Phase-transfer catalysis

A phase transfer catalyst can be defined as a substance that will increase the rate of reaction between substrates present in separate phases. Phase transfer 

There are a number of advantages to be gained in using a phase transfer system to conduct a reaction, including  

1 Elimination of the need for organic solvents may often be performed in just water and the neat substrate. 

4 Reaction temperatures (and therefore rates) may be controlled by the rate of stirring. 

However, there are a number of drawbacks associated with PTC, including  

Phase-transfer catalysis describes the action of special catalysts that assist the transfer of reactive molecules from a polar ( aqueous ) solvent to a nonpolar ( organic ) solvent. In the absence of the phase-transfer catalyst, one of the reagents is confined to one solvent, and the other reagent is confined to the other solvent, so no reaction occurs. Addition of a small amount of catalyst, however, enables one of the reagents to pass into the other solvent thereby initiating a reaction. 

Electrostatic potential map for benzyltrimethylammonium ion shows most positively-charged regions (in blue) and more nearly neutral regions (in red). 

What properties oibenzyltriethylammonium ion make it soluble in diverse solvents Examine its electrostatic potential map and atomic charges. Which groups facilitate water solubility Explain. Which groups facilitate chloroform solubility Explain. 

Compare electrostatic potential maps for tetrabenzyl-ammonium ion and tetraethylammonium ion with that of benzyltrimethylammonium ion. Are they likely to be as effective or more effective as phase-transfer catalysts as benzyltrimethylammonium ion Explain. (Hint Predict solubility properties for the three ions.) 

Phase transfer catalysis is nowadays a well-established technique in preparative chemistry. However, it has been confined almost exclusively to nucleophilic substitution reactions. Nevertheless some examples of phase transfer catalyzed azo coupling ructions ate known. 

Gokel and coworkers have shown that diazonium tetrafluoro- 

Recently Griffiths and coworkers reported the first example of a liquid-liquid phase transfer catalysis in an electrophilic substitution reaction They showed 

Phase transfer catalysis increases the rate of reaction between nonelectrolytes located in organic phases and ionic species located in a contacting aqueous phase. The catalytic agents are salts of macromolecular organic ions. 

Weber and G. W. Gokel Phase Transfer Catalysis in Organic Synthesis . Springer-Verlag, New York, 1977. 

The importance of (he distribution of the ions between the phases, a physical factor, has been emphasized as a factor contributing to catalysis. 

The activity of a phase transfer catalyst does not necessarily imply its partial solubility in water and thus that the transfer of the anion can occur without a concomitant transfer of the organic cation from one phase to another. The effectiveness of the catalyst is dependent upon its organophilicity .  

The reaction between inorganic nucleophilic anions and n-octyl methane-sulphonate is catalysed by quaternary salts in chlorobenzene-water mixtures and occurs in the organic phase. The relatively narrow reactivity range and sequence of the nucleophilic anions in the two phase system is attributed to the specific solvation of the anion by a limited number of water molecules.  

Work in the area of micellar catalysis in both aqueous and nonaqueous solvent systems is certain to continue to grow in importance as a tool for better understanding the chemistry and mechanics of enzymatic catalysis, as a probe for studying the mechanistic aspects of many reactions, and as a route to improved yields in reactions of academic interest. Of more practical significance, however, may be the expanding use of micellar catalysis in industrial applications as a method for obtaining maximum production with minimum input of time, energy, and materials. 

While PTC does not involve solubilization or micellar catalysis in the sense discussed above and seldom involves what are generally considered to be surfactants, it does require the use of catalysts that are amphiphilic in nature. Its basic mechanism, as described below, also brings up some potentially interesting questions related to interfaces, the activity of amphiphilic molecules in multiphase systems, and the transport of ionic species from one phase to the other across such interfaces. Because of those loose, but interesting connections between micellar catalysis and phase transfer catalysis, the following introduction to the theme has been included. 

Reviews of phase-transfer catalysis continue to appear.  

There has been interest in employing chiral catalysts in phase-transfer reactions in order to achieve absolute asymmetric synthesis. Chirality may be contained in the carbon skeleton, or the nitrogen of the quaternary ammonium salt catalyst, or in a combination of these. However, unless the nucleophilic or basic anion forms a very tight ion pair with the ammonium cation so that it is associated on only one face of the tetrahedron, simple chiral tetralkylammonium salts will be incapable of producing a significant amount of asymmetric induction.  

Optically active benzyl c S-2-(hydroxymethyl)cyclohexylldimethylammonium bromide acts as a chiral phase-transfer catalyst for the alkylation of active methylene-containing compounds.  

Pantin, A. V. Levashov, K. Martinek, and I. V. Berezin, Dokt. Akad, Nauk SSSR, 1979, 247, 1194. 

Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis , 1980, Weinheim, Verlag-Chemie C. M. Starks and C. Liotta, Phase Transfer Catalysis , 1978, Academic Press, New York C. Starks. Chemlech., 1980, 10, 110 E. V. Dehmlow, Chimia, 1980, 34, 12 R. Oda, Hyomen, 1979, 17, 653 Hyomen, 1980, 18, 112 L. Lindblom and M. Elander, Pharm. TechnoU 1980, 4, 59 J. P. Antoine, 

We met the synthetic ionophores, the crown ethers, in Section 4.3.3 these not only act as PT catalysts to transfer ions into organic media but also encapsulate cations, and hence break up ion pairs. Naked, unpartnered, ions are much more reactive . Potassium permanganate is insoluble in benzene, so if an aqueous solution of K[Mn04] is shaken with benzene, there is no color in the organic layer. However, when 18-crown-6 (18-C-6 is the appropriate size to coordinate IC) 

FIGURE 23.17 Permanganate oxidations in two-phase systems containing crown ethers. 

Potassium acetate is rather insoluble in MeCN, and acetate is generally considered to be a poor nucleophile. The half-life for the substitution of PhCHjCl by potassium acetate in MeCN at room temperature is 685 h. When 18-crown-6 is added to the solution, the rate of the reaction is increased, and the half-life is reduced to 3.5 h. Explain. 

The condensation of the disodium salt of bisphenol A with phosgene is carried out in a two-phase system as shown in the following. Explain the function of the [Bu4N]l. 

5 This is a classic crown ether effect. The 18-C-6 sequesters potassium ions, carrying them, and the acetate counterions, into the acetonitrile. Thus, part of the effect derives from the solubilizing of the reagent. Additionally, the 18-C-6 breaks up the potassium acetate ion pairs, leaving the acetate naked and hence enhancing its nucleophilicity in the 5 2 substitution reaction. 

The role of a catalyst molecule in phase transfer catalysis (PTC) is very different from that in other types of catalysis as described earlier in Subsection 2.5.1, Subsection 2.5.2, and Subsection 2.5.3. Phase transfer catalysis is required for those bimolecular reactions in which both reactant molecules differ so much in terms of molecular characteristics such as polarity, hydrophobicity, etc., that both of them cannot solubilize in the same phase of the reaction medium. Such bimolecular reactions require two immiscible phases in which each phase solubilizes only one of two types of reactant molecule. Thus, these bimolecular reactions do not take place simply because the reactant molecules cannot come in close proximity — an essential requirement for any reaction to occur. However, such reactions might occur at the interface of the two immiscible phases provided the interface is capable (energetically) of bringing the two reactant molecules in close proximity of each other. 

A membrane can be used in the so-called phase transfer catalysis as a separator between two immiscible liquids or a liquid and a gas. It serves as a well controlled contact surface. An interesting type of membrane reactor has been suggested in which a ceramic membrane is applied to regulate the contact between a gas and a liquid stream on the opposites of the membrane [De Vos, 1982 De Vos et al., 1982]. Hydrogenation of nitrobenzoic acid can be effectively performed with a porous calcium-aluminum silicate membrane reactor which essentially becomes a gas-liquid reactor. 

These applications will be briefly treated in this section. As will become evident, the solid electrolyte membrane materials are either stabilized oxides or mixed oxides. Further details of science and technology of electrocatalytic membrane reactors beyond the scope of this chapter can be found in a number of excellent reviews [Ceilings et al., 1988 Stoukides, 1988]. 

The pioneering contribution from Maruoka and coworkers [37] on the enantioselec-tive phase-transfer alkylation of Schiff bases derived from glycine has opened the way to other related, more recent MBTs. 

In addition to solvent-free processing, phase-transfer catalytic conditions (PTC) have also been widely employed as a processing technique in MAOS [15]. In phase-transfer catalysis, the reactants are situated in two separate phases, for example liquid- 

Frequently, incompatible solubility is overcome by adding a small amount of a tefraalkylammonium or phosphonium salt or a crown ether. This is called phase-transfer catalysis [29-31]. The term phase-transfer catalysis is applied to both solid-liquid reactions and liquid-liquid cases. 

FIGURE 9.1 The equilibria present in a phase transfer reaction [32], 

Quaternary cations with sufficiently large alkyl groups have an affinity for organic solvents and will carry reactive anions with them into solution in the organic layer. These anions are particularly reactive because they carry only a small hydration shell. Some stirring is still necessary because the quaternary salts are used in catalytic amounts and must repeatedly exchange product anions for reactant anions at the phase boundary (Fig. 9.1). 

Oxidation reactions using permanganate [35] (Section 6.1.1), dichromate or hypochlorite are very effective with phase-transfer 

Quaternary salts can be used in catalytic amount in liquid-sobd phase transfer conditions. For example, solid potassium acetate reacted with benzyl chloride in acetonitrile using A -methyl-MMA -trioctylammonium chloride (Aliquat 336) as the phase transfer catalyst (PTC) (Eq. 9.10) [38]. 

As is wdl known, the solubility of apolar guest compounds in water is (in general) increased when they forms indusion complexes with CyD. Thus, CyDs are potent phase-transfer catalysts [29]. Applications to organometallic catalysis are especially attractive from practical viewpoints [30]. As shown in Fig. 4.5, CyDs form inclusion complexes with hydrophobic substrates (S) at the Uquid/liquid interface and transfer them into the aqueous phase where they contact the water-soluble organometallic catalyst. After the reaction, the product (P) is released in the organic phase and the transfer cycle can go on. 

Reactivity of Included Guest , in Comprehensive Supramolecular Chemistry Vol 3, Ed by Szejtli, J. and OsA, T., Chapter 11, Pergamon (1996). 

28 Eor example, Komiyama, M. Shigekawa, H. in Comprehensive Supramolecular Chemistry, Vol. 3, Ed by SzEjTLi, J. OsA, T. Chap. 11, Elsevier Science (1996). 

30 CyDs were previously used for phase-transfer catalysis by metal ions (a) Harada, a. Hu, Y. Takahashi, S. Chem. Lett., 1986, 2083. (b) Hu, Y. Uno, M. Harada, A. Takahashi, S. Chem. Lett., 1990, 797. 

36 PiNEL, C. Gendeeau-Diaz, N. Beeheeet, a. Lemaiee, M./. Mol. Catal. A. Chem., 1996, 112, L157. 

In a later publication,[51] Heck reactions (between iodobenzene and styrene) were performed in the same way. In contrast to the PTC, the catalyst for the Heck reaction 

The retentions of the catalysts were also measured on a synthetic reaction mixture. The Heck-catalyst showed a retention of 96% while under experimental conditions retentions lower than 90% were obtained. For the PTC the values are both higher than 99%. The authors assume that this big difference for the Heck-catalyst is caused by the formation of smaller Pd species in the catalytic cycle. However, no precipitation or Pd-black formation was observed. 

There are many possible green advantages in using PTC. These include  

As a cautionary note PTC should not be considered a panacea for all of the problems associated with green chemistry. Two-phase reactions involving water are often difficult to deal with industrially, particularly if the water is contaminated with trace amounts of hazardous organic substances. In some cases it may be more practical, cost effective and environmentally prudent to avoid production of aqueous waste in favour of a recyclable less benign solvent. 

The reactions between two substances which exist in two mutually insoluble 

The phase transfer catalysis not only promotes the reactions between the reagents which are mutually insoluble in immiscible phases, but also offers a number of process advantages such as, increase in rate of reactions, increase in product specificity, lowering of energy requirement, use of inexpensive solvents and catalysts, extraction of cations or even neutral molecules from one phase to another etc. 

Onium salts, crown ethers, alkali metal salts or similar chelated salts, quaternary ammonium and phosphonium are some of the salts which have been widely used as phase transfer catalysts (PTC). The choice of phase transfer catalysts depends on a number of process factors, such as reaction system, solvent, temperature, removal and recovery of catalyst, base strength etc. 

The problem of bringing together two substances of markedly different polarities is one which has been a continual challenge to chemists. The traditional solution has been the use of dipolar aprotic solvents, such as dimethylsulfoxide or iV,iV-dimethylformamide, in which both covalent and ionic substances are soluble. These solvents, however, are expensive, toxic, and their low volatilities can make product purification tricky. Environmental pressure means that many of the better organic solvents are becoming unacceptable, and industry is being forced to look for cleaner alternative technologies. 

Since the discovery of phase transfer type phenomena in the late 1960s by workers such as Starks [2], Brandstrom [3], and Makosza [4], there has been a flood of papers and patents [5], and several books [6]. This chapter will briefly outline the concepts and applications of phase transfer catalysis, and will highlight a few of the more interesting recent advances in the subject. This can only be a distillation of the thousands of publications already produced on the subject, and the interested reader should note that there are already several excellent reviews of the subject [6, 7, 8]. 

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The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

Aryl sulfides are prepared by the reaction of aryl halides with thiols and thiophenol in DMSO[675,676] or by the use of phase-transfer catalysis[677]. The alkenyl sulfide 803 is obtained by the reaction of lithium phenyl sulfide (802) with an alkenyl bromide[678]. 

NaH must be used when the starting thiazolones are not easily enolized (453, 467). Phase-transfer catalysis could be helpful for this t pe of reactivity. 

More recently, the use of phase-transfer catalysis to promote the deproto-deuteration of thiazole and various alkylthiazoles enabled Spil-lane and Dou (435) to increase considerably the rate of H/D exchange and afforded the possibility of labeling alkylthiazoles in preparative quantities and at positions otherwise difficult to label. 

Sulfides (172) in which Rj = alkyl can be obtained also by direct alkylation of the 2-mercaptothiazoles either in alcaline medium (156, 597) or by phase-transfer catalysis in better yield (824). 

This property of quaternary ammonium salts is used to advantage m an experi mental technique known as phase transfer catalysis Imagine that you wish to carry out the reaction... 

Phase transfer catalysis is the subject of an article in the April 1978 issue of the Journal of Chemical Educa tion (pp 235-238) This arti cle includes examples of a variety of reactions carried out under phase transfer conditions... 

Phase transfer catalysis succeeds for two reasons First it provides a mechanism for introducing an anion into the medium that contains the reactive substrate More important the anion is introduced m a weakly solvated highly reactive state You ve already seen phase transfer catalysis m another form m Section 16 4 where the metal complexmg properties of crown ethers were described Crown ethers permit metal salts to dissolve m nonpolar solvents by surrounding the cation with a lipophilic cloak leav mg the anion free to react without the encumbrance of strong solvation forces... 

Quaternary ammonium salts compounds of the type R4N" X find application m a technique called phase transfer catalysis A small amount of a quaternary ammonium salt promotes the transfer of an anion from aqueous solution where it is highly solvated to an organic solvent where it is much less solvated and much more reactive... 

Phase separation Phase structure Phase-transfer agents Phase-transfer catalysis... 

Phase Transfer Catalysis in Industry, PTC Interface, Inc., Marietta, Ga. 

C. M. Starks and C. Liotta, Phase Transfer Catalysis, Academic Press, Inc., New York, 1978. 

A method for the polymerization of polysulfones in nondipolar aprotic solvents has been developed and reported (9,10). The method reUes on phase-transfer catalysis. Polysulfone is made in chlorobenzene as solvent with (2.2.2)cryptand as catalyst (9). Less reactive crown ethers require dichlorobenzene as solvent (10). High molecular weight polyphenylsulfone can also be made by this route in dichlorobenzene however, only low molecular weight PES is achievable by this method. Cross-linked polystyrene-bound (2.2.2)cryptand is found to be effective in these polymerizations which allow simple recovery and reuse of the catalyst. 

C. Starks, Ind. Appl. Surfactants IZ, 77, 165 (1990) C. Starks, ed., Phase-Transfer Catalysis Neir Chemisty, Catalysts and Applications American Chemical Society, Washington, D.C., 1987 E. Dehmlov, Phase-Transfer Catalysis Vedag Chemie, Deerfield Beach, Fla., 1983 M. Halpem, Phase-Transfer Catalysis in Climan s Tnyclopedia of Industrial Chemisty Vol. A19, VCH V6, New York, 1991 M. Halpem, Phase-Transfer Catalysis Commun. 1, 1 (1995). Specialty Sufactants Worldwide in Specialty Chemicals SRI International, Menlo Park, Calif., 1989, pp. 81—94. 

The reaction of thiophosgene with various bisphenols using phase-transfer catalysis gives polythiocarbonates (44) ... 

Industrial examples of phase-transfer catalysis are numerous and growing rapidly they include polymerisa tion, substitution, condensation, and oxidation reactions. The processing advantages, besides the acceleration of the reaction, include mild reaction conditions, relatively simple process flow diagrams, and flexibiHty in the choice of solvents. 

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