George W. Gokel The Pennsylvania State University University Park. 16802 and William P. Weber University of Southern California Los Angeles. 90007
Phase Transfer Catalysis Part I: General Principles
If one assumes that a crucial difficultyin certain reactions that proceed by a bimolecular mechanism is that the nucleophilic reactant is salt-like and water-soluble while the electrophilic substrate is organic and water-insoluble, the obvious solution i s . . . For most reactions which proceed by a bimolecular mechanism, the transformation occurs only when the reactants are in the same phase and proximate to one another. There are certainly examples of successful heterogeneous reactions, hut these generally depend on some slight soluhility of one reactant in the other or of hoth in a mutualcosolvent. For example, phenylacetonitrile can he hydrolyzed by heating a heterogeneous mixture of it and 10% aqueous sodium hydroxide solution toeether for two hours ( I ) . As the hvdrolvsis . . occurs, ammonia is released and the phenylacetic acid salt dissolves in the aqueous phase. The success of this reaction depends on the slight hut significant soluhility of phenylacetonitrile in the basic aqueous phase. The observation that 1-chlorooctane can he heated for days with a concentrated aqueous solution of sodium cvanide to no avail is an example of the failure of a heterogenkous reaction (2).
-
Ph-CH2-CN
H20 + NaOH +Ph-CHz-COz-
+ NH3t
(1)
Organic chemists have sought a solution to the mutual insolubility problem for many years. A number of approaches have been tried and several have proved successful. For example, if one assumes that the crucial difficulty in such reactions is that the nucleo~hilicreactant is salt-like and water-soluble while the electrophilic substrate is organic and water-insoluble, the obvious solution is to add a cosolvent which will dissolve hoth the salt and the organic. A solvent which is hoth water-like and organic-like is ethyl alcohol. The hydroxyl group confers polarity (hydrophilicity)' on the molecule and also allows it to participate in hydrogen hooding (3).The organic portion of the molecule (the ethyl group) confers upon it organic soluhility (lipophilicity).' It seems clear that addition of a small amount of ethanol to a mixture of aqueous sodium cvanide and 1-chlorooctane might afford just enough mutual s&bility for the reaction toproceed successfully.
In recent years, a great deal has heen learned about a group of compounds known as dipolar aprotic solvents (4). These materials do not depend on the presence of a hydroxyl group to achieve hydmphilicity. Their polarity derives from the presence of such functional groups as nitro, amide, or sulfoxide. Prohahly the three most commonly used dipolar aprotic I Hydrophilic and hydrophobic ("water-loving"and "water-fearing," respectively) are used to characterize the relative affinity of a substance for an aqueous or water like environment. Lipophilie and lipophobie (lipid or hydrocarbon-loving and fearing) describe the relative affinity of a substance for a nonpolar or hydrocarbon-like environment. Although it might appear that a molecule which is lipaphilic is also hydrophobic, this is not necessarily the case. The authors prefer to use the word which describes an affinityrather than a repulsive interaction.
350 / Journal of Chemical Education
solvents are acetonitrile, dimethyl formamide (DMF), and dimethylsulfoxide (DMSO). These substances all have lipuphilic methyl groups and polar functional groups so that they dissolve in water and such organic media as hydrocarbons, alcohols, and chlorocarhons. Because the dipolar aprotic solvents do not contain hydroxyl groups, they do not hydrogen bond (and thereby solvate) anions. As a result, many anions react with substrates a t rates considerably greater than observed in aqueous or alcoholic solutions (4). In a sense, this is an added advantage of dipolar aprotic solvents, above and beyond the simple question of soluhility. One might imagine that the dipolar aprotics resolved the mutual solubility problem. Unfortunately, dipolar aprotic solvents have certain disadvantages as well as advantages. In general, the dipolar aprotic solvent,^ are high boiling and quite difficult to remove from a reaction mixture after the reaction is complete. In addition, it is often bothersome and time consuming to purify these materials. Finally, they tend to he substantially more expensive than the more commonly encountered alcoholic, hydrocarbon and chlorocarhon solvents. Although the latter consideration may not he significant on a typical laboratory scale, from the industrial point of view, it can he of enormous consequence. The Phase Transfer Technique In the late sixties, the phase transfer technique appeared as a new method for overcoming problems of mutual solubility
This paper is the fourth in a series of Resource Papers, intended primarily for college and university teachers. The publication of this series is supported in part by a grant from the Research Corporation. Part I1 will appear in the July issue. George W. Gokol obtained the R.S. (19fiR)in Chemistry at Tulane University and the Ph.l), at the University of Southern California in 1971. After postdoctoral work at UC1.A and a brief stay at DuPont's Central Flewarch Department, he went to the Pennsylvania State University in the fall of 1974 where he is involved in crown ether chemistry, phase transfer catalysis and the chemistry of sulfones. William P. Weber received his BS from the University of Chicago in 1963 and his PhD from Harvard University in 1968. He spent a year at Dow Chemical r Company and then joined the faculty of the University of Southern Californiac where he has carried on work particularly in the areasof pyrolysis and phase transfer catalysis. He received the University of Southern California Associates Award for Excellence in Teaching in 1971.
For a substance to function as a phase transfer catalyst means that it must be lipophilic and either a charge-diffuse or buried-charge cation capable o f pairing with an anion.
as well as offering the potential for activation of anions (5). The catalytic nature of this technique also presented the promise of substantial cost savings over more traditional approaches. The rudiments of the phase transfer techniaue are orohahlv best understood hy consideration of a specific example. It was noted ahove that I -chlorooctane is inert to heating with concentrated aqueous sodium cyanide solution (2,6). It was found that if. instead of the insoluble salt sodium cyanide, an organic curred rapidly and in good yield. Because the cyanide ion is paired with a large organic soluble (lipophilic) cation, the salt dissolves readily in nonpolar organic solvents in which the l-chlorooctane suhstrate is also soluble. The result is that reaction (3) is successful.
-
n-CsH,,CI + ( C I H ~ ) ~ N + C Nn-CaH17CN + (C1Hy)rNfC1- (3) The key feature of this approach is the use of the quaternary ammonium cation (sometimes abbreviated Q+ or "quat") to nnduce s~luhilizdtimof the ryilnidr anim. Ir unuld oh\.iously IIC derird,lr 1%)d r v r l w a mrthod for a c h i e v ~ wrh:s result which did not require stoichiometric amountof the quaternary ammonium salt, hut rather was catalytic in the quat. Notice that the hy-product of reaction (3) is tetrahutylammonium chloride. All that is required to convert this quaternary ammonium chloride into the corresponding quaternary ammonium cyanide is an exchange of anion with an external source of cyanide ion, preferably present in excess. A total scheme for the catalytic conversion of 1-chlorooctane into I-cyanooctane was first given by Starks and is shown below
a
(2)
+ -QtCN- + R-CI QtCN-
+ NatCI-
-
R-CN
= NatCN-
an anion. Quaternary ammonium salts such as tetrahutvlammonium~chloride'provide a source of a singly charged lipophilic cation. I t should he noted, however, that not all quaternary ammonium cations serve effectively as phase transfer catalysts (10). Tetramethylammonium cation is not lipophilic en&h to afford a significant reaction rate in nucleophilic two-phase systems. In practice, the most commonly used quaternary ammonium salts are tetrahutylammonium hisulfate (bromide or iodide), trioctylmethylammonium chloride (sold under the trade names Aliquat 336 and Adogen 464V and henzyltriethylammonium chloride. Tetrahutylammonium iodide and hisulfate offer the advantaee that thev muy twdrtained in a high atateof purify. Henzyltrierhglamrnuniun, rhlc,ride IHTF:.\(' > perchlorate > iodide >> nitrate > bromide > choride > acetate (5b, 31). It seems obvious from this scale that hydroxide (37.38) low . . . and fluoride should eniov . -prohibitively solubilities. Recent work has shown that the solubility of hydroxide ion is indeed low in most nonpolar media and Makosza has suggested that a number of reactions commonly referred to as phase transfer catalysis (PTC) should, in fact, he referred to as catalytic two-phase (CTP) (39, 40). The important distinctionderives from the lack of hydroxide ion's organic phase solubility. Makosza has suggested that reactions involving hydroxide prohahly occur G t h e interface rather than in the hulk organic phase. An example is the alkylation of phenylacetonitrile (40). Rather than forming Q+OH- which diffuses into the organic phase and there deprotonates phenylacetonitrile, it seems more likely that the nitrile is deprotonated a t the interface, ion pairs with Q+ and the quaternary ammonium cation/carhanion pair dissolves in the organic phase where further reactions of this species occur. Makosza's stereochemical data (40) and Dehmlow's extraction data make this catalytic two-phase suggestion quite plausible indeed (37). The quat cation which is present in the organic phase will ion-nair. and therehv soluhilize. the softest anion availahle to it: In the discussion ahove, the carbanion generated by interfacial deprotonation is a much softer anion than is hydroxide, and it is this ion pair which is freely soluhle in the oreanic phase. In considerinz which sorts of transformations . are possible under phase transfer catalytic conditions, one must consider all of the anions which will be availahle to the cation a t various stages of reaction. If one desired to displace iodide by chloride, a difficulty commonly referred to as "catalyst poisoning" would he encountered (41 ). As soon as iodide was disdaced from the substrate by chloride, the quat would pair with the soft iodide rather than the hard chloride ion. The onlv nucleophile availahle in the organic solution would he iodcde and a r ~ o n productive halozen-exchanze reaction would occur rather than the desired reaction. There arr a nurntwr o l < w m p l en~i this h hen omen on available in the litcraturr and n knowli,dge of this problem should facilitate the appropriate choice of nucleophile and leaving group when planning a phase transfer synthesis. Solvents
The two factors, then, which contribute to the rate enhancements observed in phase transfer catalytic processes are ion pair separation and lack of aqueous solvation. There should he an additional comment offered on the latter point, however. In liquid-liquid phase transfer processes, some water (a few molecules per ion) has invariably been found to accompany phase-transferred ions when appropriate analyses were conducted (2, 6, 10, 32, 33). For the solid-liquid phase transfer reactions, no such analyses have been reported, although the effect of water on certain reactions has been mentioned (34, 35). Freedman has found that a small amount of water aids in the crown assisted dissolution of potassium permanganate in benzene. The addition of water retards a number of phase transfer reactions and in a t least one case, the transformation seems indifferent.to its presence in small amounts (34). Ion Solubilities It will prohahly seem obvious to the reader that the most lipophilic quaternary ammonium cations are more soluble in organic media and more useful as phase transfer catalysts than are the less lipophilic ammonium compounds. I.ikewise, it stands to reason that those anions which are more c h a w diffuse (softer in the hard-soft acid-base theory of Pearson) (36) will be more soluble in nonpolar media than those which
In liauid-liauid phase transfer catalvsis, one of the phases is almoit invariably water. The organic phase may b e the liquid electrophile itself or it may he a hydrocarbon, chlorocarbon, or chloroa~omatic.~ The most commonly used solvent for solid-liquid phase transfer processes has been acetonitrile . . (42), although many other sdvents including the general classes above have been utilized. The choice of solvent depends on the kind of reaction, the anion involved, the desired temperature, and the rather empirical parameter: success. Ethvl acetate has been utilized as solvent in reactions involving hypochlorite ion, principally because the best yields were realized in this solvent. Dimethvlsulfoxide has been used as a solvent for superoxide ion reactions although it is not inert IAC,
I?",.
Literature Cited (1) Cann1zulru.S.. Ann., 36.247 (1865). 121 SUlrka.C. M.. J. A m w Chem Suc.. 93. I95 (1971).
~~~~.~~~~
:j n i r h l o r o m d h a n ~ h a s heen used moat often desnite the fact that ~~~-~~ in liquid.liquidphase transferreactionsit will undergo nucleophilic substitution with surprising ease ( 4 4 , 4 5 ) . Chloroform has also been used but is readily depmtonated under basic phase transfer conditions (40). ~~
~
~
~~~~
~~~~~
~~~~~~
Volume 55. Number 6, June 1978 / 353
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354 1 Journal of Chemical Education
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