and the borohydride reaction in a PTC single-solvent one pot process without isolation of intermediates (just exchange the aqueous phase between reactions) then perform the separation by chromatography.
In fact, PTC-borohydride reactions in water at the right pH usually need to a lower excess of the expensive borohydride than when more conventionally performing such reactions in ethanol.
The inventors might have been medicinal chemists just trying to get product and not process chemists trying to optimize a process. This PTC Tip of the Month is directed at process chemists who find literature procedures and are responsible for developing them into practical processes that minimize cost in real world unit operations upon scale up.
Another example reported this month that begs to use PTC instead of DMF is the S-alkylation of 2-amino-4-chloro-benzenethiol with ethyl iodide in the presence of tetrabutylammonium iodide in DMF (see Example 14 in US Patent 9,567,304). They even used cesium carbonate as the base instead of potassium carbonate. What were they thinking?
Now contact Marc Halpern of PTC Organics to assure that you are developing viable PTC processes, not publishing procedures that look like you’re an academic chemist who can’t manage his/her supplies budget.
As we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” there are three major reasons that phase-transfer catalysis works so much better than non-PTC systems for nucleophilic substitutions using inorganic anions and they are [1] the inorganic nucleophilic anion is actually dissolved in the bulk organic phase by the phase-transfer catalyst where it reacts with the substrate already soluble in the organic phase [2] a looser more reactive ion pair is formed between the inorganic nucleophilic anion and the large quat cation than between the inorganic nucleophilic anion and an alkali metal [3] the anionic nucleophilic anion has little to no hydration when transferred into a non-polar organic phase.
However, in some cases there is no aqueous phase and the advantageous effects are limited to ion pair looseness and solubility.
In US Patent 9,540,455 issued this month, there is described a nucleophilic substitution between ionic azide and allyl bromide groups attached to a butyl rubber. We examined the extensive data in Table 1 in that patent and we make several observations.
First, when sodium azide is used as the azide source, a combination of THF and DMF are used as the solvent. When tetrabutylammonium azide is used as the azide source, DMF is not needed. We may assume that this is due to solubility requirements that are more challenging for the sodium azide.
Secondly, we observe that 6-10 equivalents of NaN3 are used to achieve 76% conversion in 4 days reaction time versus 1.1-1.4 equivalents of tetrabutylammonium azide in 1 day reaction time to achieve 100% conversion.
Clearly, tetrabutylammonium azide greatly outperforms sodium azide in this nucleophilic substitution.
It appears that the polymer is dissolved in the solvent system, so apparently these are homogeneous systems. If so, then we speculate that the loose ion pair of tetrabutylammonium azide is responsible for the greatly increased reactivity versus sodium azide. We also speculate that the sodium azide system requires the DMF since it may not be fully soluble in THF alone.
At a minimum, we expect that the loose ion par of tetrabutylammonium azide is playing a key role in achieving high reactivity in this system.
Can you improve your process development performance? Of course! Now contact Marc Halpern to integrate PTC Organics’ highly specialize expertise in industrial phase-transfer catalysis with your process development program to achieve low-cost high-performance green chemistry processes.
A very interesting patent was issued to Dow Corning that compares a variety of phase-transfer catalysts for esterification performed at 120 C. The inventors were justifiably concerned by the thermal stability of conventional phase-transfer catalysts such as TBAB, so they screened more stable catalysts such as HEG Cl (see figure). As can be seen in the reaction profile graph, HEG Cl did not improve reactivity (possibly due to a co-catalysis effect of bromide from TBAB).
The inventors then screened several quaternized polyazabicyclics, such as those derived from DBU and MTBD (see structure diagram). They found that these new phase-transfer catalysts (in the bromide form) performed better than TBAB and HEG Cl.
Changing from sodium acrylate to potassium acrylate further increased reactivity. If the physical system is a PTC solid-liquid reaction, then it is possible that the potassium salt enhances the possibility of removing the acrylate anion from the solid surface more than the sodium salt.
This patent has additional interesting aspects and it is worthwhile to read it in detail.
If your company wants to improve process performance and profit using phase-transfer catalysis, now contact Marc Halpern of PTC Organics Inc to explore integrating highly specialized expertise in industrial PTC with your commercial process development goals and to increase your profit of existing PTC and non-PTC processes in production.
Demetallization of heavy oil petroleum fractions (asphaltenes) is required in order to eliminate undesirable metalloporphyrins present in these streams. The high level of metal contaminants in these fractions cause fouling, catalyst deactivation and other problems in downstream refining processes. Various metals are removed with varying degrees of difficulty using upgrading processes. Nickel and vanadium metalloporphyrins are more resistant to removal than other metals such as iron.
The inventors of US Patent 9,505,987 (29-Nov-2016) found that using Aliquat 336 as phase-transfer catalyst and tungstic acid with phosphoric acid as oxidation catalyst for hydrogen peroxide treatment, removes 99% of nickel and vanadium from the heavy oils and separates them into aqueous streams. Both the Aliquat 336 and the phosphotungstic acid are required to achieve 99% removal of nickel and vanadium. Only 28%-38% of nickel and vanadium are removed by hydrogen peroxide treatment without Aliquat 336 and phosphotungstic acid. That level of removal is not enough to sufficiently prevent fouling and catalyst deactivation in refining plants.
If your company wants to develop the most cost effective PTC process, now contact Marc Halpern of PTC Organics Inc. to explore collaboration by integrating the highly specialized expertise of PTC Organics with your company’s commercial goals for increased profit and process performance.
Two patents issued last week that use catalytic amounts of tetraalkylammonium salts. Such reactions usually mean phase-transfer catalysis, but in both cases, the role of the quats was to solubilize an anion that served in a catalytic capacity. One was tribromide and one was chloride.
Tetrabutylammonium tribromide (TBATB) is a known bromination agent for adding a single bromine at the alpha position of acetophenone (if not used in excess) while generating HBr and TBAB. TBATB is used at a level of 1.5 mole% relative to the iodoacetophenone. Reaction with triethylorthoformate, likely catalyzed by the HBr liberated from the bromination, produces the ketal shown in 85% yield.
In another patent, tetramethylammonium chloride was used to solubilize chloride in DMSO that acted as a catalyst for the esterification shown in the diagram. The chloride opened the epoxide of glycidyl methacrylate that produced an alkylating agent in situ. Esterification followed liberating the chloride for another cycle.
The concept of solubilizing anions in an organic reaction phase using quaternary ammonium salts is obviously useful. In phase-transfer catalysis, the quat transfers a reacting anion for consumption. In the two cases cited here, the quat solubilized anions used as catalysts themselves.
If you are working on organic reactions that require the use of anions as reactants or as catalysts, now contact Marc Halpern of PTC Organics Inc. to improve the process performance and profit of your company AND saving your company weeks or months of development cycle time due to the highly specialized expertise of PTC Organics in industrial phase-transfer catalysis.
US Patent 9,441,169 by Gargano and Halpern was issued this month to Ultraclean Fuel that uses phase-transfer catalysis to impressively remove sulfur from hydrocarbons to comply with the strictest standards for petrochemical products.
In particular, “ultralow sulfur diesel” (ULSD) containing only 10 ppm or less of sulfur was achieved in a single step from refinery diesel at about 4000 ppm sulfur, from transmix diesel at about 400 ppm sulfur and from jet fuel at about 1500 ppm sulfur using a phase-transfer catalyst, a phosphotungstate catalyst and hydrogen peroxide. The sulfur compounds in the diesel are mostly thiophene derivatives and they are oxidized to sulfones and separated from the diesel.
Phase-transfer catalysis enables this breakthrough that has the potential to revolutionize sulfur emissions from fossil fuels and make a huge impact on reducing acid rain.
If your company wants to achieve breakthroughs using phase-transfer catalysis, now contact Marc Halpern of PTC Organics Inc., as done by Ultraclean Fuel, to explore a path to make your mark on saving jobs (maybe your own), improving the environment or just plain increasing profit.
Last week, two patents that were published using PTC also used THF as solvent and both appear to use conditions that were somewhat disappointing. One will be described in the PTC Tip of the Month here and the other will be described in the PTC Reaction of the Month below.
US Patent 9,422,305 describes the etherification of a diol with epichlorohydrin to form the diglycidyl ether (bisepoxide). The disappointing warning sign is that the inventors used 14 equivalents of epichlorohydrin and 12 equivalents of NaOH when they needed only 2 equivalent in theory. Why would they need such huge excesses of reactants?
The inventors note “intense” stirring of a huge excess of the epichlorohydrin in the presence of the concentrated NaOH while dropping in the diol “slowly”. It may be speculated that the intense stirring could promote hydrolysis of the epichlorohydrin, especially since the diol is being added last leaving the epichlorohydrin open to attack before the diol is available to consume the epi. Addition of THF could also promote hydrolysis by co-dissolving some water/base with the epichlorohydrin and organic epoxide product.
Unless a PTC system is transfer rate limited (etherifications are typically intrinsic reaction rate limited not transfer rate limited), in cases in which there are water-sensitive reactants and products, it is usually preferable to reduce the agitation efficiency and allow the phase-transfer catalyst to bring the reactants together while minimizing non-catalyzed interfacial hydrolysis of the sensitive functional group (epoxide in this case). In addition, PTC enables us to use a less polar solvent that would reduce contact between hydroxide and the epoxide keeping them separated in different phases. All this would possibly reduce the huge excess of epi being used.
One impressive aspect of this reaction is that the etherification to the glycidyl ether takes place at room temperature. Many PTC etherifications with epichlorohydrin are reported at temperatures of about 80oC. The bromide of TBAB is likely forming epibromohydrin in situ that is more reactive than epichlorohydrin, thereby co-catalyzing the reaction.
In short, we expect that by using a non-polar solvent to separate the base from the epoxide starting material and product, avoiding over-agitation and better choice of base (perhaps with potassium salt to enhance the formation of an omega phase), the large excess of starting materials can be avoided.
To learn more about how to optimize PTC etherifications to improve process performance and profit, now contact Marc Halpern of PTC Organics.
In this patent, the inventors performed a simple esterification using a quat acetate, either tetrabutylammonium or tetramethylammonium. The solvent is acetonitrile. The yield is high at 95%-97%.
There are several interesting thoughts when reading this patent. First, they used stoichiometric quat acetate. They should have used catalytic quat salt and inexpensive sodium acetate. One would assume that the economics of recycling a full equivalent of tetrabutylammonium salt or tetramethylammonium salt would be expensive and required.
Secondly, they used acetonitrile as the solvent. If already one is using stoichiometric quat acetate, one would expect the reaction to proceed well using almost any organic solvent, preferably one that makes two phases with water for easy work up using water washes to separate the product from the waste salts. In fact, the inventors explicitly cite the use of water-immiscible solvents for the extraction step during workup. Performing a solvent exchange after reaction before isolation of product would add unnecessary and cost and complexity to the process.
The inventors do show that using ammonium acetate instead of a quaternary ammonium acetate gives no yield. This hints that true phase-transfer catalysis should work.
It should also be noted that an imidazolium ionic liquid was screened for this reaction and did not perform nearly as well as the classical much less expensive quaternary ammonium phase-transfer catalyst.
We would probably use stoichiometric sodium acetate and a few mole% tetrabutylammonium bromide that would form the bromomethyl furfural in-situ from the chloromethyl furfural to achieve bromide co-catalysis to enhance the phase-transfer catalysis by the tetrabutylammonium cation. Then again, the reaction works well in 5 minutes at room temperature homogenously in acetonitrile, so rate enhancement may not be needed. In any case, this process begs to be performed with catalytic phase-transfer catalyst in a properly chosen water-immiscible solvent.
Now contact Marc Halpern of PTC Organics to improve process performance and reduce cost if your company is developing or performing commercial specialty esterifications that must be irreversible, have very high conversion (i.e., nucleophilic esterifications using alkyl halides instead of dehydration using alcohols) and be performed in short reaction times. PTC Organics can show you how to achieve low-cost high-performance green chemistry using phase-transfer catalysis, including effective isolation of the ester product.
Example 14 of this 20-year old patent describes the high yield chlorination shown in the diagram on an 800 lb scale. PTC is used to deprotonate fluorene (pKa 23) with NaOH and the quat-fluorenyl anion ion pair attacks carbon tetrachloride to form 9-chlorofluorene. The 9-chlorofluorene is more acidic than fluorene and undergoes rapid chlorination by the same mechanism. One molecule of carbon tetrachloride provides one chlorine atom. The atomic efficiency is very high.
The phase-transfer catalyst used was tetrabutylammonium hydroxide. The inventor did a nice job in showing that tetrabutylammonium bromide (TBAB) is NOT an effective phase-transfer catalyst for this reaction. Since this is not an academic paper, she does not speculate why but we speculate that the reason is that bromide hinders the extraction of hydroxide. As we teach in our 2-day PTC course, the affinity of the tetrabutylammonium cation for bromide is about 3,000 times more than for hydroxide.
We do not like to use the hydroxide form of tetraalkylammonium salts due to both high cost as well as the potential for decomposition by Hofmann Elimination during storage. The inventor concluded that quat hydroxides are better than quat bromides and that is a good conclusion, but there may be better alternatives.
We expect this reaction to be a T-Reaction based on the “Halpern pKa Guidelines for Evaluation and Optimization of PTC Applications.” Accordingly, we expect “accessible” quat cations with a q-value of about 1.75 to work better than tetrabutylammonium. If we had to do this reaction today, we would screen the use of methyl tributyl ammonium chloride (MTBAC) as the phase-transfer catalyst. It is possible that the chloride will also hinder hydroxide extraction, though to a much lower degree than bromide. We would be very curious about the combination of MTBAC with 50% NaOH for this reaction. MTBAC also washes into water more easily during workup which minimizes aqueous waste.
Now contact Marc Halpern of PTC Organics if your company wants to achieve higher profit and improved process performance for strong base reactions that you expect may be improved using phase-transfer catalysis.
This impressive new May 2016 patent highlights one of the most obscure though useful strengths of phase-transfer catalysis. Phase-transfer catalysis is known to excel in transferring anions into non-polar and moderately polar organic solvents and greatly enhance their reactivity in those solvents. Less known is that PTC can transfer polar neutral molecules with hydrogen bonding functional groups, into organic non-polar and moderately polar organic solvents and greatly enhance their reactivity in those solvents. In this case, urea is reacted with isobutyraldehyde.
Urea is highly polar and dissolves in water but doesn’t dissolve in most common organic solvents. Although not cited in the patent, we speculate that the role of the quaternary ammonium phase-transfer catalyst is to hydrogen bond with the urea and make it available to the less polar isobutyraldehyde reactant (which is also the organic phase). At the end of the reaction, the inexpensive quat remains in the aqueous phase for easy separation from the solid product.
Prior art for this reaction uses sulfuric acid and phosphoric acid added in an alternating manner at temperatures between 60 C and 100 C and requires an additional unit operation of neutralization with hydroxide. Materials of construction must resist corrosion. In contrast, the PTC process uses benzyl trimethyl ammonium chloride (though benzyl triethyl ammonium chloride is cited in the abstract) at a temperature of only 40 C and no corrosion. Compare these results described in US patents 3962329 and 9340495.
Using the same mole ratios of BTMAC catalyst as sulfuric/phosphoric acid catalyst and at 40C, the conversion with BTMAC was 100% at 20 min while the mixed acids gave 0% at 30 min.
PTC Organics has experience dissolving insoluble amines and other neutral molecules in organic reaction phases to achieve low-cost high-performance green chemistry.
Now contact Dr. Marc Halpern of PTC Organics to explore integrating PTC Organics’ highly specialized expertise in industrial phase-transfer catalysis with your process development goals to increase profit and R&D efficiency.
