Phase Transfer Catalysis

Overview

The Industrial
Phase-Transfer
Catalysis Experts
 

PTC Mechanism        Impressive PTC Applications

Phase-Transfer Catalysis Overview

Saving $Millions$ in the Production of Organic Chemicals

Using Phase-Transfer Catalysis

Marc Halpern, Ph.D.

PTC Organics, Inc.

900 Briggs Road, Suite 145, Mt. Laurel, New Jersey 08054 USA

tel +1 856 222 1146, fax +1 856 222 1124, E-mail: mhalpern@ptcorganics.com; www.ptcorganics.com

Scope, Benefits and Barriers of Commercial Phase-Transfer Catalysis Applications

Phase-Transfer Catalysis, "PTC," technology is used in the commercial manufacture of more than $10 billion per year of chemicals shown in Table 1.1 PTC technology is also used in pollution prevention, pollution treatment and the removal or destruction of impurities in waste and product streams. PTC technology is used in these applications, because it provides many compelling benefits, primarily related to reducing the cost of manufacture of organic chemicals and pollution prevention. The many significant and advantageous process performance achievements which are routinely realized by using PTC are shown in Step 1 of Table 2.2 With such a long list of highly desirable benefits achieved in commercial applications (usually multiple benefits are achieved in each application), it is no wonder that PTC technology is used in a wide variety of applications! Cost reduction and pollution prevention are the two most powerful driving forces in the chemical industry today, and they match precisely the strengths and benefits provided by Phase-Transfer Catalysis.

The scope of PTC technology is most appropriately addressed by considering the range of reactions to which PTC is applicable. The 1700 patents and 8000 publications on PTC fall into about 30 major reaction categories, most of which are shown in Step 2 of Table 2. This scope of application is extremely broad and is responsible for the commercial PTC applications found in the wide range of industries listed in Table 1.

Despite these great benefits and wide scope of application, many chemical companies are still NOT using PTC technology, mostly due to lack of awareness, lack of expertise, lack of applicability and/or organizational resistance to change (not-so-amusing anecdotes3,4). A detailed discussion of the five top reasons and excuses why companies miss great opportunities to improve profit and process performance using PTC, can be found in the PTC journal5 and also on the web at www.phasetransfer.com/missopty.htm and www.phasetransfer.com/excuse.htm.

 


Table 1: Commercial Chemical Production Benefiting from Phase-Transfer Catalysis

Monomers

Additives

Surfactants

Polymers

Flavors & Fragrances

Petrochemicals

Agricultural Chemicals

Dyes

Rubber

Pharmaceuticals

Explosives

 

and a wide variety of other commodity, specialty and fine organic chemicals

 


Table 2: The 60-Second Phase-Transfer Catalysis Test2


Does your existing plant process or process in development meet any of the criteria in Steps 1 and 2?

STEP 1: mark all that apply

Desired Process Improvement

  • Increase Productivity

increase yield
reduce cycle time
reduce or consolidate unit operations
increase reactor volume efficiency

  • Improve Environmental Performance

eliminate, reduce or replace solvent
reduce non-product output

  • Increase Quality

improve selectivity
reduce variability

  • Enhance Safety

control exotherms
use less hazardous raw materials

  • Reduce Other Manufacturing Costs

eliminate workup unit operations
use alternate less expensive or easier to handle raw materials
       are you currently using 
       NaOMe/OEt/t-butoxide, NaH, NaNH2, LDA, 
       water sensitive reactants,
       chlorinated hydrocarbon solvents, DMSO, NMP, DMF, DMAC?

STEP 2: mark all that apply

Desired Reaction

O-Alkylation (Etherification)

N-Alkylation

C-Alkylation & Chiral Alkylation

S-Alkylation

Dehydrohalogenation

Esterification

Displacement With

   Cyanide Hydroxide, Hydrolysis

   Fluoride Thiocyanate, Cyanate

   Iodide Sulfide, Sulfite

   Azide Nitrite, Nitrate

Other Nucleophilic Aliphatic & Aromatic Substitution

Oxidation

Epoxidation & Chiral Epoxidation

Michael Addition

Aldol Condensation

Wittig

Darzens Condensation

Carbene Reactions

Thiophosphorylation

Reduction

Carbonylation

HCl/HBr Reactions

Transition Metal Co-Catalysis

Any Reaction Above for Polymerization

Any Reaction Above for Modifying Polymers

STEP 3: IF your new or existing process:

  1. could benefit from at least one desired process improvement listed in Step 1

    AND

  2. includes at least one reaction listed in Step 2

THEN

you should definitely consider Phase-Transfer Catalysis

to improve process performance

 


A full description of all of the benefits and opportunities to improve profit and process performance using PTC are described in Volume 2 Issue 16 of the journal "Phase-Transfer Catalysis Communications."

What is Phase-Transfer Catalysis?

Phase-Transfer Catalysis is useful primarily for performing reaction between anions (and certain neutral molecules such as H2O2 and transition metal complexes such as RhCl3) and organic substrates. PTC is needed because many anions (in the form of their salts, such as NaCN) and neutral compounds are soluble in water and not in organic solvents, whereas the organic reactants are not usually soluble in water. The name phase-transfer catalysis does what it says...the catalyst acts as a shuttling agent by extracting the anion or neutral compound from the aqueous (or solid) phase into the organic reaction phase (or interfacial region) where the anion or neutral compound can freely react with the organic reactant already located in the organic phase. Reactivity is further enhanced, sometimes by orders of magnitude (!), because once the anion or neutral compound is in the organic phase, it has very little (if any) hydration or solvation associated with it, thereby greatly reducing the energy of activation. Since the catalyst is often a quaternary ammonium salt (e.g., tetrabutyl ammonium, [C4H9]4N+), also called the "quat" and symbolized by Q+, the ion pair Q+X- (X- being the anion to be reacted) is a much looser ion pair than say Na+X-. This looseness of the ion pair is a third key reason for enhanced reactivity, which will ultimately lead to increased productivity (reduced cycle time) in commercial processes. At the end of the reaction, an anionic leaving group is usually generated. This anionic leaving group is conveniently brought to the aqueous (or solid) phase by the shuttling catalyst, thus facilitating the separation of the waste material from the product. This mechanism is called the "extraction mechanism" of phase-transfer catalysis and is shown in Figure 1.7

Figure 1: The Extraction Mechanism (Starks, 1971)

The extraction mechanism easily accounts for the benefits of PTC which include: achieving high reactivity (reactants are in the same phase with less hydration in a loose ion pair); extreme flexibility in choosing or eliminating solvent (a properly chosen quaternary ammonium catalyst can extract almost any anion into almost any organic medium, including into the product or into one of the organic reactants resulting in a solvent-free process); reducing the excess of water-sensitive reactants (such as phosgene, benzoyl chloride, esters and dimethyl sulfate since they are protected in the bulk organic phase from the aqueous phase by interfacial tension); higher selectivity (lower energy of activation allows reduction of reaction temperature and time); the use of inexpensive and less hazardous bases (hydroxide is easily transferred and activated in nearly all organic solvents) and many other benefits.

Selected Applications and Impressive Performance

There are hundreds of commercial applications of Phase-Transfer Catalysis and they were commercialized due to the competitive advantages which they truly provide. Following is a selection of applications which would offer clear commercial benefit. This is only a selection and is not intended to be comprehensive or even to represent the best commercial applications.

Continuous Dehydrohalogenation to Produce a Large Scale Monomer8

Achieved:

Productivity @ 16 tons/hr, yield @ 99.2% and NaOH usage @ only 0.8 mole % excess!

Outstanding Reduction of Excess Hazardous High Volume Raw Material9

Achieved:

Great improvement in safety and environmental by reducing phosgene excess by 94%!
PTC provides 200X less hydrolysis of phosgene/chloroformate according to GE patent.

Thiolation (Methyl Mercaptan)10

Achieved:

High yield for > 40 triazines, reduced cycle time by eliminating unit operations;

no isolation of intermediates; achieved single solvent for 3 steps with low emissions.

Etherification (O-Alkylation)11

  • PTC usually best Williamson ether synthesis

  • high yield etherification

  • no need for excess pre-formed alkoxide

  • usually short cycle time and easy workup

  • non-dry mild reaction conditions

  • aliphatic and phenolic O-alkylation many commercial bis-phenol A processes

High Yield Solvent-Free Hazardous Nucleophilic Displacement12

Achieved:

High yield, with no solvent; explosive reactant in small excess; scaled up.

Sulfur Removal from Diesel Fuel13

PTC is used in problem solving in real world applications. Legislation in the US and Europe reduced the permitted sulfur levels in diesel fuels by 84% during the past five years. PTC/H2O2 was used as part of a process to achieve excellent desulfurization of diesel oil. A key sulfur component of diesel oil is dibenzothiophene and was quantitatively oxidized using 0.5 wt% Aliquat 336, 0.3 wt% phosphotungstic acid and 11% aq. H2O2 (6.4 wt% on a 100% basis) at 60oC. Since H2O2 is expensive, the PTC oxidative desulfurization (ODS) is preceded by hydrodesulfurization (HDS). HDS of gas oils to < 0.5wt% sulfur is difficult. Thus, sequential HDS followed by PTC ODS was used to achieve 0.005 wt% sulfur, which is an order of magnitude lower than US and European requirements.

Thioesterification for Lubricant14

Carbonylation

Phase-transfer catalysis offers a variety of conceptual and practical advantages when performing carbonylations as described in reference.15 Among these advantages unique to PTC are the ability of quats to transfer the anionic forms of metal carbonyls to the organic phase, in which CO is about 10 times more soluble than in water, which further leads to less hydrolysis of CO to formate and esters to acids. For example, malonic esters can be made by PTC carbonylation of ethyl chloroacetate at 1 atm CO at 25oC in the presence of cobalt carbonyl.16 Ni(CN)2 was used for the PTC double carbonylation of alkynols, using PEG-400 as the phase-transfer catalyst, LaCl3 as an additional co-catalyst, toluene as the solvent, and 5.0 N NaOH as the optimum base concentration.17 Yields of ene-dicarboxylic acids were up to 97%. PTC carbonylation has also been used to convert alkyl halides to acids and esters, and aryl halides to aryl carboxylic acids.

Oxidation (Hypochlorite)18

Achieved:

High yield in short reaction time at room temperature;

inexpensive oxidizing agent/no transition metal with high selectivity (vs. over-oxidation)

Oxidation (Air)19

Oxidation (H2O2)20

Epoxidation21 & Chiral Epoxidation22

Cyanation23

Achieved:

Yield increase of 19% vs previous DMSO process. 100% recycle of toluene solvent vs no recycle of DMSO with 40% less solvent taking up reactor space. 95% (!) less cyanide excess, 85% (!) less aqueous waste, 3 less workup unit operations and better controlled exotherm through agitation vs. stepwise cyanide addition

Michael Addition24

Achieved:

Eliminated very expensive hazardous organic strong base (LDA)

at very expensive very low temperature with 19% yield increase!

Multiple Michael addition to acrylates used for lubricants also reported

Chiral Alkylation25, 26

 

How to Identify Opportunities to Improve Profit and Process Performance Using PTC?

Take the 60-Second PTC Test! All you have to so is ask yourself, for every existing commercial process and every new process in development: [1] Do you want to achieve higher process performance according to ANY of the criteria shown in Step 1 of Table 2? [2] Is the reaction you are performing on the list in Step 2 of Table 2? If the answer is "yes" to BOTH questions, you should probably consider Phase-Transfer Catalysis for your process.

How to Actually Profit from Opportunities Using PTC?

You have two choices to realize profit by using PTC for commercial manufacturing processes:

  1. Develop PTC technology in-house for the specific application.

  2. Outsource the development and/or manufacture of the PTC process to PTC manufacturing experts with development and manufacturing facilities.

Develop PTC processes in-house:

Specific departments in a handful of chemical companies have significant internal expertise in phase-transfer catalysis. These departments routinely consider PTC as a process option when developing new processes. When problems arise in existing non-PTC processes, these departments will often consider and implement retrofit of the existing process with PTC to achieve the desired high performance. The author is aware of only two cases (one of which was induced after training by the author) in which chemical companies established a temporary team to identify opportunities to increase profit and improve performance by incorporating PTC into existing processes and into processes in development. Both of these companies use PTC in multiple processes with great success.

Departments and chemical companies which have some, though limited, expertise in PTC can implement a cost effective PTC opportunity identification & evaluation program. PTC Organics, Inc. offers a "PTC Cost Savings Program," in which PTC Organics, Inc. conducts a review of selected company processes, under secrecy agreement, and identifies opportunities to increase profit and improve processes using PTC. The program usually begins internally within the company, by having a senior scientist or manager (who is familiar with a broad range of company processes for the manufacture of organic chemicals) apply the criteria of the 60-Second PTC Test (Table 2) to many commercial processes or processes in development. This stage usually requires an investment of up to an hour of time of the senior scientist or manager. Alternatively, PTC Organics, Inc. can perform the initial evaluation, though this requires greater disclosure (under secrecy agreement) of processes by the company seeking to achieve higher profit/performance. A senior manager in the company then approves which processes will be evaluated by PTC Organics, Inc. A Confidential Disclosure Agreement is executed. A joint review of the processes is conducted by personnel from both companies. PTC Organics, Inc. determines which processes have the highest probability of success and makes specific recommendations for process improvements. The companies agree on well-defined Criteria For Success upon which performance is measured. PTC Organics, Inc. performs process development in its Willingboro, NJ lab and PTC Organics works with your company to shepherd the advantageous PTC process from concept through development and scale up to commercialization. Mutual incentive for both companies is achieved by linking the compensation of PTC Organics, Inc. to performance or to a commercialization contingency.

Outsourcing PTC Development and/or Manufacture:

The trend toward increased outsourcing of manufacture is being applied to enjoying higher profit by outsourcing the development and manufacture of organic chemicals by Phase-Transfer Catalysis. PTC Organics, Inc. is the only company dedicated exclusively to developing high performance processes for the manufacture of organic chemicals using Phase-Transfer Catalysis technology, which is based on its leadership position in this technology. PTC Organics, Inc. has partnering arrangements with custom manufacturers in the US and Europe, whereby processes developed by PTC Organics can be transferred into commercial manufacture. Through these facilities, PTC Organics, Inc. provides organic chemicals and custom manufacturing at attractive prices and high quality.

Conclusion

Phase-Transfer Catalysis delivers high productivity, enhanced environmental performance, improved safety, better quality and increased plant operability in hundreds of commercial manufacturing processes for organic chemicals in dozens of reaction categories. The companies who use PTC do so because PTC provides high performance in real world applications, primarily in reducing cost of manufacture and pollution prevention. Enormous opportunity exists right now (!) to increase corporate profits and process performance by retrofitting existing non-PTC processes with PTC and by developing new processes using PTC. Companies can achieve higher performance using PTC by developing these processes and manufacturing in-house or by outsourcing the development and/or manufacture using PTC. Most companies are not even aware that they can gain short term benefit ("low hanging fruit") to long term benefit using PTC. As a result, much opportunity is being missed. Strategic alliances exist specifically for helping companies enhance performance by identifying, evaluating and commercializing opportunities using PTC. Is your company achieving all it can using Phase-Transfer Catalysis? Would you like to be a hero?

References:

  1. Starks, C.; Liotta, C.; Halpern, M.; "Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives," Chapter 16, Chapman & Hall, New York 1994

  2. reproduced with permission from PTC Communications, Inc. from Halpern, M. Phase-Transfer Catalysis Communications, 1997, 3, 17

  3. In one not-so-amusing case in 1995, one R&D executive remarked regarding a potential cost saving PTC retrofit: "we are cutting costs...we canít afford to look at PTC right now." Depending on the potential gain to the company, could the executive afford NOT to evaluate the PTC Retrofit? The executive was laid off in 1997 (together with 10,000 others).

  4. A plant manager once said to me "We already have 95%, yield so we donít need PTC!" It turned out that the plant process suffered from long cycle time and the use of a dipolar aprotic solvent. PTC was able to shorten the cycle time and replace the solvent with a solvent which was inexpensive, easy to handle, easy to recover and recycle. The combination of lack of PTC awareness, lack of PTC expertise and resistance to change is powerful enough to prevent companies and their management to achieve very significant corporate and personal gains. This may not be the case at YOUR company, but chances are that it is!

  5. Halpern, M. Phase-Transfer Catalysis Communications, 1997, 3, 33

  6. Halpern, M. Phase-Transfer Catalysis Communications, 1996, 2, 1

  7. Starks, C.; J. Amer. Chem. Soc., 1971, 93, 195; Starks, C.; Owens, R.; J. Amer. Chem. Soc., 1973, 95, 3613

  8. Maurin, L.; (DuPont) 1983, US Patent 4,418,232

  9. Boden, E.; Phelps, P.; Ramsey, D.; Sybert, P.; Flowers, L.; Odle, R.; (General Electric) 1995, US Patent 5,391,692

  10. Grace, H.; Wood, M.; (Ciba-Geigy) 1994, EP 0 648 755 A1

  11. McKillop, A.; Fiaud, J.; Hug, R.; Tetrahedron, 1974, 30, 1379

  12. Malik, A.; Manser, G.; Carson, R.; Archibald, G. (Aerojet-General Corporation) 1996, US Patent 5,523,424

  13. Collins, F.; Lucy, A.; Sharp, C. J. Mol. Catal. A, 1997, 117, 397; Abstract reproduced with permission from PTC Communications, Inc.

  14. Farng, L.; Horodysky A.; Nipe, R. (Mobil) 1996, US Patent 5,514,189

  15. Starks, C.; Liotta, C.; Halpern, M.; "Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives," Chapter 13, Chapman & Hall, New York 1994

  16. Kantam, M.; Reddy, N.; Choudary, B. Synth. Comm., 1990, 20, 2631

  17. Zhou, Z.; Alper, H. Organometallics, 1996, 15, 3282

  18. Lee, G.; Freedman, H.; (Dow Chemical) 1978, U.S. Patent 4,079,075

  19. Dakka, J.; Zoran, A.; Sasson, Y. (Gadot) Eur. Pat. Appl. EP 0 300 921

  20. Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Amer. Chem. Soc., 1997, 119, 12386

  21. Sato, K.; Aoki, M.; Ogawa, M.; Hashimoto, T.; Noyori, R. J. Org. Chem., 1996, 61, 8310

  22. Lygo, B.; Wainwright, P. Tetrahedron, 1999, in press

  23. Dozeman, G.; Fiore, P.; Puls, T.; Walker, J. Org. Proc. Res. Dev., 1997, 1, 137

  24. Gestmann, D.; Laurent, A.; Laurent, E. J. Fluorine Chem., 1996, 80, 27

  25. Sabahi, M.; Irwin, R.; (Albemarle) 1994, U.S. Patent 5,347,043

  26. Corey, E.; Xu, F.; Noe, M. J. Amer. Chem. Soc., 1997, 119, 12414; Lygo, B.; Wainwright, P. Tetrahedron Lett., 1997, 8595

 

 If your company would like to have a seminar about the content of this article, contact us
mhalpern@ptcorganics.com

 

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