Top 10 PTC Applications

PTC Organics' top 10 choices for using Phase Transfer Catalysis to achieve cost savings and significant improvement of industrial processes for the manufacture of a wide range of organic chemicals:

#1
Replace expensive and hazardous strong base
with inexpensive inorganic base

Compelling Benefits: Savings are usually in the range of up to $1,250 to $18,000 per ton of base currently purchased, depending on the base. Many safety, environmental and handling advantages are also achieved by avoiding the use and handling of flammable, explosive or high VOC compounds associated with methoxide, hydride, sodamide, etc. Work with water-sensitive functional groups.You can't afford not to consider this option. A complete description of this opportunity can be found at Strong Base - Strong Savings.

Typical Barriers: The greatest barriers in developing commercial strong base PTC applications are [1] not considering PTC due to the perception of the inability of NaOH (or other inexpensive inorganic base) to be a strong enough base to work in many situations, [2] not considering PTC due to the perception of the inability to use NaOH in situations involving highly water-sensitive reactants or products (such as esters, phosgene, benzoyl chloride, sulfonyl chlorides, etc.) and [3] the highly specialized PTC expertise required to achieve high performance in these justifiably challenging applications, especially with water-sensitive reactants or products. The development cycle time may be extended to develop these applications. PTC Organics has both the highly specialized PTC expertise and the dedicated development time to develop high performance low cost PTC-base applications.   

Description: This is not only one of the best cost savings opportunities using PTC ($1,250 to $18,000 per ton of base), it is usually also the most surprising. Replacing strong base with sodium hydroxide (or other inexpensive inorganic bases) is often considered against conventional chemical wisdom and requires "out-of-the-box" thinking. Yes, it is possible to replace NaOCH₃, NaNH₂, NaH, etc. with PTC/NaOH in many cases.

The first question you need to ask, assuming you are using an expensive strong base, is "how much money could we save if we use NaOH (or other inexpensive base) instead of sodium methoxide (methylate), sodium hydride, sodium amide, t-butoxide, sodium metal or other expensive hazardous strong base?" If the answer is in the range of $250,000 to $3,000,000 per year (or more), then it is probably worthwhile to consider PTC. Members of PTC Organics staff have developed PTC strong base reactions since the 1970's. Contact PTC Organics to evaluate if the replacement of strong base is possible, even if you may be justifiably skeptical.

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#2
Etherification (O-Alkylation)

Compelling Benefits: Very high yield. Short reaction time. Easy workup. No need to maintain dry conditions. No need to pre-form an alkoxide or phenoxide. Minimize excess reactants. Work with water-sensitive functional groups.

Typical Barriers: Dehydrohalogenation of certain alkyl halide reactants may be a side reaction. This can be minimized/eliminated by proper choice of reaction and process conditions (requires specialized PTC expertise). Classical non-PTC systems sometimes involve pre-forming and drying alkoxides/phenoxides, so it may not be obvious to consider PTC (in one case a company spent 20 hours drying an alkoxide made from ROH/NaOH before a short etherification; PTC could have eliminated this costly drying step). The perception that etherifications of water-sensitive compounds may be difficult to perform in the presence of NaOH may prevent one from considering PTC. Resist this notion, since in one case, PTC Organics developed a process to form an ether-ester in the presence of concentrated NaOH with < 0.1% hydrolysis of the ester.

Description: Phase Transfer Catalysis excels in all types of etherification of alcohols and phenols. PTC is usually the method of choice for the Williamson ether synthesis. Highly specialized PTC expertise is required to simultaneously obtain the shortest reaction time, lowest reactant mole ratio, minimize side reactions and develop etherifications in the presence of water-sensitive functional groups.  PTC Organics has developed high performance PTC etherifications. PTC can also shorten the reaction time of etherifications which may have difficulty in completing the last 10% of the etherification without requiring a large excess of alkylating agent (e.g., etherifications using methyl chloride). Contact PTC Organics to evaluate your potential application.

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#3
Esterification 

Compelling Benefits: Very high yield (often quantitative). No equilibrium restrictions. Short reaction time. Easy workup. Minimize excess reactants. Avoid hydrolysis.

Typical Barriers: PTC esterification is ideal for many specialty esterifications when it is feasible to react alkyl halides and carboxylate salts/acids by nucleophilic substitution. However, PTC may not be appropriate for commodity esterifications performed by dehydration of alcohols and carboxylic acids. Alkyl halides are usually more expensive than alcohols, except for benzyl chloride vs benzyl alcohol. Thus, even the largest scale benzyl esters could be advantageously produced by PTC. PTC esterification generates one equivalent of salt as a byproduct. The major tradeoff decision for choosing PTC for esterification is to obtain very high yield in very short time using alkyl halide instead of alcohol and generating one equivalent of salt. 

Description: Phase Transfer Catalysis excels in esterification for specialty esters.  Highly specialized PTC expertise is required to simultaneously obtain the shortest reaction time, lowest reactant mole ratio and minimize side reactions. PTC Organics has developed high performance PTC esterifications. PTC is generally used when you really need complete reaction, high isolated yield and short reaction time and/or the equilibrium of the classical esterification alternative by dehydration is limited by engineering capabilities for removing water. Esterification was the most highly patented PTC reaction in the 1980's. Contact PTC Organics to evaluate your potential application.

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#4
Transesterification 

Compelling Benefits: Short Reaction Time. Low Temperature.

Typical Barriers: PTC transesterification patents and publications are rare, therefore, there is very little public knowledge upon which non-PTC-experts can build an experimental scouting program. 

Description: PTC transesterification is little known, and as a result, is rarely practiced in industry. PTC Organics has unique expertise is performing high performance transesterifications at greatly reduced temperature and/or greatly reduced time. The heat history of many transesterifications is critical to minimize color and byproduct formation. Great unrealized opportunity exists for PTC transesterification. Contact PTC Organics to evaluate your potential application.

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#5
Cyanide Reactions 

Compelling Benefits: Very low excess cyanide = greatly enhanced safety, reduced waste treatment and lower cost. High yield. Short reaction time. No need to use dilute or even concentrated aqueous solutions. Avoid use of DMSO or other hard to recover water-soluble polar aprotic solvents.

Typical Barriers: Conventional wisdom (and DMSO supplier literature) claims that DMSO and other polar aprotic solvents are best for performing reactions of cyanide, azide and phenoxide, thus, these solvents are often tried first. DMSO is indeed effective for cyanide reactions, but an aqueous workup of cyanide-laden DMSO streams can be very difficult, hazardous and expensive. Highly specialized PTC expertise is required to simultaneously obtain the shortest reaction time, lowest reactant mole ratio and minimize side reactions, especially when performing cyanide displacements on secondary alkyl halides (minimize dehydrohalogenation).

Description: PTC excels in cyanide reactions and in fact, Dr. Charles Starks (the inventor of industrial PTC) published the cyanide reaction to exemplify the Extraction Mechanism in the first publication in which he coined the term "Phase Transfer Catalysis." PTC transfers cyanide very well into most organic liquids (which allows for tremendous flexibility in choosing a solvent or solvent-free conditions; see choice of solvent below) and once transferred, cyanide is an effective nucleophile. PTC cyanide reactions are usually cyanide/halide displacements, though other cyanide-induced condensations, rearrangements and other reactions can be effectively performed. The great efficiency with which cyanide is transferred and reacted provides the highly practical opportunity to reduce the excess cyanide and 2 mole% excess is typical. Many cyanide reactions are followed by additional PTC reactions, such as C-alkylation. For example, convert benzyl chloride derivatives to benzyl cyanide derivatives then C-alkylate with PTC/NaOH and an alkylating agent. One can save a lot of money in cycle time and avoid handling losses by avoiding isolation of intermediates when performing consecutive PTC reactions.  Contact PTC Organics to evaluate your potential application.

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#6
Eliminate Solvent!

Compelling Benefits: Reduce emissions and enhance pollution prevention. Increase reaction kinetics. Increase reactor volume usage/efficiency. Avoid unit operations associated with recovering an additional solvent and removing it from the product. Overall simplification of workup.

Typical Barriers:  Solvent-Free PTC works only when one of the reactants and/or product is a liquid at the reaction temperature. It is often not obvious to consider solvent-free conditions.

Description: By choosing an appropriate set of process parameters, PTC can be used to transfer and react almost any anion in any organic liquid. Thus, in cases in which at least one reactant or the product is a liquid, PTC conditions may be found to use the reactant and/or solvent as the reaction medium. PTC Organics has the specialized expertise and practical experience to identify and develop Solvent-Free PTC systems. Contact PTC Organics to evaluate your potential application.

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#7
Replace DMSO, NMP, DMF, DMA, polar aprotic solvents 

Compelling Benefits: Perform a wide variety of nucleophilic substitutions in high yield and short cycle time using recoverable solvents after easy and effective workup procedures. PTC provides enormous flexibility in choosing solvent based on a variety of desired criteria, such as recoverability, low volatility, cost, toxicity, boiling point, solubility, flash point, etc.

Typical Barriers:  The use of polar aprotic solvents is standard practice in early stage laboratory synthesis. Process development chemists under tight project deadlines may not have the time (or sometimes the expertise) to develop PTC processes which replace solvents such as DMSO with solvents such as toluene.

Description: Almost every nucleophilic substitution reaction performed in DMSO, DMF, NMP and DMA should be considered as a high probability candidate for PTC retrofit using a phase transfer catalyst with any common highly recoverable organic solvent which provides two phases in the presence of water. Many commercial processes use DMSO, DMF, NMP and dimethyl acetamide as solvent for organic synthesis because they are very effective in simultaneously dissolving  inorganic salts as well as organic substrates. These polar aprotic solvents also enhance the rate of nucleophilic substitutions due to their polarity. However, these solvents have a great affinity for water and usually the byproduct salts of substitution reactions require a water wash during the workup. Once the polar aprotic solvent enters an aqueous waste stream during aqueous workup, it is difficult and costly to treat and usually not practical to recover and reuse the polar aprotic solvent. PTC solves this problem by using the phase transfer catalyst to solubilize inorganic or organic anions in just about any organic liquid and once the anion is in the organic phase (reaction medium), it enjoys greatly enhanced reactivity due to a loose ion pair with the large catalyst cation and reduced solvation. Thus, the solvent for the process can be chosen based on any desired criteria. Solvents commonly chosen for PTC reactions include toluene and MIBK because they are easily separated from water by a simple phase cut, they are highly recoverable and recycled, they are low cost and emissions can be well controlled. The flexibility in choosing solvent for PTC systems (including solvent-free; see #6) is one of the great benefits of using PTC. PTC Organics has specialized expertise and experience in developing PTC processes with desirable solvents, and in particular, retrofitting DMSO processes with high performance PTC processes with easy workup. Contact PTC Organics to evaluate your potential application.

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#8
O-/N-Acylation and other work with highly water-sensitive compounds

Compelling Benefits: Reduce excess acylating agent required for high conversion. High yield. Short reaction time.

Typical Barriers:  Highly specialized PTC expertise is required to recognize and develop opportunities to use PTC in commercial processes which react alcohols, phenols, amines, amides and other O-H and N-H groups with highly activated chlorides and bromides such as phosgene, acyl chloride (e.g., benzoyl chloride), sulfonyl chlorides, phosphorous trichloride/tribromide, phosphorochloridothioates, carbamoyl chlorides and others. Such reactions are often counter-intuitive.

Description: Though hard to believe, PTC has been used to reduce the amount of excess phosgene used in the presence of 50% NaOH in a commercial process by 94% (from 30 mole% excess to 2 mole% excess)! Members of PTC Organics have highly specialized expertise and extensive experience in significantly increasing the yield and reducing the cycle time of processes containing the P-Cl bond and acyl chlorides in highly basic systems, since the 1980's. Contact PTC Organics to evaluate your potential application.

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#9
S-Alkylation (thiolation)

Compelling Benefits: High yield. Short reaction time. No need to pre-form sodium mercaptide salts. Reactions may fast enough to convert to continuous process!

Typical Barriers:  Sulfur nucleophiles may deactivate certain phase transfer catalysts. Sodium methyl mercaptide is used in existing commercial processes and the PTC alternative may have not been previously considered.

Description: Sulfur based nucleophiles are excellent PTC substrates because they are usually easily transferred to the organic phase by a phase transfer catalyst and they are usually excellent nucleophiles. Quantitative yield within minutes can often be achieved. The nucleophile can be an alkyl mercpatide (thiolate) formed in situ from NaOH and RSH, it can be pre-formed NaSR, NaSH or Na₂S (inorganic sulfide). Members of PTC Organics have specialized PTC expertise using mercaptans since the early 1980's.  Contact PTC Organics to evaluate your potential application.

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#10
Avoid Isolation of Intermediates 

Compelling Benefits: Significantly reduce process cycle time. Significantly reduce handling losses. Maintain other benefits of PTC.

Typical Barriers:  This opportunity is limited to cases in which either [1] multiple PTC processes may be performed consecutively or [2] a solvent used in a prior or subsequent step is suitable for use under PTC conditions.

Description: Highly desirable streamlining of processes may be achieved when performing consecutive PTC reactions. This streamlining of processes is built upon integrating many of the unique advantages of PTC. In particular, since PTC provides high yields for reactions in 30 reaction categories, all with highly flexible choice of solvent, this provides the opportunity to consider performing different combinations of organic reactions in a single solvent and avoid isolation of intermediates. Increased productivity results from high yield, avoiding solvent exchange and isolation unit operations and minimizing handling losses. PTC Organics developed a 3-step 1-pot process which provided very high yield and low handling losses using a single solvent which was effective for all three steps. The reactions were performed consecutively without removing the organic phase (containing the product) from the vessel and replacing the aqueous phase at the end of each of the reactions. Examples of such sequences are 1-esterification 2-etherification 3-hydrolysis or 1-cyanation 2-first C-alkylation 3-second C-alkylation or 1-N-alkylation 2-dehydrohalogenation. In the last case there was no need to replace the aqueous phase between the reactions.

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