C. M. Starks

In all PTC reactions, mass transfer to and from phase boundaries is a key step. The rate of all PTC reactions can be limited by mass transfer across a phase boundary. One difference between various PTC reactions is the threshold range of kinetic energy, imparted by agitation, at which the PTC reaction will transform from being mass transfer limited to being limited by the intrinsic reaction in the reaction phase. Considering how important agitation is to PTC systems, it may be surprising that very little has been published regarding the role of agitation in the rates of PTC reactions. This analysis requires interdisciplinary application of the principles of agitation engineering to PTC. Dr. Starks has developed a series of equations, relevant to PTC systems, which relate various variables of agitation to calculate "adjusted interfacial area," "average droplet radius" and "specific interfacial area." In a typical liquid-liquid PTC system, 75% of the interfacial area available for mass transfer activity is located in the 25% of the outer radius from the paddle center. The specific interfacial area is inversely proportional to the reactor radius. The average droplet size is inversely proportional to the squares of the agitator speed and radius from the paddle center and directly proportional to the interfacial tension. We are looking forward to taking a closer look at Dr. Starks’ analysis when it is published in full.

Some Questions of Mechanism and Application of Phase-Transfer Catalysis

M. Makosza

Prof. Makosza presented work which he presented at Pacifichem 95 in Hawaii and which he published as Chapter 4 in [Makosza, M. "ACS Symposium Series 659, Phase-Transfer Catalysis: Mechanisms and Syntheses" 1997, Halpern, M., editor, American Chemical Society, Washington DC, pp. 41-51]. Prof. Makosza’s major message is that the "interfacial mechanism" he proposed in the early 1970’s is valid for many hydroxide ion reactions such as carbene additions and the alkylation of phenylacetonitrile. Makosza rejects Liotta’s "modified interfacial mechanism" (see Liotta paper below). One of the more interesting observations cited by Makosza is the higher reactivity of the C-alkylation of substituted phenylacetonitriles bearing electron withdrawing groups with propyl iodide in the presence of tetrabutyl ammonium and aq. NaOH. Makosza claims that an interfacial mechanism must be invoked because the higher acidity (lower pKa) carbon acids give higher conversion, thereby creating a higher concentration of ArCHCN(-) anions at the interface. It is reasoned that, in such a case, the inhibitory effect of iodide should be dependent on the acidity of the substrate. Whereas, this observation is consistent with an interfacial mechanism, there are other mechanisms with which this observation is consistent. Liotta’s paper showed actual kinetic analyses for the interfacial and modified interfacial mechanism and treats these systems in a more systematic and mathematical manner. Makosza highlighted a synthetically useful tip, namely, strong base dehydrohalogenations can be enhanced by using an alcohol or acidic N-H compound (such as indole). In these systems, the alcohol or indole is deprotonated and more easily extracted into the organic phase relative to hydroxide. The alkoxide or N-anion then serves as a more effective base and co-catalyzes the reaction.

Critical Evaluation of PTC/OH Reactions: The Starks-Brandstrom-Montanari Extraction Mechanism vs. The Makosza Interfacial Mechanism

C. L. Liotta

Liotta addressed the ongoing PTC/OH mechanism controversy using three logical and convincing approaches: [1] mathematically deriving proper rate expressions, [2] providing relevant experimental results to reach firm conclusions [3] offering explanations consistent with the theoretical rate expressions and the experimental results. Liotta began by deriving rate expressions for three cases: [a] the classic Starks’ extraction mechanism, [b] the classic Makosza interfacial mechanism which assumes no quat involvement in the deprotonation step and [c] a modified interfacial mechanism. In the modified interfacial mechanism, the quat participates in the deprotonation by modifying the hydrophilic-lipophilic properties of the "interfacial region" such that the hydrated hydroxide ion as well as the quat and the organic substrate can partially co-reside in this interfacial region. In this interfacial region, the quat, the hydroxide and the organic substrate would all participate in the deprotonation. Liotta showed that, depending on the specific reaction conditions (which can vary widely from reaction to reaction) a "spectrum of mechanisms" exists. Thus, it would incorrect to say that a single mechanism accounts for all PTC reaction systems. Liotta also showed that, mathematically, depending on the specific reaction conditions (i.e., rate constants, concentrations, etc.), sometimes the classical extraction mechanism is mathematically indistinguishable from the classical interfacial mechanism. Sometimes, the two extreme mechanisms (extraction and interfacial) CAN be differentiated. Liotta designed and executed deuteration experiments using CHCl3, phenylacetonitrile and fluorene as substrates. In all cases, in the absence of catalyst, the rate of deuteration decreased as the [NaOD] increased. In the presence of catalyst the rate of deuteration increased as the [NaOD] increased. One can only conclude that the catalyst must be affecting the rate determining step. This single piece of evidence refutes the classical Makosza interfacial mechanism with regard to the deprotonation of such substrates as chloroform and phenylacetonitrile, which Makosza used extensively in his important synthetic papers as well as model compounds in his explanation of the interfacial mechanism. Liotta proposed that the role of the quat, as explained above, is to help form an interfacial region, in which the organic substrate and the hydroxide ion can co-reside and react in a deprotonation process. Such a mechanism is consistent with the qualitative and quantitative observations. Liotta also pointed out that there still may be other mechanisms at work in this reaction, however, the classical interfacial mechanism was refuted in the deuteration systems studied.

New Experiments with Selective and Enantiopure Phase Transfer Catalysts

Dehmlow, E.

Dehmlow screened 10 reactions for chiral PTC and very low enantiomeric excesses were achieved. One interesting result was that a Michael addition achieved 71% ee using a crown with side chains that had two equivalent faces. Large substituents decreased ee. Dehmlow synthesized a number of chiral catalysts based on proline, quinoline and quiniclidine. Unfortunately, unremarkable ee’s were achieved. Dehmlow’s approach was to try to isolate the structural factors responsible for inducing ee in chiral PTC reactions (Dehmlow did not discuss three-point interactions). Conceptually, that is a reasonable approach, however, the key achievement in the work presented was that many factors for inducing ee were eliminated instead of being identified. This appears to be tedious work which is further complicated by the frustration of not being able to obtain good crystals for X-ray analysis (Dehmlow also made this point at Pacifichem 95 in Hawaii) It is hoped that in the future, more progress will be made. To our regret, Dehmlow announced that he would retire by PTC 2000. We wish him well in his retirement and we hope that he will continue to be active at least at PTC conferences.

Synthesis of Ether-Ester Compounds via Phase-Transfer Catalysis: A Study of Substitution and Hydrolysis

Wang, M.

Wang presented a very good paper with a clear and practical message: if you want to make an ether-ester under PTC conditions, it is possible to almost totally inhibit hydrolysis of the ester by adding potassium carbonate. The general chemical community is often not as aware as the PTC experts that PTC often offers the opportunity to work with hydrolytically sensitive compounds in the presence of water. Wang’s systematic work and presentation highlighted the usefulness of potassium carbonate in minimizing hydrolysis of hydrolytically sensitive reagents. We are looking forward to the publication of the full paper.

Correction: In addition to the invited lecturers noted in the previous issue, Professor Howard Alper University of Ottawa) and Professor Tomoi (Yokohama National University) also presented invited lectures, though they were not present in the invited speakers picture (www.phasetransfer.com/ptc97spk.htm).

Utility of Hexaalkyl-guanidinium Salts as Stable Phase-Transfer Catalysts D. J. Brunelle

Dr. Brunelle presented an excellent paper demonstrating the remarkable performance of hexaethyl guanidinium chloride (HEGCl) as a phase-transfer catalyst at elevated temperatures. HEG Cl was the best catalyst (four times better than HEG Br and much better than 18-crown-6, Bu₄P and Bu₄N). HEG Cl was shown to be quite effective at 150C. DSC showed HEGCl decomposition starting at 293C (vs 195C for TBAB). Brunelle noted that the catalytic activity of HEG Cl was two fold: its phase-transfer ability at high temperature and the guanidinium catalyst activates the anion, possibly by a mechanism of addition of the anion to the guanidinium nucleus. HEG Cl is likely to be the most commercially attractive high temperature phase-transfer catalyst and we anticipate to see more commercial interest in this catalyst in the near future.

Copper Catalyzed tert-Butylhydroperoxide Oxidation of Alcohols Under Phase-Transfer Conditions
L. Feldberg and Y. Sasson

Professor Sasson presented an excellent paper describing the oxidation of 2^o alcohols to ketones (useful also for 1^o alcohols to aldehydes and for aniline to nitrobenzene) using t butylhydroperoxide (TBHP), Cu (II) chloride (other copper salts were also good) and a phase-transfer catalyst (Aliquat 336 and cetyl trimethyl ammonium bromide better than TBAB/HSO₄, though TBAB was used as the standard catalyst). CuCl₂ is a milder catalyst than RuCl₃ (which was too exothermic) and gave 100% selectivity, though the conversions were sometimes low. Copper catalyst degradation is a barrier to catalyst recycle. Sasson is always industrially oriented and he presented feasibility comparisons for oxidations on 10,000 MT/yr scale using hypochlorite, air oxidation and peroxide. Sasson also presented three interesting posters, one of which described the surprising behavior of the cyclization of 4-chloro- and 4-bromo-butyronitrile. The fascinating conclusion was that the chloro and bromo compounds react by two different mechanisms. It is worthwhile to note that the mechanism of PTC systems can differ greatly from reaction to reaction. Sometimes, we tend to oversimplify or make assumptions about PTC reaction mechanisms. These assumptions can have significant impact on optimal reaction conditions, and are often overlooked when designing commercial applications.

Recent Findings and Applications of Phase-Transfer Catalysis
D. Landini, A. Maia, M. Penso, D. Albanese and G. Podda

Professor Landini is one of the premier scientists in the history of PTC. Landini covered a variety of interesting PTC reactions. Some of the most interesting items included: [1] conversion of 1-alkenes to 1o alcohols using NaBH₄, QX and BuBr; [2] Hex₄N⁺ HF₂^- is a good source of anhydrous F^- (though not as active as Hex₄NF), whereas Hex4N⁺ H₂F₃^- is a good source of HF which can be handled in glass; [3] cyclophosphazenic polypodands are good phase-transfer catalysts which are stable up to 3 days at 60C in the presence of solid NaOH and can be removed by filtering through silica gel; [4] regioselective opening of epoxides under solid-liquid PTC conditions in which TEBA gave more than twice the yield at less than half the reaction time compared to using no TEBA. The last reaction can be found at: Albanese, D.; Landini, D.; Penso, M. Tetrahedron, 1997, 53, 4787

Some Industrial Applications of PTC: Processes in Liquid/Liquid, Liquid/Solid and Liquid/Solid/Liquid Systems
F. Sirovski

Dr. Sirovski covered some of the reactions shown in the cover article of Volume 4 Issue 1 of Phase-Transfer Catalysis Communications. Dr. Sirovski has demonstrated excellence both in PTC process chemistry as well as in theoretical PTC chemistry.

Reducing Cost of Manufacture of Organic Chemicals Using Phase-Transfer Catalysis
M. Halpern

Twelve commercial applications were described in detail, highlighting the advantages in terms of productivity, quality, safety, plant operability and environmental performance. The 60-Second PTC Test was presented for identifying commercial opportunities to improve existing processes or develop superior new processes.

Formation of a Third Liquid Phase in the System of Toluene/R4NBr/(NaOPh+NaOH) Aqueous Solution
P. W. Wang and H. S. Weng

Wang and Weng presented a poster describing one of the hot "new" items in PTC (some articles date back to 1988), namely, the highly remarkable performance of PTC systems, in which it is possible to generate a catalyst-rich third liquid phase. It is difficult to design "tri-liquid-phase" PTC systems, but when they are found, high reactivity can be achieved and a specially designed reactor can be used to recycle the catalyst, even in a continuous process. An outstanding article describing this reactor is Weng, H.S.; Wang, C.M.; Wang, D.H. Ind. Eng. Chem. Res., 1997, 36, 3613. The subject of tri-liquid-phase PTC has become important enough to warrant a special section which was added to the 1998 version of the course "Practical Phase-Transfer Catalysis" offered by PTC Technology.

Microwave Activation in Phase Transfer Catalysis
A. Loupy and A. Petit

Loupy reviewed his work which integrates microwave irradiation with PTC to achieve extremely short reaction times (usually 1-15 min!). These systems provide heating rates of 10C/sec, high efficiency even for poor heat conductors, very homogeneous heating and reduced decomposition of products. Solvent-free systems are preferred because explosions can happen due to the boiling points of most solvents. Loupy showed that 500 g reactions can be done with a 10 cm radius tube in a commercially available microwave unit.

Phase-Transfer Catalysis Reactions Involving Organosilicon Compounds
Y. Goldberg

Yuri Goldberg is the author of an excellent book on PTC published by Gordon and Breach and is quoted in Sirovski’s article for having commercialized an important industrial PTC process. In this paper, Goldberg described a variety of PTC reactions of organosilicon compounds. PTC alkylation of mono-, di-, tri- and tetrazoles with 3-halopropylsilanes was used to obtain new antimicrobial agents in almost quantitative yield. Insertion of dihalocarbenes at a Si-H bond of sterically hindered silanes readily occurred under alkaline PTC conditions giving rise to the corresponding dihalomethylsilanes in high yield and no by-products being formed. Hydrosilylation of carbon-carbon triple bonds can be carried out using PTC/KPtCl6. Other reactions included the preparation of Mosher’s acid and 2-silylaziridines.

A Practical Method for Epoxidation of Olefins with 30% Hydrogen Peroxide under Halide-Free Conditions
K. Sato, M. Aoki and R. Noyori

Noyori’s group has published several impressive papers which describe epoxidation of olefins and oxidation of 2^o alcohols to ketones in very high yield using 30% H₂O₂, Aliquat 336 HSO₄-form and Na₂WO₄ without added solvent and sometimes without phosphorous containing compounds. One of these papers was already reviewed in PTC Communications Volume 3 Issue 1 and was similar to the work presented at PTC ‘97. The presentation at PTC ‘97 included work published in Bull. Chem. Soc. Jpn., 1997, 70, 905.

The best recent paper from this group was not discussed at PTC ‘97 [Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Amer. Chem. Soc., 1997, 119, 12386 (not many organic papers make it into JACS anymore, so this one is a must-read] and describes the oxidation of 2^o alcohols to ketones in very high yield.

Soluble Polymer-Bound Quaternary Phase-Transfer Catalysts
S. Grinberg and V. Kas'yanov

This is a fascinating new concept in PTC...using a phase-transfer catalyst which is soluble and active at high temperature, but which separates out of solution upon cooling. The biggest barrier to commercializing PTC reactions is often catalyst separation. This concept provides a refreshing potential solution for balancing catalyst activity and catalyst separation, though it is in the embryonic stage at this point. Nine such catalysts were prepared by reacting commercially available oxidized polyethylene with diamino-Jeffamines, followed by quaternization.. The best catalyst in the series did not induce as high reactivity as TBAB, however the catalyst was easily recycled after nucleophilic substitutions at 170C by cooling and filtering the catalyst nearly quantitatively. A good reference is Grinberg, S.; Kasyanov, Srinivas, B. Reactive & Functional Polymers, 1997, 34, 53.

Application of Polymeric Phase-Transfer Catalysis to the Microanalysis of Aqueous Compounds in Forensic Chemistry and Toxicology
A. Miki, M. Katagi, H. Tsuchihashi and M. Yamashita

The Osaka Police Forensic Science Laboratory presented a very nice paper on the practical application of previously published derivatizations to pentafluorobenzyl esters and analysis by GC, GC-MS and GC-ECD. Detection levels of 1 100mg were achieved for phosphonates and other analytes and was used in an actual forensic investigation involving nerve gas. Some of this good work was published: Miki, A.; Tsuchihashi, H.; Yamono, H.; Yamashita, M. Analytica Chimica Acta, 1997, 356, 165

Asymmetric Synthesis by Shioiri’s Group

As noted in the previous issue, Professor Takayuki Shioiri did an outstanding job in organizing all aspects of the program and logistics of the PTC ‘97 Conference (PTC Technology recognized Professor Shioiri’s efforts with a special engraved plaque which can be viewed at the PTC website www.phasetransfer.com/shoiri.htm. In addition, Professor Shioiri’s group contributed four interesting posters at the conference.

In the paper entitled "Catalytic Asymmetric Darzens Reaction under Phase Transfer Conditions" by S. Arai and T. Shioiri, up to 69% ee was achieved using chiral quats in the reaction between aldehydes and phenacyl chloride to afford optically active epoxy ketones. In the paper entitled: "Catalytic Asymmetric Epoxidation of a, b-Unsaturated Ketones promoted by Chiral Quaternary Ammonium Salts" by H. Tsuge, S. Arai and T. Shioiri, chiral PTC catalysts based on quaternized cinchonine were used to prepare epoxy ketones, this time, by hydrogen peroxide oxidation of chalcone achieving up to 92% ee. In another paper "Catalytic Asymmetric Horner-Wadsworth-Emmons Reaction Promoted by Chiral Quaternary Ammonium Salts Under Phase Transfer Conditions" by S. Hamaguchi, S. Arai and T. Shioiri, phosphonates were reacted with prochiral ketones to form carbon-carbon double bonds in up to 76% yield and 41% ee. Cyclopropanation by addition of cyanoacetates to the double bond of cyclic a halo enones was achieved in up to 94% yield, as described in "A Steroeselective Construction of Cyclopropane Rings Under Phase-Transfer Catalysis Conditions" by K. Nakayama, S. Arai and T. Shiori.

Other interesting papers and posters were presented at PTC ‘97. Information about the science presented can be obtained directly from the authors, who are listed in Volume 3 Issue 3 of PTC Communications and a complete list of authors can be found on the PTC ‘97 Program page on the PTC website www.phasetransfer.com.