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10Phase Transfer Catalysis: Fundamentalsand Selected Systems

JING-JER JWO National Cheng Kung University, Tainan, Taiwan, Republic ofChina

I. INTRODUCTION

Heterogeneous chemical reactions between two reacting species located in immisciblephases are often inhibited due to the encounter problem. Conventional techniques tocircumvent this mutual insolubility problem rely on the use of rapid agitation and theuse of cosolvent, which exhibits both lipophilic and hydrophilic properties. If the reactiontakes place at the phase boundary, it is expected that the rapid agitation may have anaccelerating effect by increasing the interfacial contact. The addition of cosolvent mayeliminate the phase separation and provide a homogeneous mixing state for the reaction totake place. The cosolvents commonly used are the protic solvents such as methanol andethanol, and dipolar aprotic solvents such as acetonitrile, dimethyl formamide, anddimethyl sulfoxide. Although these cosolvents might resolve the mutual insolubility pro-blem, they render certain disadvantages such as the problem of promoting competinghydrolysis pathways and the difficulties in their purification and removal. A plausibletechnique now widely known as ‘‘phase transfer catalysis’’ (PTC) developed for overcom-ing the encounter problem due to the mutual insolubility of solvents appeared in the late1960s. In a PTC reaction, an added phase transfer catalyst is capable of transferring one ofthe reactants from its normal phase into a different phase where it can normally encounterand react under an activated state with the second reactant.

PTC, preceeded by some early reports [1–3], has emerged since 1971 as a versatiletechnique and become a very fascinating field of chemistry. Undoubtedly, it is worthy tocredit and compliment Starks [4,5], Makosza [6], and Brandstrom [7] for laying the foun-dations of PTC. The term ‘‘phase transfer catalysis’’ coined by Starks has been widelyaccepted and generally used. Other descriptive terms include ‘‘ion extraction,’’ ‘‘extractivealkylation,’’ and ‘‘catalytic two-phase reactions,’’ etc. PTC has attracted tremendousattention since 1965 and been applied to hundreds of reactions. The catalytic methodologyoffers many significant advantages over conventional methods, e.g., (1) acceleration of therate under mild reaction conditions, (2) use of inexpensive, recoverable, and nontoxicsolvents, (3) use of solvent-free reaction condition, (4) use of inexpensive and commerciallyavailable catalysts, (5) use of inexpensive inorganic bases for anion generation, (6)improvement of yield and enantioselectivity of products, and (7) use of continuous opera-tions for large-scale industrial applications. Based on the physical states of the phases,

Copyright © 2003 by Taylor & Francis Group, LLC

systems of PTC generally include liquid/liquid, liquid/solid, liquid/liquid/liquid, and gas/liquid. Although an overwhelming majority of publications and paterns in PTC deal withthe transfer of reactant anions from an aqueous or solid phase into an organic phase, theconcept of PTC is broader. It extends to the transfer of cations, neutral molecules, and freeradicals and includes reactions occurring exclusively or primarily at the interface. Ingeneral, PTC is an efficient methodology for the synthesis of a variety of compounds,such as haloalkanes, alkenes, aliphatic nitro compounds, nitriles, azides, sulfides, organo-metallic compounds, pharmaceuticals, amino acids, epoxides, peptides, pesticides, andpolmers. It has found widespread applications not only in research laboratories but alsoin numerous industrial processes.

In this chapter, an overview of the fundamentals, specific features, and selectedsystems of PTC is presented. An attempt is made to describe the basic concepts of PTCas clearly as possible and to confine its attention to those features of PTC that seem to beimportant for those who are interested in gaining a general knowledge of this attractivemethodology. It is hoped that those embarking on research in PTC may find this chapter auseful initial guide. Undoubtedly, they are required to read more comprehensive reviews,series chapters, and books [8–19] for advanced study in the field of PTC.

II. FUNDAMENTALS

A. Thermodynamic Aspects

1. Intermolecular Forces

The electrical properties of particles (molecules, atoms, or ions) play a key role in manyproperties of matter. The electrostatic attraction between opposite charges results in bond-ing (intramolecular) forces and intermolecular forces. Bonding forces (ionic, covalent, andmetallic bonds) are relatively strong because they involve larger charges that are closertogether. In contrast, intermolecular forces are generally weak because they typicallyinvolve partial charges that are farther apart. The types of intermolecular forces generallyconsidered in the molecular interactions are described briefly as follows.

(a) Ion–Dipole Forces. These forces arise from the attraction between an ion and apolar molecule (dipole) and are important in solutions of ionic compounds in polar sol-vents, e.g., the hydrated Me4N

þðaqÞ and Cl�ðaqÞ ions for Me4NþCl� in water. The

potential energy of an ion–dipole attraction is expressed as Eion-dipole ¼ �Z�=a"r2 whereZ is the absolute value of the charge on the ion, � is the dipole moment of the dipole, ris the distance between the ion and the dipole, a ¼ 4�"0, "0 is the vacuum permittivity,and " is the dielectric constant.

(b) Dipole-Dipole Forces. These forces arise from the interaction between the partialcharges of molecular dipoles. The interacted dipoles tend to orient themselves to maxi-mize the attraction between them. These forces are important in solutions of polar com-pounds in polar solvents, e.g., CH3Br in CH3CN. In a fluid of freely rotating polarmolecules, the interaction between dipoles average to zero. In fact, the molecules do notrotate freely even in a gas and there is a nonzero average interaction between polarmolecules. The average energy of interaction of two rotating dipoles is expressed asEdipole-dipole ¼ �2�2

1�22=ð3a2"2kTr6).

(c) Ion-Induced Dipole Forces. An uncharged nonpolar molecule can have a dipolemoment induced by the electric field of a nearby ion. The polarization of the nonpolarmolecule depends on its inherent polarizability (softness), �. The attractive interaction


between an ion and the induced dipole is important in solutions of ionic compounds innonpolar solvents, e.g., Bu4N

þBr� in benzene. The energy of interaction of an ion andan induced dipole is expressed as Eion-induced dipole ¼ �Z2�=ð2a"r4Þ:(d) Dipole-Induced Dipole Forces. A dipole can induce another dipole in a nearbynonpolar molecule, which results in an attractive interaction between them. These forcesare important in solutions of polar compounds in nonpolar solvents or vice versa, e.g.,CH3Br in toluene. The energy of interaction between a dipole and an induced dipolecan be expressed as Edipole-induced dipole ¼ �4�2�=ða2"2r6Þ:(e) Dispersion (London) Forces. Even in nonpolar molecules, instantaneous dipoleswill arise due to the momentary imbalance in electron distribution, which are capableof inducing dipoles in adjacent nonpolar molecules. The electrons in two or more ofthese nonpolar molecules tend to synchronize their movements at least partially to mini-mize electron–electron repulsion and to maximize electron–nucleus attraction. Theseinstantaneous dipole-induced dipole interaction are sometimes referred to as dispersion(London) forces and are responsible for the formation of condensed phases of nonpolarcompounds. These forces are important for solutions of nonpolar compounds in nonpo-lar solvents, e.g., benzene in toluene. The energy of such interactions may be expressedas Edispersion ¼ �ð2�1�2I1I2Þ=½3a2"2ðI1 þ I2Þ�, where I1 and I2 are the ionization energiesof the two nonpolar molecules.

(f) Hydrogen Bond. A hydrogen bond is an attractive interaction between moleculesthat have an H atom bound to a small, highly electronegative atom with lone electronpairs such as N, O, and F. If hydrogen bonding is present, it generally dominates theother intermolecular interactions with the exception of ion–dipole interactions.Hydrogen bonding is a primary factor in the ability of water to dissolve numerous O-and N-containing organic and biological compounds such as alcohols, amines, sugars,and amino acids.

2. Solubility

The intermolecular forces play an important role in determining the solubility of a solutedissolved in a solvent. The old rule of thumb ‘‘like dissolves like’’ usually provides a goodqualitative means to predict solubility. The energetics of solutions can be summarized asfollows. Keep in mind that there will usually be an entropy-driving force favoring theformation of solution. The solute–solute, solvent–solvent, and solute–solvent interactionsmust be considered in qualitative estimation of the enthalpy effect, i.e., the enthalpyof solution (�HsolutionÞ can be expressed as �Hsolution ¼ �Hsolute-solvent ��Hsolute-solute��Hsolvent-solvent, where the enthalpies may result from the various intermolecular forces.Solutions of nonpolar solutes in nonpolar solvents represent the simplest type of solution.The forces involved are all dispersion forces. If �Hsolution ¼ 0, the only driving force is theentropy of solution and an ideal solution is likely to form. At the other extreme fromthe ideal solutions of nonpolar compounds in nonpolar solvents are solutions of ioniccompounds in water. The enthalpy of solution may be expressed as�Hsolution ¼ �Hsolvation �U, where �Hsolvation is the total enthalpy of solvation and Uis the lattice energy of the ionic compound, respectively. The ion–ion bonding force in thelattice is inherently stronger than the ion–dipole forces between the ion and the polarsolvent molecules, but there are several of the latter interactions for each ion. As a result,�Hsolution may be either positive or negative or even close to zero. When �Hsolution isnegative, the free energy of solution ð�GsolutionÞ, �Gsolution ¼ �Hsolution � T�Ssolution, will


be especially favorable since both �Hsolution and the entropy of the solution (�SsolutionÞreinforce each other.

On the other hand, a compensation effect is exhibited when both �Hsolution and�Ssolution are positive. When �Hsolution has a small positive value, the mixing tendencyof entropy may force the solution to do work to pull the ions apart at the expense ofinternal energy, and the solution cools. If �Hsolution is sufficiently positive, such that theentropy factor is unable to overcome this, then the ionic compound will be insoluble. Thelattice energy of an ionic compound is inversely proportional to the sum of the ionic radii(i.e., rþ þ r�) whereas �Hsolution is the sum of enthalpies of solvation of the cation andanion, which are inversely proportional to the individual ionic radius (i.e., rþ or r� alone).For the dissolution of ionic compounds in water, the lattice energy is generally favoredrelative to the enthalpy of the solution when rþ ¼ r� and the reverse is true for r� � rþ orrþ � r�. For example, LiF is the least soluble lithium halide and the least soluble alkalifluoride in water, and CsI is the least soluble cesium halide and the least soluble alkaliiodide in water. In contrast, CsF and LiI are the most soluble salts in the series. A verypractical consequence of this argument is that the isolation of large complex ions likeR4N

þ is facilitated by isolating them as salts of equally large counterions. The solvationenergies of ionic compounds in nonpolar solvents are limited to those from the weak ion-induced dipole forces that are generally not large enough to overcome the very strong ion–ion forces of the lattice. Therefore, ionic compounds generally have limited solubility innonpolar solvents. The insolubility of nonpolar solutes in some polar solvents like watermight be rationalized by saying that the solute would willingly dissolve in water but thewater molecules would rather tie themselves together.

3. Surface Chemistry [20,21]

A molecule in the interior of a liquid interacts equally in all directions with its neighbors.Molecules at the surface of a liquid that is in contact with its vapor experience an unba-lanced intermolecular force normal to the surface, which results in a net inward attractionon the surface molecules. Subsequently, drops of liquids tend to minimize their surfacearea and to form an ideal spherical shape in the absence of other forces. Similarly, a liquidthat is suspended in another immiscible liquid so as to eliminate the effects of gravity alsotends to become spherical. Work must be done in creating a new surface. A fundamentalrelation of surface chemistry is shown in Eq. (1):

� ¼ �G=�Að ÞT;P;n¼ GS ð1Þ

where A is the surface area, � is the surface tension, and GS is the surface free energy perunit area with the unit of J=m2 or N/m. The surface tension of a liquid generally decreaseswith increased temperature due to the increased kinetic energy of molecules partially toovercome the attractions between molecules. The values of � at 293 K are (72.75, 21.69,28.88, 26.77, and 476Þ � 10�3 N/m for water, octane, benzene, CCl4, and mercury, respec-tively, and they are (51.68, 35.00, 45.0, and 37:5Þ � 10�3 N/m for the two-phaseH2O=C8H18, H2O=C6H6, H2O=CCl4, and H2O/Hg systems, respectively [22]. The workof cohesion is the reversible work per unit area required to separate a column of liquid andcreate two new equilibrium surfaces, which are beyond the range of their forces of inter-action. For a liquid X in contact with its vapor (V), the work of cohesion of X isWXX ¼ 2�XV. The work of adhesion per unit area between two different immiscible liquidsX and Y may then be expressed as WXY ¼ �XV þ �YV � �XY. A liquid will wet another


substance (liquid or solid), if its own work of cohesion is less than that of adhesionbetween it and the substrate.

A curious example is that of the distribution of benzene in water; benzene willinitially spread on water, then as the water becomes saturated with benzene, it willround up into lenses. Virtually all of the thermodynamics of a system will be affectedby the presence of the surface. A system containing a surface may be considered as beingmade up of three parts: two bulk phases and the interface separating them. Any extensivethermodynamic property will be apportioned among these parts. For example, in a two-phase multicomponent system, the extra amount of an ‘‘i’’ component that can be accom-mondated in the system due to the presence of the interface (ni) may be expressed asni ¼ ni � CIiVI � CIIiVII, where ni is the total number of molecules of i in the wholesystem, VI and VII are the volumes of phases I and II, respectively, and CIi and CIIi arethe concentrations of i in phases I and II, respectively. The surface (excess) concentrationof i is defined as �i ¼ ni=A, where A is the surface area. At equilibrium, the chemicalpotential of any component is the same in each bulk phase and at the surface. The Gibbsadsorption equation, which is one of the most widely used expression in surface andcolloid science is shown in Eq. (2):

�d� ¼Xi

ni=Að Þd�i ¼Xi

�id�i at constant T ð2Þ

where �i is the chemical potential of i component. Since the absolute value of �i isextremely dependent on the choice of dividing surface, the Gibbs dividing surface isnormally chosen so that ni and, hence, �i for the solvent are equal to zero so that allother components are measured with reference to that surface, giving the relative surfaceconcentrations. For example, �i;1 is the surface concentration of i relative to the solvent 1.Consider the simplest two-component system, containing solvent 1 and solute 2. For anideal solution, the surface concentration of solute 2 relative to solvent 1 may be expressedas follows:

�2;1 ¼ �ð1=RTÞd�=dðln c2Þ ð3Þ

where c2 is the molarity of solute 2. Surface-active substances that lower the surfacetension will have positive values of �, e.g., n-aliphatic (C6–C10) alcohols in water. Incontrast, electrolytes tend to raise the surface tension of water, indicating that they arenegatively adsorbed at the air–water interface, i.e., they tend to be repelled towards thebulk of water. In general, lyophobic solutes tend to accumulate at the surface in preferenceto remaining in the bulk solvent whereas lyophilic solutes tend to be repelled away fromthe air–solvent interface and thus raising the surface tension. For two liquid phases incontact at constant T and P, the Gibbs–Duhem equation requires that

Pnid�i ¼ 0 in

each phase [21]. Therefore, if two solvents are partially miscible, then the surface excess ofsolute 3 relative to solvents 1 and 2 may be expressed as follows:

�3;12 ¼ �3 � �1 n22n31 � n21n32ð Þ � �2 n12n31 � n11n32ð Þ� �= n22n11 � n21n12ð Þ ð4Þ

where nij’s are the moles of component i in solvent j; components 1, 2, and 3 are solvent 1,solvent 2, and solute 3, respectively. If solute 3 is distributed between the mutuallyinsoluble bulk solvents 1 and 2, then �3;12 reduces to Eq. (5) [23]:

�3;12 ¼ �3 � n31�1=n11ð Þ � n32�2=n22ð Þ ð5Þ


4. Mass Transfer [24]

Mass transfer, an important phenomenon in science and engineering, refers to the motionof molecules driven by some form of potential. In a majority of industrial applications, anactivity or concentration gradient serves to drive the mass transfer between two phasesacross an interface. This is of particular importance in most separation processes andphase transfer catalyzed reactions. The flux equations are analogous to Ohm’s law andthe ratio of the chemical potential to the flux represents a resistance. Based on the stag-nant-film model, Whitman and Lewis [25,26] first proposed the two-film theory, whichstated that the overall resistance was the sum of the two individual resistances on the twosides. It was assumed in this theory that there was no resistance to transport at the actualinterface, i.e., within the distance corresponding to molecular mean free paths in the twophases on either side of the interface. This argument was equivalent to assuming that twophases were in equilibrium at the actual points of contact at the interface. Two individualmass transfer coefficients (kcI and kcII) and an overall mass transfer coefficient (kc) couldbe defined by the steady-state flux equations:

JA ¼ kcI aIb � aIið Þ ¼ kcII aIIb � aIIið Þ ¼ kc aIb � aIIbð Þ ð6Þwhere JA was the flux of solute A, aIb and aIIb were the activities of A in the bulk phases Iand II, respectively, and aIi and aIIi were the activities of A at the place of contact forphases I and II, respectively. Under the assumption of equilibrium at the interface, theactivities aIi and aIIi were equal and then the following equation could be derived:

1=kc ¼ 1=kcI þ 1=kcII ð7ÞFor practical purposes, it was convenient to express transport rates in terms of the

bulk phase concentrations employed in the stoichiometry of the process. Furthermore, inthe simple two-film theory, it was assumed that the phases were in equilibrium at theinterface, i.e., there was no diffusional resistance at the phase boundary. However, sig-nificant interfacial resistances might be affected by the interfacial turbulence caused by thediffusion of solute or by the presence of surfactants that tended to concentrate at thesurface. For the system of solid particles suspended in a liquid in an agitated vessel, therewere many factors involved in the mass transfer, such as geometry of the vessel, the natureof the baffles, the type of impeller, the speed of agitation, the liquid viscosity, the mole-cular diffusivity of solute, and the size and porosity of particle, etc. It is not surprising thatthere is no reliable general correlation of mass transfer coefficients for such systems. Masstransfer between two liquids can be promoted by dispersing or suspending one liquid inthe second liquid as small drops, which provides a large surface of contact between the twophases. Applying the film theory to the system with simultaneous diffusion and chemicalreaction near an interface at constant temperature, the approximate rate of mass transferacross the interface for a first-order irreversible reaction could be expressed byNi ¼ ðkDÞ1=2Ci, where k was the rate constant and D was the diffusion coefficient of i [27].

5. Distribution Between Phases

The distribution of the phase transfer catalyst plays a crucial role in the success of PTCprocesses. For the distribution of a species A between the aqueous and organic phases,Aorg Ð Aaq, the distribution at equilibrium is determined by the standard free energychange (�G0

r ) of this process, which equals to �G0Aaq ��G0

Aorg. The distribution of Ain the organic phase is favored by positive �G0

r . The extraction of ionic compounds intoan organic phase from the aqueous phase or their solubilization in the organic phase


involves in many PTC reactions. A comprehensive review of the subject about the stateand properties of such solutions can be found in textbooks or monographs [28–30]. Theintermolecular forces are responsible for the stability and properties of an ion pair inorganic solvent. Polar protic solvents are expected to solvate both cations and anionsand lead to a high degree of dissociation of the ion pair into free solvated ions. Polaraprotic solvents such as dimethylsulfoxide (DMSO) and dimethylformamide (DMF) willsolvate cations easily. However, since the positive end of the solvent dipole cannot beapproached easily, anions are only poorly solvated. Salts are highly solvated in polaraprotic solvents. PTC reactions are usually carried out in low polar aprotic solvent withdielectric constants ranging from 8.9 (CH2Cl2) and 4.7 (CHCl3) to 2.3 (C6H6) and 1.9(C6H14). Although typical inorganic salts are negligibly soluble in aprotic solvents, organicquaternary onium salts are often quite soluble, especially in CH2Cl2 and CHCl3, with ionpairs being the dominant species.

Solvent extraction of ionic compounds from the aqueous to organic phase is wellknown to analytical and industrial chemists. For the extraction equilibrium of QþX� salt,Qþaq þX�aq Ð ðQþX�Þorg, the stoichiometric extraction constant EQX is defined by Schilland Modin [31,32] as

EQX ¼ QþX��

org= Qþ� �

aqX�½ �aq ð8Þ

To include the effects of competing side reactions such as association or dissociationequilibria of ion pairs in the organic phase, and pH-dependent equilibria in the aqueousphase, they also define a conditional extraction constant:

E QX ¼ EQX �QX=�QðXÞ�XðQÞ� � ð9Þ

where � coefficients serve as correction factors that deviate from unity. Extraction con-stants depend not only on the solvent system but also on the presence of foreign salts andare, therefore, determined generally at constant ionic strength of the aqueous phase.Quaternary ammonium (R4N

þ) ions have wide applications in PTC reactions. There isa relationship between the size of the R4N

þ ion and the extraction constant [9,33]. It isexpected that increasing the number of carbon atom in the R group will increase thelipophilicity (or organophilicity) of the R4N

þ ion and thus raise the extraction constantEQX. Gustavii [34] observed a linear relationship between logEQX and the total number ofcarbon atoms for the extraction of R4N

þ picrate� salt in CH2Cl2. The extraction of theR4N

þ ion is strongly influenced by the counterion. Combining the results of literature,Dehmlow and Dehmlow [18] arrived at the following order of lipophilicities of anions:picrate� �MnO

�4 > ClO�4 > SCN� > I�ðClO�3 , toluenesulfonate�Þ > NO�3 > Br� >

ðCN�;BrO�3 ; PhCOO�Þ > ðNO�2 ;Cl�Þ > HSO�4 > ðHCO�3 ; OAc�Þ > ðF�;OH�Þ > SO2�

4

> CO2�3 > PO3�

4 . A similar order of lipophilicities of anions is applicable to Ph4Pþ,

Ph4Asþ, and Ph3Sþ. In the practice of PTC, it is important to consider the competitive

extractions of two or more anions in the presence of a quaternary cation. For the compe-titive extraction reaction, ðQþX�Þorg þY�aq Ð ðQþY�Þorg þX�aq, the selectivity constant[KselðY=XÞ] is defined as:

KselðY=XÞ ¼ EQY=EQX ¼ QþY��

orgX�½ �aq= QþX�

� �org

Y�½ �aq ð10Þ

Selective constants, KselðCl=XÞ, are known for various anions and organic solvents[18,19,35–37]. It should be emphasized that the effects of side processes must not beneglected. Although the conditional extraction constants and the derived selectivity con-stants might not represent true constants, they are useful guides to the understanding of


anion exchange. For the competitive exchange of the simple anions, the percentageexchange in the organic phase is quite independent of the structure of the quaternaryammonium cation. In contrast, the percentage exchange increases with increasing stericavailability of the cationic nitrogen in halide–hydrogen sulfate and halide–sulfateexchange experiments [38]. Increasing the polarity and hydrogen-bonding ability of theorganic phase would exhibit a favorable effect on the extraction of small ions from theaqueous phase, but less effect on larger anions. Therefore, a leveling effect would beobserved [35]. Numerous PTC reactions are performed in the presence of the hydroxideion. In the absence of a residual amount of protic solvents, QþOH� ion pairs are veryinsolubile in nonpolar solvents. The amount of OH� ion extracted into the organic phasedepends on the structure of the Qþ cation [39]. In IPTC reactions involving OH� ions suchas alkylation, carbene additions and insertions, and isomerization, the OH� ion competeswith the other anions for the phase transfer cation. For the competitive extraction process,(QþOH�Þorg þX�aq Ð ðQþX�Þorg þOH�aq, the selectivity constant is defined as KselðX=OHÞ¼ ½QþX��org½OH��aq=½QþOH��org½X��aq. The values of KselðX=OHÞ in PhCl/NaOH(aq) med-ium are 30, 50, 120, 950, 2� 103, 3� 103, 1� 104, 5� 104, and > 1� 105 for X� ¼ SO2�

4 ,F�, OAc�, Cl�, PhCOO�, Br�, I�, SCN�, and MnO�4 , respectively [40]. In general, thehard monovalent anions compete much more favorably than the soft monovalent anionsand the divalent anions. In the presence of alcohols (ROH) (pKa � 18), the transfer ofRO� ions other than OH� can be important in promoting the base-initiated PTC reac-tions. Two processes are considered for this system. An acidity–selectivity constant isdefined as

ð1Þ ROHaq þOH�aq Ð RO�aq þH2O

ð2Þ ðQþOH�Þorg þRO�aq Ð ðQþRO�Þorg þOH�aq

ð3Þ K selðRO=OHÞ ¼ KaKselðRO=OHÞ ð11Þ

where Ka ¼ ½RO��aq=½ROH�aq½OH��aq and KselðRO=OHÞ ¼ ½QþRO��org½OH��aq=½QþOH��org½RO��aq.

Concluding remarks deduced from the experimental results [19,40,41] are:

1. The acidity–selectivity constant increases as the organophilicity of the alcoholincreases.

2. In general, the extraction of alkoxides of the diols is more favorable than thoseof monoalcohols, due in part to the intramolecular hydrogen bonding of themonoanion of the diol.

3. The extracted alkoxide ion may be solvated by unionized alcohol molecules viathe intermolecular hydrogen bonding.

It might be expected from simple pKa considerations that alkoxides would be more basicthan hydroxides. However, it turns out that hydroxide is a stronger base than alkoxideunder PTC conditions, similar to that observed in the gas phase.

6. Equilibria Involving Ion-Pair and Ion Aggregates

In principle, in the quaternary onium cation-catalyzed PTC reaction, the reactive speciescould be the free anion, the ion pair of the onium cation and anion, their complexaggregates, or a combination of all of these species. The behavior and structure of ionpairs and higher aggregates have been studied extensively using conductometric, spectro-photometric, spectroscopic, and magnetic resonance techniques [30]. In general, at low


concentrations, solvents with dielectric constant (") greater than 40 contain mainly dis-sociated ions whereas in those with " lower than 10–15 almost no free ions exist even athigh dilution. In aprotic solvents of low polarity, self-association between ion pairs leadsto the formation of aggregates [18,19,42,43] as shown below:

Qþ þX� Ð ðQþX�Þ Ð ðQ2XþÞX� Ð QþðQX2Þ� Ð ðQþX�Þ2 Ð etc.

In principle, the quaternary onium salt can exist as free ions, ion pairs, triple ions½ðQ2X

þÞX�, QþðQX2Þ��, quadrapole [(QþX�Þ2�; or higher aggregates. Electrochemicalconductance measurements of Bu4N

þNO�3 in benzene indicated that at a concentrationof less than 10�4:5 M, the salt existed mainly in the ion-pair form whereas within the range10�4:5–10�3 M it was probably in quadrapole form. In contrast, in solvents of higherpolarity like CH3CN and CH3OH, the salt was completely ionized within the range10�3–10�2 M.

B. Kinetic Aspects

1. Rates Involved in Phase Transfer Catalyzed Reactions

In general, PTC reactions involve processes occurring in series and/or parallel. A classicexample of PTC reaction is the two-phase reaction of 1-chloro-octane and aqueoussodium cyanide catalyzed by ðC6H13Þ4NþCl�ðQþCl�Þ [4,5]: ð1-C8H17Clorg þNaþCN�aq! 1-C8H17CNorg þNaþCl�aqÞ. In this reaction, the Qþ cation transfers CN� ion fromthe aqueous phase into the organic phase, activates the transferred CN� ion for reactionwith 1-C8H17Cl in the organic phase, and then transfers the product Cl� ion from theorganic phase back to the aqueous phase to start a new catalytic cycle. At least twoimportant steps are involved in this catalytic sequence, namely, the mass transfer stepand the intrinsic reaction in the organic phase. The kinetics of both steps are closely inter-related through the mediation of catalyst and reasonably high rates of both steps arenecessary to offer good PTC reactions. The overall rate of a PTC reaction will be deter-mined by the relative rates of both steps. If the transfer rate is faster than the intrinsicreaction rate, then the overall rate is limited by the rate of intrinsic organic phase reaction(e.g., the PTC reaction of 1-chlorooctane and aqueous sodium cyanide). On the otherhand, if the intrinsic reaction rate is faster than the transfer rate, then the overall rate islimited by the rate of mass transfer (e.g., the PTC reaction of benzyl chloride and aqueoussodium cyanide). Variables that may exhibit effects on the rates of mass transfer andintrinsic reaction include agitation, structure of catalyst, nature of reactant, organic sol-vent, and temperature, etc. These variables usually do not affect both rates equally, e.g.,the rate of agitation exhibits a strong effect on the transfer step whereas it shows littleeffect on the intrinsic reaction step. To increase the overall rate of an intrinsic reactionrate-limited PTC reaction, it is necessary to vary the factors such as catalyst, organicsolvent, and temperature to increase the rate of the intrinsic reaction in the organicphase. On the other hand, to increase the overall rate of a mass transfer rate limitedPTC reaction, it is helpful to vary the factors such as agitation, catalyst, and type ofinorganic anion to increase the rate of the mass transfer step. If both rates of transferand intrinsic reaction are very fast (e.g., in the PTC reactions of permanganate oxidation),it is easy to plan the reaction conditions to obtain satisfactory rates. In fact, the mainconcern is to think how to keep the reaction under control. If both transfer and intrinsicrates are very slow, it is then required to apply all possible skills to achieve a reasonableoverall reaction rate, e.g., use of dual catalysts, one to assist the mass transfer step and the


other to accelerate the intrinsic reaction step. It is reasonable to apply the rule, ‘‘likedissolves like,’’ to the kinetics of transfer as well as the thermodynamics of solubility, inwhich the nature of molecular interactions are similar.

For an intrinsic rate-limited reaction in the organic phase, if the rate equation can beexpressed as rate ¼ kirl½catalyst�org½substrate�org, then for a given substrate the rate ofreaction depends mainly on the concentration of the active catalytic species in the organicphase and on the intrinsic rate coefficient, kirl. The distribution of catalyst in the organicphase can be determined by the extraction constant for the two-phase organic/aqueoussystem. If the transferred catalyst is in the form of a catalyst–anion pair, then it is impor-tant to take the extent of aggregation into account to obtain the effective concentration ofthe active catalytic species.

The factors that affect the intrinsic rate coefficient include the nature of catalyst andsubstrate, the solvation of reactants, the transition state formed by the substrate and theactivated reactant anion, and the temperature. If the transferred catalyst is in the form ofcatalyst-anion pair, then it is important to understand the equilibria involving ion pair andion aggregates. The reactive ion in a different state of aggregation will exhibit differentvalues of kirl.

The thermodynamic formulation derived from the transition-state theory [44,45] isapplicable to the intrinsic reaction in the organic phase. The intrinsic rate constant may beexpressed as

kirl ¼ ðkT=hÞ exp ��G0 6¼=RT� � ¼ ðkT=hÞ exp �S0 6¼=R

� �exp ��H0 6¼=RT

� � ð12Þwhere, for kirl expressed in units of mol/dm3 (concentration) and seconds (time), theappropriate standard state for �G0 6¼ (standard free energy of activation), �H06¼ (standardenthalpy of activation), and �S0 6¼ (standard entropy of activation) is 1mol=dm3. It is alsopractical to apply the Arrhenius equation to understand the intrinsic reaction in theorganic phase, in which kirl can be expressed as

kirl ¼ A exp �Ea=RTð Þ ð13Þwhere A is the frequency factor and Ea is the activation energy, if A is temperatureindependent in the temperature range studied. A useful approach to the solvent effecton the reaction rate is in terms of the extent of solvation of the reactants and activatedcomplex (transition state) [46,47]. For example, consider the homogeneous displacementreaction of a tertiary amine (R3N) with an alkyl halide (R 0X) to form a quaternaryammonium halide:

R3NþR 0X! R3N�þ R 0 X�� ! R3NR

0þX�

Since the activated complex is partially ionized, it will be more solvated than thereactants in a polar solvent like nitrobenzene. The stabilization of the transition state leadsto a decrease in the free energy of activation and will accelerate the reaction rate. On theother hand, in the displacement reaction of an alkyl halide (RX) and a free anion (Y�):

RXþY� ! Y�� R X�� ! RYþX�

there is a decrease in polarity as the activated complex is formed. A polar solvent solvatesthe transition state less than the reactants and thus will decelerate the reaction rate. InPTC reactions, strong solvation of the reactant anion (including the hydration) will reduceits nucleophilicity.


2. Kinetic Order with Respect to Catalyst

In a PTC reaction catalyzed by quaternary onium salt involving the extraction of catalyst–anion ion pair, the kinetics is complicated by the reactive form of the reactant anion in theorganic phase. From both physical and kinetic points of view, two types of ion pairs canbe considered to exist, namely, the loose or solvent separated ion pairs and the tight orcontact ion pairs. Since any form of the anion (free ion, catalyst–anion ion pair, or ionaggregates) could be the reactive species in the PTC reactions, it is worthwhile exploringthe kinetics associated with the following two limiting cases of the reactive form of theanion.

Case 1. The quaternary salt is mainly in the monomeric ion pair form, which is inequilibrium with free ions, e.g., (QþX�Þorg Ð Qþorg þX�org. If the ionization equilibriumconstant (K) is very small and [QþX��org is approximately equal to the total concentra-tion of quaternary salt [QþX��t, then Eq. (14) can be easily derived:

½X��org ¼ ½Qþ�org ¼ K QþX��tÞ1=2�� ð14Þ

It then follows that the kinetic order with respect to the catalyst is expected to be 1/2,if the free anion (X�) is the reactive species. In contrast, if the ion pair is almost completelyionized (K � 1) or the ion pair is the reactive species (K � 1), then the kinetic order withrespect to the catalyst will be unity. The values of the ionization equilibrium constants ofquaternary ammonium salts are generally less than 0.01 in organic solvents (with " ¼ 2–20)most often used in PTC reactions [48]. It is clear that these onium salts exist in theseorganic solvents as ion pairs or perhaps some higher aggregates. For the PTC displace-ment reaction of 1-bromooctane and sodium cyanide catalyzed by quaternary phospho-nium salt [49] and the PTC halide exchange reactions catalyzed by quaternary ammoniumsalts [50], first-order kinetics with respect to the quaternary salt was observed, indicatingthat a monomeric ion pair was the reactive species of the anion. These results were con-sistent with the observations that ion pairs could react actively with alkyl halides with thereactivity of the anion correlating well with the cation–anion electrostatic interactionenergy [51].

Case 2. A quadrapole ion aggregate is the dominant species present, which is in equi-librium with the monomeric ion pair, e.g., ðQþX�Þ2org Ð 2ðQþX�Þorg. If the dissociationequilibrium constant K is very small and [(QþX�Þ2�org is approximately equal to half ofthe total concentration of quaternary salt [QþX��t, then Eq. (15) can be derived:

QþX��org ¼ K=2ð Þ1=2 QþX�� 1=2

t

hð15Þ

If the monomeric ion pair is the reactive species, then the kinetic order with respect to thequaternary salt is 1/2. If both the quadrapole and the monomeric ion pair are present incomparable amounts, then the kinetic order with respect to the quaternary salt depends onthe values of K and [QþX��t as indicated by

QþX��

org¼ �ðK=4Þ þ ðK=4Þ2 þ K QþX�

� �t=2

� �� 1=2 ð16ÞIn general, the kinetic order with respect to the quaternary salt is expected to be

between 1/2 and 1 [19]. It is important to point out that many anions and ion pairs areextracted into the organic phase along with hydrated water molecules. Typically, two tofive molecules of water are transferred along with an anion or ion pair from the diluteaqueous phase [5,49,52]. In general, the larger the charge/volume ratio of the anion thelarger the hydration number, e.g., the hydration numbers of Cl�, Br�, and I� ions in the


PhCl=H2O medium are 3.4, 2.1, and 1.0, respectively [5,49]. The presence of hydratedwater molecules tends to reduce the anion activation and vary the relative nucleophilicitiesof anions. For example, in the displacement reaction of n-octylmethanesulfonate andhalides under homogeneous conditions, the order of relative nucleophilicities isCl� > Br� > I� whereas it is Br� > I� > Cl� under PTC conditions [5,49,53]. The desic-cating ‘‘salting-out’’ effect provided by the presence of inorganic salt, especially concen-trated 50% aqueous NaOH solution, reduces substantially the hydration of anions and ionpairs [9].

3. Agitation

In principle, an ion pair is required to transfer physically from at least one bulk phase orinterface into another bulk phase in a PTC reaction. Without agitation, the interfacialarea is minimal and the PTC reaction tends to be mass transfer limited and is frequentlytoo slow to be useful. Agitation leads to an increase in the interfacial area as well as thesurface excess concentration of reactive species, and will thus accelerate the mass trans-fer rate. As the efficiency of agitation is increased, the reaction rate of a mass transferlimited PTC reaction becomes faster. As the transfer rate surpasses substantially theintrinsic reaction rate, then the rate of a PTC reaction will become independent ofagitation rate as reported in the classic example of the PTC reaction of alkyl halideand sodium cyanide [49]. Every PTC reaction tends to be dominated by either thetransfer limited or the intrinsic reaction limited, or both. Since the inherent maximumrate of an organic reaction is fixed under given reaction conditions, then the efficiency ofagitation will determine whether the overall reaction will be transfer rate limited orintrinsic reaction rate limited. Factors affecting the efficiency of agitation include thestirring speed, baffles, impeller shape, and positioning, etc. Since the transfer rate issolvent dependent, different rates of agitation may be required to maintain a constantlevel of transfer rate for a given PTC reaction performed in different solvents. A PTCreaction involving the transfer of anions having a high transfer rate such as I� andMnO�4 ions needs only minimal agitation. In PTC reactions involving transfer of anionshaving medium to slow transfer rate such as Cl�, CN�, OH�, HSO�4 , and SO2�

4 ions,more efficient agitation is required. The use of ultrasound may provide an extraordina-rily efficient means of agitation.

4. Temperature

The rates of most organic reactions increase with increasing temperature as expected fromthe transition-state theory. Therefore, increased temperature is likely to be considered forPTC systems that have slow organic phase reactions. However, in PTC reactions the effectof temperature is complicated by the thermal stability of the catalyst. Quaternary ammo-nium and other onium salts usually decompose at high temperatures (120–150�C) underneutral conditions and at lower temperatures (50–70�C) in the presence of concentratedNaOH (aq). The stability of complex formation of polyether catalyst with salts decreaseswith increasing temperature and thus reduces the catalytic activity of polyethers [54].Microwave irradiation is a good method of choice for heating in a PTC reaction [55].Under microwave irradiation, in the PTC reaction of o- and p-chloronitronenzene withethanol in the presence of NaOH (aq), a 144- to 240-fold increase in the reaction rate wasobserved due to the enormous increase in the reactivity of ethoxide ion resulting from thedehydration effect of the irradiation [56].


III. METHODOLOGY

Variables in reaction design for PTC reactions are more than those for homogeneousreactions. Since any PTC reaction can be transfer rate limited, intrinsic reaction ratelimited, or a combination of both, it is conceivable that there is no simple guideline forthe design, evaluation, and optimization of PTC reaction conditions. Rates of intrinsicreaction rate limited PTC reactions can be estimated by examining similar homogeneousreactions in the literature and also taking into account the deactivation of reactant anionsby hydration. The relative mass transfer rate of most anions into the organic phase can beestimated by examining similar PTC reactions using the same or a similar anion. If pre-liminary experiments or literature data indicate that the objective PTC reaction is feasible,then one can perform this reaction further by varying the reaction variables to optimizethe reaction conditions. Halpern and Lysenko suggested a guideline for exploring a newPTC reaction, based on substrate acidity [57,58]. More comprehensive approaches existfor considering separately the optimization of reaction variables in PTC reactions under avariety of conditions [19]. Based on the physical states of phases, PTC reactions aregenerally performed in the following systems: liquid/liquid, liquid/solid, gas/liquid, andliquid/liquid/liquid systems. In this section, the choice of some reaction variables and theireffects on the main features of PTC reactions are briefly described.

A. Catalysts

Selection or development of a phase transfer catalyst often plays the most important rolein developing a new PTC system. Two main factors considered in selecting a PTC catalystare the ability to transfer one of the reactants into the normal phase of the other reactantand the ability to activate the transferred species to facilitate the chemical reaction. Inpractice, other features of PTC catalysts considered by chemists or engineers in developinga PTC process include the stability, cost and availability, toxicity, recovery, recycling, anddisposal of catalysts.

1. Types of Catalysts

(a) Organic Soluble Catalysts for Extracting Anions into Organic Phase.

Quaternary onium salts. Quaternary ammonium salts include trioctymethylammo-nium chloride (Starks’ catalyst), Aliquat 336, tricaprylmethylammonium chloride,tetrabutylammo-nium hydrogen sulfate (Brandstrom’s catalyst), and benzyltrimethylam-monium chloride (Makosza’s catalyst); quaternary ammonium salts can also be generatedin situ from trialkylamines, etc. Other quaternary onium salts include tetrabutylphospho-nium bromide, tetraphenylphosphonium bromide, triphenylbenzylphosphonium chloride,tetraphenylarsonium chloride, and triphenylsulfonium chloride, etc. Special quaternarysalts are 4-aminopyridinium salts, bis-(quaternary ammonium) ½R3N

þ-ðCH2Þn-NRþ3 ;R3N

þ-ðCH2Þn-O-ðCH2Þn-NRþ3 � salts, 4,4 0-dialkylbipyridinium salts, cluster quaternaryammonium [e.g., PðC6H4SO

�3 NRþ4 Þ3] salts, crown-quaternary salts [e.g. (18-crown-6)-

(CH2Þ9PBuþ3 Br�], and chiral N-(4-trifluoromethyl)benzylcinchonium bromide, etc.

Macrocyclic polyethers. Crown ethers and cryptands include 18-crown-6, 15-crown-5, dibenzo-18-crown-6, dicyclohexane-18-crown-6, and [2.2.2]-cryptand, etc.

Open-chain polyethers (podands). Examples are polyethylene glycols (PEGs)[R-O-ðCH2CH2OÞn-R, R ¼ alkyl group] and tris-(3,6-dioxaheptyl)amine[(CH3-O-CH2CH2-OCH2CH2Þ3N, TDA-1].


(b) Water-Soluble Catalysts for Extracting Cations into Organic Phase. Examples arealkali metal salts of a lipophilic anion such as iodide, sulfonate, long-chain carboxylate,or tetra-arylborate, especially tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate.

(c) Water-Soluble Catalysts for Extracting Organic Reactants into AqueousPhase. Examples are cyclodextrins, pyridine-1-oxide, 4-(dimethylamino)pyridine, tetra-methyl ammonium chloride, the rhodium complex of the trisodium salt of triphenylpho-sphine trisulfonic acid, and cuprous chloride.

(d) Insoluble Catalysts. Examples are:

1. Resin-bound PTC catalysts include polymer-NR3+, -PPh3

+, -SR2+, -crown

ethers, and -cryptands, etc.2. Inorganic solid-bound PTC catalysts include:

a. adsorption quaternary salts on organophilic clays such as smectite clay(hectorite), e.g., (n-C8H17Þ3NMeþ-hectorite;

b. adsorption of PhCH2NEtþ3 on SiO2, Al2O3-KF, SiO2-KF, Al2O3, C, orsand, and PEG chemically bonded to silica gel.

3. Third-liquid phase catalysts:Examples are toluene/Bu4N

þBr�=NaBr, toluene/Bu4NþBr�=NaOHðaqÞ,

Bu4NþHSO�4 =NaBr=NaOClðaqÞ, and toluene/PEG/KOH(aq), etc.

2. Quaternary Onium Salt Catalysts

Many quaternary ammonium, phosphonium, and arsonium salts are used as catalysts fortransferring anions in PTC reactions. Quaternary ammonium salts are the most frequentlyused due to their cost and availability. The criteria for selecting a quaternary onium salt asa PTC catalyst include extraction of the catalyst and reaction species into the organicphase and anion-activating ability, accessibility, and stability of the quaternary salt. Thestructural aspects and characteristics of quaternary onium salts, especially the quaternaryammonium salts are summarized as follows.

(a) Stability of Quaternary Onium Salt. Quaternary ammonium salts tend toundergo the following two main types of decomposition reactions: (1) the internal dis-placement (or dequaterization) reaction at high temperatures (100–200�C) to yield atrialkylamine and a displacement product, i.e., R4N

þY� ! R3NþRY; and (2) theHoffmann elimination reaction to yield a trialkylamine and an olefin in the presence ofa strong base, i.e., R 0CH2CH2NR3 þOH� ! R 0CH ¼ CH2 þR3NþH2O. The inter-nal displacement is usually not a serious problem at low temperatures (< 100�C).However, the presence of highly active substituents such as methyl and benzyl groupsattached to the central nitrogen atom tends to facilitate the internal displacement reac-tion. For the decomposition reaction, R 0R3NþOH� ! R3NþR 0OH, the relativereactivity of the R 0 group is allyl > benzyl > ethyl > propyl > methyl > isobutyl >phenyl [59]. Quaternary ammonium cations containing a methyl group tends to undergothe SN2 nucleophilic substitution reaction in the presence of a good nucleophile likethiophenoxide [60], e.g., MeðC8H17Þ3Nþ þ PhS� ! ðC8H17Þ3Nþ PhSMe. For the dis-placement of benzyl group from benzylpyridinium chloride in the absence of addedorganic solvent, the experimental results are somewhat surprising, which give the orderof relative reactivity of the neutral nucleophiles as Bu3N > Bu2NH > BuNH2 >HOAc > RSH � NH3 [61]. In contrast, quaternary phosphonium salts are much moreinert to internal displacement than the corresponding quaternary ammonium salts andare, therefore, more thermally stable under nonalkaline conditions. However, in the pre-


sence of a strong basic solution (NaOH) they become unstable and tend to undergodecomposition to trialkylphosphine oxide and alkane, i.e., R4P

þOH� ! R3POþRH.A comprehensive study of the stability of quaternary onium cations in the presence ofNaOH (aq) has been made by Landini et al. [62,63].

Some concluding remarks are:

1. Symmetrical tetraalkylammonium cation with longer alkyl chains tend to bemore stable e.g., ðn-C6H13Þ4Nþ > ðn-C4H9Þ4Nþ.

2. The presence of benzyl groups in quaternary ammonium cations tends to reducethe stability, e.g., ðn-C6H13Þ4Nþ > PhCH2ðn-C6H13Þ3Nþ.

3. Decomposition rates of quaternary ammonium and phosphonium cations inPhCl/NaOH(aq) medium increase dramatically with increased concentration ofNaOH(aq), due to the desiccating effect of concentrated NaOH(aq).

4. For a given quaternary ammonium or phosphonium cation in PhCl/NaOH(aq)medium, the relative order of the effect of halide ions on the decomposition rate isCl� > Br� > I�, e.g., (n-C6H13Þ4NþCl� > ðn-C6H13Þ4NþBr� > ðn-C6H13Þ4NþI� andPh4P

þCl� > Ph4PþBr� > Ph4P

þI� [64]), due to the increasing reluctance of halide ionto exchange with hydroxide ion to produce quaternary onium hydroxide in the organicphase.

5. Decomposition of a quaternary salt increases with agitation rate up to a pointand then levels off, which is consistent with the slow hydroxide transfer rate limitedprocess at low agitation rates, but slow intrinsic reaction rate limited process at highagitation rates.

(b) Extraction Ability, Anion-Activation Ability, and Accessibility of QuaternaryAmmonium Salts.

Extraction. A quaternary ammonium cation can be a successful catalyst only if ittransfers a sufficient quantity of the reactant anion from the aqueous phase into theorganic phase. In general, the ‘‘hard and soft acids and bases (HSAB)’’ empiricism [65]is applicable in considering the quaternary ammonium cation–anion–solvent interac-tions. Based on the intermolecular forces, it is expected that hard anions prefer to pairwith hard cations, and soft anions prefer to pair with soft cations [19]. The partition ofa catalyst cation–anion pair in the organic phase depends strongly on the structure ofthe quaternary ammonium cation for small anions such as Cl�, Br�, and CN�, but lessstrongly for large anions having considerable organophilicity such as picrate, MnO�4 ,and PhO�. Salts of Me4N

þX� (X ¼ F, Cl, Br, and CN, etc.) are not easily extractedinto most organic phase and are usually not good catalysts for extracting anions intothe organic phase, but may be useful for extracting cationic reactant into the aqueousphase. Tetra-alkylammonium (R4N

þ) cations with R ¼ C2H5 or C3H7 are usually poorfor extracting small anions, but may be useful for extracting organic anions, whereasthose with R ¼ n-butyl to n-decyl groups extract anions quite easily into almost allorganic phases.

Anion activation. It is generally required in PTC reactions that the reactantanion not only be transferred from the aqueous phase into the organic phase, but alsothat it is sufficiently activated for reaction with the other reactants in the organic phase.Bulky quaternary ammonium cations activate anions by increasing the distance separat-ing the cation from anion in the ion pair [e.g., Naþ Br� (r ¼ 285 nm) versusBu4N

þ Br� (r ¼ 0:628 nm)], which in turn will lower the energy of activation. Alarge bulky (‘‘soft’’) quaternary ammonium cation generally provides the required anionactivation for PTC reactions that tend to have slow intrinsic organic phase reactions. In


contrast, highly polar solvents tend to enhance the anion activation by reducing thecation–anion binding and allow less bulky or hard quaternary ammonium cations to besuccessful.

Accessibility. In contrast to PTC performed in neutral conditions in which orga-nophilic ammonium salts usually exhibit the highest activity, the base-promoted PTCreactions are effectively catalyzed by hard and even hydrophilic ammonium salts. Inparticular, the hydroxide-promoted PTC reactions were reported to have optimum reac-tivity with alkyltriethylammonium cations [17,19]. Halpern et al. [66] suggested the term‘‘accessibility’’ to rationalize the structural factor that determines the reactivity of aquaternary ammonium cation. This accessibility is important for PTC reactions whererates are limited due to slow anion transfer, e.g., those normally encountered in reac-tions with OH�, F�, OCl�, HSO�4 , and divalent anions. The accessibility of quaternaryammonium salt is especially important since hydroxide-promoted reactions account forover half of the PTC applications [19]. Quaternary ammonium cations that are rela-tively open-faced or accessible such as the hexadecyltrimethyl- or benzyltriethyl-ammo-nium cation readily occupy the interfacial positions and increase the interfacial areabetween the organic and aqueous phases via reduction of interfacial tension.Consequently, they increase the transfer rate of the anion into the organic phase [67].Benzyltriethylammonium chloride is extensively used in hydroxide-promoted alkylationPTC reactions due to the very strong tendency to lower the interfacial tension whereasthe use of hexadecyltrimethylammonium salts often leads to undesirable formation ofemulsions. Halpern suggested a quantitative parameter (q) for characterizing the accessi-bility of quaternary ammonium cations, which can be expressed as

q ¼X

1=CRið Þ ði ¼ 1; 2; 3; and 4Þ ð17Þ

where CRi is the number of carbon atoms of the alkyl group Ri, e.g. for CH3ðC8H17Þ3Nþ,q ¼ 1þ 3ð1=8Þ ¼ 1:38, and for CH3ðC4H9Þ4Nþ, q ¼ 1þ 3ð1=4Þ ¼ 1:75. Quaternaryammonium cations with q > 1 are generally considered to be accessible. Good correlationbetween q and reactivity in the PTC reaction of methylation of deoxybenzoin was obtained[19] using literature data [6,14,66]. It should be emphasized that the accessibility of aquaternary ammonium cation is not the only structural factor for determining the out-come of the transfer rate limited PTC reactions. A threshold organophilicity of the qua-ternary cation is generally required in order to form an ion pair with an anion that will besoluble to some extent in a suitable organic phase. Quaternary ammonium cations withq ¼ 1–2 are usually applicable in transfer rate limited PTC reactions. From the considera-tion of organophilicity, anion activation, and accessibility, it is not surprising that the n-Bu4Nþ cation is the most cited ammonium cation in patents as well as general PTCliterature, although it is usually not the optimal catalyst [19].

3. Uncharged Chelating Catalysts

Chelating agents such as macrocyclic polyethers (crown ethers, cryptands), open-chainpolyethers (polyethylene glycols), and acyclic cryptands have important applications inPTC reactions, attributed to their unique properties such as specific complex formationwith metal ions, the ability to solubilize and transfer ionic reagents from the aqueous orsolid phase to the organic phase, and the ability to activate the transferred anion in theorganic phase. The organic masking of the alkali metal ion provides an onium ion-likespecies that can be extracted or solubilized with the counteranion into nonpolar organic


solvents. Chelating ligands that complex Naþ and Kþ ions are particularly interestingsince sodium and potassium salts are the most frequently used salts in organic syntheses.

(a) Crown Ethers and Cryptands. The simple ‘‘lock and key’’ approach is helpful forselecting the crown ether; e.g., 18-crown-6 (cavity diameter, 0.26–0.32 nm) is more spe-cific for the Kþ ion (diameter, 0.266 nm) and 15-crown-5 (cavity diameter, 0.17–0.22nm) is more specific for the Naþ ion (diameter, 0.194 nm). However, the exact corre-spondence between cavity size and ionic diameter is not always a critical factor inorganic reactions. The solubilities of potassium salts in CH3CN are dramaticallyincreased by the presence of 18-crown-6 [68]. It is reasonable to believe that an impor-tant driving force for the increased solubilization of these salts is the organophilicity ofthe complex ion, which has a hydrophobic exterior. The solubility of a particular potas-sium salt is expected to be a complex function of the lattice energy of the salt and theorganophilicity of the crown ether. Distribution coefficients of alkali metal complexesof 18-crown-6 paired with inorganic counterions in H2O=CH2Cl2 medium were known[69]. It is misleading to describe the crown ether-mediated ‘‘anion activation’’ PTC reac-tions as the ‘‘reactions of naked anions,’’ since solvent–solute interactions are strongeven in weakly solvating or nonsolvating medium [69]. A leveling effect in nucleophilereactivity was observed in the investigation of 18-crown-6-mediated anion activation inCH3CN [70]. A total variation of less than one order of magnitude was observed in therate constants for displacements of benzyl tosylate for F�, Cl�, Br�, I�, CN�, N�3 , andOAc� ions. It should be emphasized that anion activation is suppressed substantially bythe presence of traces of water in the medium [71]. Cryptands (macrobicyclic multiden-tate ligands) are usually much superior to their macrocyclic counterparts in their abilityto complex alkali metal ions and to activate anions [72–74].

(b) Polyethylene Glycols and Acyclic Cryptands. Polyethylene glycols (PEGs), beingreferred to as a poor chemist’s crown ether, are open-chain analogs of crown ethers andare able to complex cations, to transfer anions into the organic phase, and to activatethe transferred anions. The formation constants of the Naþ–PEG complexex in anhy-drous MeOH for PEGs in the molecular weight range 200–14,000 range from 44 to12,000 [75]. It was concluded that the binding strength of complexation is a function ofthe total number of binding sites present and not the number of polymer chains, imply-ing that a long PEG chain may bind more than one cation. To obtain good partition ofa PEG into an organic phase may require the use of its mono- or di-ether derivative,since PEGs are themselves soluble in a dilute aqueous phase [76,77]. Based on the studyof the transfer of various potassium and sodium salts from the solid phase to PEG 400,Sasson and coworkers [78,79] made the following conclusions: (1) potassium salts aremore easily transferred than sodium salts; and (2) anions capable of hydrogen bondingwith the hydroxyl groups of PEG 400, such as OH�, F�, HSO�4 , and HCO�3 ions, aretransferred relatively easily from the solid phase to PEG 400. It is believed that theseanions are relatively free of hydration (‘‘naked’’) and that other anions such as Cl�,Br�, I�, and SCN� ions exist with significant hydration shell. Tris-(3,6-dioxaheptyl)-amine (TDA-1), an acyclic cryptand, is a highly effective catalyst for liquid/solid PTCreactions due to its hydrophilicity [80]. TDA-1 is an especially effective catalyst for thetransfer of sodium and potassium salts from the solid phase into the organic phase andis capable of dissolving sodium and potassium metals alloy in tetrahydrofuran (THF)to produce a deep blue solution which is useful for deoxygenation of acetates anddehalogenation reactions [81].


4. Insoluble Catalysts

Insoluble catalysts offer an important advantage of simple catalyst removal by filtration orcentrifugation after the completion of a PTC reaction. Regen [82] demonstrated thatquaternary onium cations chemically bound to insoluble resins could act as PTC catalystsand suggested the term ‘‘triphase catalysis’’ to describe the related PTC reactions.Insoluble PTC catalysts can be grouped into three categories, namely, the resin bound,the inorganic solid bound, and the third-liquid-phase catalysts as described in SectionIII.A.4(c).

(a) Resin-Bound Phase Transfer Catalysts. Tomoi and Ford [83] suggested the term‘‘polymer-supported’’ PTC to describe the PTC reactions occurring within the polymerphase. Resin-bound PTC catalysts include polymer-NRþ3 , -PPh

þ3 , -SR

þ2 , -crown ether,

-cryptand, -azacrown, -PEG, etc. In contrast to ordinary PTC reactions using solublecatalysts, PTC reactions using resin-bound catalysts require that both reactants diffuseto active PTC sites or the resin surface or to active sites inside the resin bulk phase forthe intrinsic reaction rate limited reactions. These also imply that both reactants arerequired to diffuse and penetrate the stagnant outer layer of the liquid(s) (i.e., theNernst layer) coating the resin particle as demonstrated in the reaction of 1-bromo-octane with NaCN(aq), known to have a slow intrinsic reaction rate, catalyzed by thestyrene–divinylbenzene resin-bound tributylphosphonium catalyst [84]. The resin-boundPTC catalysts generally consist of three elements, namely, the insoluble supportingcross-linked resin backbone, a spacer chain (optional), and the PTC functional group.Taking advantage of the huge amount of available ion-exchange resins, most publishedstudies on resin-bound PTC reactions use styrene–divinylbenzene resins and relatedresins.

Important factors affecting the efficiency of a resin-bound catalyst include levels ofcross-linking, ratios of chloromethylated rings to nonsubstituted ring (‘‘percent ring sub-stitution’’), and degrees of macroporosity. If percent ring substitution (RS, or PT-groupdensity) is too high, the resulting catalyst may tend to be too highly hydrophilic aroundthe active site, which inhibits the diffusion of hydrophobic organic reactants to the activesite. Resins having higher degrees of cross-linking tend to have smaller pores and are lesseasily swollen by liquids. Thus, catalyst activity decreases with increased cross-linking dueto increased resistance to reactant diffusion caused by increased tortuosity and rigidity ofthe resin. It is usually observed that catalysts with about 2% cross-linking exhibit thehighest catalyst activities whereas those with about 8–10% cross-linking exhibit bettermechanical stability.

Macroporous resins have greater internal porosity and surface area (up to 588 m2/g)than microporous or gel-type resins (0.06 m2=g), consequently allowing faster diffusionrates of reactants to active sites. For example, in the oxidation of benzyl alcohol tobenzaldehyde by NaOCl(aq) catalyzed by resin-bound catalysts, the observed effectivesurface diffusivity for the macroporous resin was 1.7-fold faster than that of the gel-type resin [85]. However, in the triphase-catalyzed reaction of 1-bromo-octane withNaCN(aq), the macroporous resin showed slightly slower rates than resin catalyst withlower porosity, which was explained by invoking that the pores in the macroporous resinwere completely filled with organic phase reactant, inhibiting the diffusion of anionicreactant to active sites, and consequently retarding the displacement rate [86]. The pre-sence of spacer chain (typically 8–20 carbon atoms) serves to separate the active sites fromthe resin backbone and from other active sites, especially the quaternary onium ions, so asto avoid the formation of ion aggregates, and to provide a reaction environment close to


that provided by soluble PTC catalysts [87]. Thus, the presence of space chains raises therates of reactions having a slow organic phase reaction, such as nucleophilic displacementreactions, by two- to four-fold [88,89]. The choice of functional group (such as quaternaryammonium and phosphonium groups, PEG chain, crown ether groupings, and cryptands,etc.) is usually very important for the feasibility of resin-bound catalysts, just as in thechoice of soluble catalysts, and is required to match the requirements of the reaction.

(b) Inorganic Solid-Bound Phase Transfer Catalysts. Two types of inorganic solid-bound PTC catalysts employed are the adsorption-type catalysts made by simpleadsorption of quaternary salts on organophilic clays, and the chemically bonded-typecatalysts made by chemical attachment of PTC functional groups to solid inorganicsupports. Adsorption of long-chain quaternary ammonium cations on particular formsof smectite clay (hectorite) is generally successful and commercially useful [90]. Using½ðn-C8H17Þ3N�þ–hectorite as the catalyst, the nucleophilic displacement of alkyl bro-mides with NaCN(aq), NaSCN(aq), Na2SðaqÞ, and NaOH(alcohols) in toluene/watermedium yields the expected nitriles, thiocyanates, sulfides, and ethers, respectively [91].Catalysts made by adsorbing PhCH2Et3N

þCl� on inorganic solid supports such asSiO2, SiO2-KF, Al2O3, Al2O3-KF, carbon, or sand were used as PTC catalysts for theN-alkylation of 2-oxazolidone [92]. Chemically bonded-type catalysts having -O-(CH2CH2OÞnR groups made by reacting a porous refractory oxide such as silica gel,containing surface hydroxyl groups, with a polyoxyalkylene oxide or monoalkyl etherof a PEG were patented [93] and shown to match the reactivity of resin-bound cata-lysts. In contrast to polymer-bound quaternary groups, the organic cations bonded tohigh surface-area silca and alumina exhibited a high affinity for hydrophilic anions suchas F�, HCO�3 , SO

2�4 , and PO3�

4 [94].

(c) Insoluble Third-Liquid-Phase Catalysts. Although insoluble solid-bound PTC cat-alysts have versatile industrial applications in PTC reactions, insoluble liquid-phase cat-alysts can be even more attractive. In an immiscible organic/aqueous two-phasemedium, it is expected that an increase in the difference between the cohesive forces(surface tension) of both phases due to changes in the compositions of solutes willdecrease their mutual miscibility and in turn change the solubilities of solutes in bothphases. If this medium effect causes a phase transfer catalyst to have limited solubilityin both the organic and aqueous phases, then this catalyst would rather exist in a third-liquid phase of its own. A well-known phenomenon called ‘‘coascervation’’ is used todescribe the formation of an additional phase (rich in surfactant) in a system when elec-trolyte is added to an aqueous solution of surfactant in large quantities. In the PTCreaction of the isomerization of allylanisole to anethol in toluene/KOH(aq) medium cat-alyzed by PEGs, Neumann and Sasson [95] observed a third liquid (PEG-KOH com-plex) phase formed, which increased the reaction rate dramatically. Nouguier andMchich [96] reported the formation of a third-liquid phase in the alkylation of pentaery-thritol in n-C7H15Br=NaOHðaqÞ medium to produce tri- and tetra-ethers.

Tetrabutylammonium salts frequently form third-liquid phases (or catalyst layers)when used in conjunction with organic solvents with low polarity such as toluene, hexane,and 1-chloro-octane, and with a concentrated aqueous solution of inorganic salts. Anexcellent example of tri-liquid-phase catalysis was demonstrated by Wang and Weng[97] in the displacement of benzyl chloride and sodium bromide in toluene/water mediumcatalyzed by Bu4N

þBr�, in which a third-liquid phase appeared under certain criticalconditions with a concomitant sharp increase in the reaction rate. Mason et al. [98]reported that Bu4N

þBr� uniquely formed a third-liquid phase in a toluene/Bu4NþBr�/


NaOH(aq) system, whereas Et4Nþ, ðC3H7Þ4Nþ, and (C6H13Þ4Nþ salts formed only two-

phase systems. Under static condition, the three liquid phases separate according to theirrelative densities, with the catalyst-rich phase being at the interface. For a stirred system,photomicroscopic observations revealed that dispersed drops of one phase were coated bya thick layer of the catalyst-rich phase, this being suspended in the continuous third phase.Through selective staining of the catalyst and organic phases, it was shown that the innerdroplets were the aqueous phase, which was coated by a catalyst-rich phase, and the wholewas dispersed in the toluene phase [98]. Correia [99] reported that the third-liquid phaseformed by Bu4N

þHSO�4 and NaOCl(aq) in the presence of NaBr consisted largely ofBu4N

þBr�3 , but also containing H2O, OCl�, Br�, Cl�, and possibly Br2, and that theaddition of cyclohexene to this system produced trans-1,2-dibromo- and (1-bromo-2-chloro)cyclohexane.

Weng and coworkers [100–103] investigated the PTC reactions of organic bromides(such as n-butyl bromide and ethyl 2-bromoisobutyrate) with sodium phenolate catalyzedby Bu4N

þBr�, focusing on the effects of solvents (such as toluene, hexane, and chloro-benzene) and inorganic salts (such as NaBr, NaOH, and Bu4N

þBr�) on the formation ofthe third-liquid phase and also focusing on the kinetics and mechanisms of these tri-liquid-phase catalyzed reactions. It was found that no third-liquid phase was formed when usingPhCl as the solvent of the organic phase. Although the tri-liquid-phase catalyzed reactionsare somewhat different from those of simple PTC reactions, the principles involved how-ever, are generally the same.

Wang and Weng [97,100] proposed that in tri-liquid-phase catalysis, both organicand inorganic reactants are transferred to the third-liquid (catalyst-rich) phase where mostof the intrinsic reactions take place. In commercial application, tri-liquid-phase catalysiswill allow organic reactions to proceed rapidly, with easy separation of the organic andaqueous phases, and the reuse of the catalyst-rich phase, as demonstrated by the tri-liquid-phase catalyzed reaction of n-butyl bromide and sodium phenolate catalyzed byBu4N

þBr� performed in a continuous-flow stirred vessel reactor [104]. Studies on model-ing mass transfer and interfacial reactions in tri-liquid-phase catalysis rationalize the mainfeatures of these systems, especially the jump in conversion on the formation of the third-liquid phase [105,106].

5. Comparisons of Catalysts

In addition to consideration of the structure–activity relationships, the criteria for select-ing a PTC catalyst usually include the following features: (1) stability, (2) cost and avail-ability, (3) removal, recovery, and recycling, (4) toxicity, and (5) waste treatment, etc. Thetetrabutylammonium cation is the most widely used quaternary ammonium cation. It iscommercially available in a wide variety of anions at moderate cost and has a uniqueapplication in tri-liquid-phase catalysis. It can also be easily separated and recovered byextraction, then recycled. Methyltributylammonium cation will become a popular catalystdue to its high reactivity in transfer rate limited PTC reactions, its lower toxicity than mostquaternary ammonium cations, and its low price. Methyltrioctylammonium cation is alsocommercially popular and is organophilic and anion activating enough to catalyze mostintrinsic reaction rate limited PTC reactions and is accessible enough to catalyze mosttransfer rate limited PTC reactions. In comparison with quaternary ammonium salts,quaternary phosphonium salts are generally more thermally stable and more activeunder neutral or acidic conditions, but less stable under alkaline conditions. Althoughthey have been used in a variety of PTC reactions, the greater cost compared to quaternary


ammonium salts limits their industrial applications. Toxic quaternary arsonium salts areused mainly for comparative processes. Tetraphenylarsonium salts are useful for PTCanalytical titration of highly organophilic unsaturated compounds [3]. The triphenylsul-fonium cation is stable under strong alkaline conditions and is effective for catalyzing thePTC displacement of 1-bromo-octane with NaCN, NaOPh, KSCN, and KI [107].

Catalyst separation or cost will usually be the main factor rather than the structure–activity relationshps for the choice of a specific PEG ether or crown ether. In contrast toquaternary onium salts, crown compounds are thermally and chemically more stable.Their application is limited mainly by the high cost and toxicity. 18-Crown-6 and itsderivatives have become available in ton quantities and in various grades of purity. Thecommercial application of crown ethers will be more feasible due to their reduced cost andtheir high reactivity. The PEGs and their capped ethers are more stable than quaternaryammonium salts and are attractive for processes using an excess of the PEGs due to theirlowest cost and least toxicity. PEG derivatives are generally included in standard screeningprograms for industrial processes, e.g., PEG 400 is always considered for hydroxide-pro-moted PTC reactions. PEGs and TDA-1 are inexpensive, thermally stable in the absenceof strong acids, usually easy to remove and recover, nontoxic, easily biodegradable, andcommercially available. Based on the yield and rate data of the displacement of chloridefrom benzyl chloride by acetate ion, so called the standard reaction for catalyst evaluation,several crown ethers, aminopolyethers, and cryptands, etc., were evaluated [108].

PTC reactions using insoluble catalysts offers the opportunities to separate easilyand recycle the catalyst, to prepare high-purity chemicals such as pharmaceuticals, and forcontinuous operations. Insoluble resin-bound catalysts are susceptible to stability pro-blems, mostly by thermal as well as mechanical degradation. Under sufficiently mildconditions, resin-bound catalysts with onium groups may be used for extended periodsor repeated cycles. Resin-bound PEGs, crown ethers, and cryptands are more chemicallystable than the corresponding onium salts. The disadvantages of resin-bound catalysts thatmust be overcome include the higher cost, the lower reactivity, and the lower capacities.Insoluble catalysts with quaternary onium cation adsorbed on hectorite are efficient,inexpensive, stable, and recyclable. The formidable task for tri-liquid-phase catalysts isto obtain third-liquid phase conditions that provide high catalytic reactivity yet do notcause significant loss of active catalyst by its being extracted into the organic and aqueousphases.

B. Counteranions and Anionic Reactants and Products

Most of the PTC reactions deal with the transfer and reactions of anions, especially thebase-promoted PTC reactions. It is apparent that factors such as the nature of the anion,the nature of the quaternary onium cation, and the effects of solvent are closely inter-related, and the combined effects of these factors should determine the outcome of a PTCreaction. Typical anionic reactants in PTC include nucleophiles, bases, and oxidants, andanionic products generally are leaving groups. In the order of lipophilicity of anions(Section II.A.5) [18], anions with higher lipophilicities will have a greater affinity forassociating with the quaternary ammonium cation, and those with lowest lipophilicitiesmay exhibit poison effects. The HSAB principle [65] is generally applicable for choosing asuitable quaternary ammonium cation to pair with an anion. The Bu4N

þ cation appears toexhibit sufficient lipophilicity and hydrophilicity and is able to perform reasonably wellwith the widest range of anions. Hydrogen sulfate ions are not only very good counter-anions for preparing many quaternary ammonium salts but also very useful for PTC


reactions, since in the strong basic solution they will be deprotonated to produce thehighly hydrophilic sulfate ions, which prefer to remain in the aqueous phase. Chlorideions are generally the second choice of counteranions to pair with quaternary ammoniumcations. If different anionic forms of quaternary ammonium salts are available, e.g.,Bu4N

þHSO�4 , Bu4NþCl�, Bu4N

þBr�, and Bu4NþI�, it is generally preferable to use

the HSO�4 and Cl� forms, and least preferable to use the I� form. Iodide anions andother anions that tend to pair strongly with the quaternary ammonium cation in theorganic phase tend to exhibit a poisoning effect, especially with anions that are difficultto transfer such as OH� and F�.

The effect of catalyst concentration on suppression of hydroxide ion extraction wasshown in the PTC isomerization of allylbenzene in toluene/40%NaOH(aq) catalyzed byBu4N

þ salt [109]. It was observed that the presence of 100-fold OH� ion relative to thecounteranion (X�) of Bu4N

þX� salts exhibited only a 45-fold increase in the reaction rateby varying X� from Br� to HSO�4 . It is clear that the reactant anion should be moreorganophilic than the leaving product anion, otherwise the latter would accumulate in theorganic phase and retard the reaction. Sometimes this catalyst poisoning is so severe that itis necessary to use stoichiometric amounts of catalyst and a hydrophilic counteranion, or acounteranion capable of conversion into a hydrophilic anion such as HSO�4 must be usedto pair with the quaternary ammonium cation. Deprotonation of organic substrates con-taining C–H, O–H, N–H, and S–H bonds, etc., with inorganic bases is perhaps one of themost plausible methods for forming a variety of organic anions used in the PTC reactions.The hard hydroxide ion is one of the most difficult anions to transfer from the aqueousphase to the organic phase.

However, it is one of the most valuable and frequently used anions in PTC reactions.It was shown that the quantity of OH� ion extracted into the organic phase decreased asits concentration in the aqueous phase increased, and the observed overall activity of OH�

ion actually increased due to the desiccating effect of the concentrated aqueous solution ofOH� ion [110]. Addition of a small amount of alcohol to a hydroxide-promoted PTCsystem usually causes a dramatic increase in reaction rate. One reason is that the alkoxideanions produced are more easily transferred into the organic phase than the highlyhydrated OH� ion and are at least as basic as OH� ions. The other reason is that thesolvation of the OH� ion with alcohol rather than with water increases its organophilicity[111]. In the PEG-catalyzed dehydrohalogenation of 2-bromo-octane in toluene/KOH(aq)medium, a maximum 126-fold increase in the reaction rate was observed in the presence ofmethanol [112]. It was observed that the decomposition of various quaternary ammoniumcations was retarded by the addition of methanol [113].

Clark and Macquarrie showed that PTC reactions with fluoride anion transfer couldbe considerably enhanced by use of Ph4P

þBr� as the catalyst [114]. Furthermore, theapplication of PTC methodology to the oxidation reaction of organic compounds byinorganic anionic oxidants such as MnO�4 ion [115–117] and OCl� ion [118] may improvethe yields and selectivity of products or even offer the possibility of performing the reac-tion that is impractical if the conventional methodology is employed because of thenarrow range of stable organic solvents that can be used.

Borohydride ion, an important inorganic anionic reductant, is sufficiently stable inan aqueous solution and can be transferred into a nonpolar organic solvent by typicalPTC catalysts. It was found that quaternary ammonium salts containing a �-hydroxylgroup are greatly superior PTC catalysts for borohydride reduction of aldehydes andketones [119].


C. Solvents

Some PTC reactions are conducted under ‘‘solvent-free’’ conditions [5,49,120].Nevertheless, it is more common to perform a PTC reaction in the presence of an organicsolvent or cosolvent, especially if the substrate is solid. In principle, an important factorfor choosing an organic solvent for a PTC system is that at least two phases are formed.Therefore, a very wide range of solvents may be considered, according to the nature ofphases and the nature of a given PTC reaction. The most commonly used solvents forliquid/solid PTC systems include benzene (and other hydrocarbons), dichloromethane,chloroform (and other chloro hydrocarbons), and acetonitrile. In liquid/liquid PTC sys-tems, the miscibility of the organic solvent with water is of particular importance. Formost of the applications, it appears that the chlorohydrocarbons such as dichloromethaneand chloroform are somewhat better solvents than the hydrocarbons such as benzene,toluene, and hexane. Dichloromethane and chloroform are commonly and successfullyused as organic solvents in PTC systems due to the high extraction capability for thestandard salts and to the low cost and the easiness of removal, although both may undergoside reactions. Chloroform is readily deprotonated to produce either trichloromethideanion or dichlorocarbene [121] and dichloromethane suffers the nucleophilic displacementreaction [122].

During the early stage (1970s) of developing PTC methodology, the key driving forcewas to optimize the PTC reaction to obtain high yield under mild and simple conditions.However, since the late 1980s, environmental issues have become increasingly dominant inevaluation of the industrial applications of PTC systems. Some of the major issues con-cerning the ‘‘green chemistry’’ are air emissions, occupational health and other industrialhygiene, wastewater treatment, etc. Therefore, although dichloromethane is one of themost common and useful solvents in the PTC literature, there is a tendency to eliminate itand other volatile chlorohydrocarbons due to stricter emission standards and to usemethyl isobutyl ketone instead. The criteria for choosing a solvent in a PTC system includethe nature of the chemical reaction, polarity, toxicity, volatility, flammability, cost, recycl-ability, and environmental considerations, etc.

In PTC reactions involving anionic reactants, the following solvent effects aregenerally considered: (1) the solubility and extraction of the catalyst–anion ion pair/complex in the organic phase, (2) the rate of transfer of the catalyst–anion ion pair/complex from the aqueous phase to the organic phase, (3) the activation of anion bysolvent separation of the catalyst–anion ion pair/complex, (4) the deactivation of anionby solvation of the anion (including hydration), (5) the extent of aggregation of thecatalyst–anion ion pair/complex in the organic phase, and (6) the stabilization of thetransition state formed by the active form of anion and the reactant in the organicphase, etc. For example, it was found that nonpolar solvents such as cyclohexane aremore effective than polar solvents such as chlorobenzene for the PTC reaction of thedisplacement of methanesulfonate by bromide ion catalyzed by (C16H33ÞBu3NþBr� salt[123]. Since this PTC reaction is intrinsic reaction rate limited, the nonpolar solvent canpromote the rate-determining step in the organic phase by reducing the extent of solva-tion (including hydration) of reactant anion (Br�) and increasing the concentration of(C16H33ÞBu3NþBr� ion pair in the organic phase, characterized by the extraction con-stant of the larger organophilic (C16H33ÞBu3Nþ cation.


IV. SELECTED SYSTEMS

Since in PTC, at least two immiscible phases and at least one interface separating thephases are present in the system, PTC reactions usually involve the transfer of reactantfrom its resident phase into the second (reaction) phase or the interfacial region forreaction with the second reactant, and the transfer of the product away from the reactionphase or the interfacial region. Thus, PTC reactions may involve several steps taking placeconcomitantly and/or in parallel and the detailed understanding of the relationshipsbetween steps and the factors that affect each step will be helpful for exploring andapplying PTC reactions. The overwhelming majority of PTC reactions involve the transferof one reactant, usually an anion, with a PTC catalyst from the aqueous or solid phaseinto the organic phase for reaction with the second reactant. In this chapter, this PTCmethodology is named as ‘‘normal phase transfer catalysis’’ (NPTC). In contrast, a com-plementary methodology named as ‘‘inverse phase transfer catalysis’’ (IPTC) [124]involves the transfer of one reactant with the assistance of a PTC catalyst from the organicphase into the aqueous phase for reaction with the second reactant. A special methodologynamed as ‘‘tri-liquid phase transfer catalysis’’ [98,100] involves the transfer of both organicand anionic reactants from the organic and aqueous phases, respectively, into the third-liquid (catalyst-rich) phase where the reaction takes place. In the following discussion,selected PTC systems will be presented and analyzed, focusing on the kinetic and mechan-istic aspects.

A. Normal-Phase Transfer Catalysis

1. Liquid–Liquid Phase Transfer Catalysis

Two limiting mechanistic models describing liquid–liquid PTC are the Starks extractionmechanism [4,5,49] and the Makosza interfacial mechanism [121,125]. However, theexperimental results of PTC reactions indicate that there is a spectrum of mechanismsthat fall within these two limiting mechanisms. Selected systems are discussed as follows.

(a) Starks Extraction Mechanism for Simple Displacement Reactions. The Starksextraction mechanism as illustrated in the classic example of the PTC displacement of1-chloro-octane (RY) with sodium cyanide (MþX�) catalyzed by quaternary onium salt(QþX�) [5,49] is depicted in Fig. 1. In this mechanism, PTC catalyst cation (Qþ) hasboth organophilic and hydrophilic properties and is distributed between the aqueousand organic phases, and the metal salts of reactant and product anions have limitedsolubility in the organic phase. The reactant anions are transferred across the interfacialregion into the organic phase as an intact catalyst cation–anion pair, so the productanions are transferred into the aqueous phase. However, if the metal salts of reactant

FIG. 1 Starks extraction mechanism for simple phase-transfer-catalyzed displacement reaction.


and product anions have sparing organophilicity and transfer themselves from the aqu-eous phase into the organic phase, then the exchange reaction, MþY� þQþX� !MþX� þQþY�, takes place in the organic phase. As a consequence, it is not strictly aPTC reaction. Nevertheless, the reactant anion is still activated by the catalyst cation. Ifthe catalyst cation is highly organophilic and distributed exclusively in the organicphase, then the Brandstrom–Montanari modification of Starks extraction mechanism(Fig. 2) is applicable [9,126], while the exchange reaction takes place at the interfacialregion. In these mechanisms, the catalyst cation–anion pair is considered as the reactivespecies in the organic phase. It is worthwhile noting that in the PTC cycle the ion pairtransferred into or generated in the organic phase does not need to be identical to theion pair added as PTC catalyst. It is only necessary that there is a lipophilic catalystcation or some equivalent cation solvator present in the solution, which dominates topair with the reactant anion (nucleophile) to be selectively extracted into the organicphase.

The Starks extraction mechanism and the Brandstrom–Montanari modification canbe described by the following reaction steps [19]:

ðQþY�Þorg þX�aq

k1

Ðk�1

ðQþX�Þorg þY�aq ð18Þ

ðQþX�Þorg þRYorg

k2!ðQ

þY�Þorg þRXorg ð19Þ

Step 1 [Eq. (18)] describes the competitive extraction reaction of reactant and productanions between the aqueous and organic phases in the presence of a catalyst cation. Therate constants k1 and k�1 include the effects of mass transfer across the interfacial regionand depend on the change in the interfacial area, i.e., on the agitation rate. Step 2 [Eq.(19)] describes an irreversible displacement reaction in the organic phase to produce theproduct RX and the product ion pair (QþY�Þorg, which subsequently exchanges with(QþX�Þaq by repeating Step 1. It should be emphasized that Step 2 need not be irrever-sible, the kinetics of the reaction will be more complicated, and the extent of reaction willdecrease. If Step 2 is irreversible, the rate equation can be expressed as

�d½RY�org=dt ¼ d½RX�org=dt ¼ k2½QþX��org½RY�org ð20Þ

FIG. 2 Brandstrom–Montanari modification of Starks extraction mechanism for simple phase-

transfer-catalyzed displacement reaction.


If there is no change in the individual [QþX��org and [QþY��org, then the steady-stateapproximation can be applied for [QþX��org, i.e., d[QþX��org dt ¼ 0, and the followingrate equation can be derived [19]:

�d½RY�org=dt ¼ k1k2½Qþ�org½X��aq½RY�orgÞ= k1½X��aq þ k�1½Y��aq þ k2½RY�org� ��

ð21Þwhere ½Qþ�org ¼ ½QþX��org þ ½QþY��org ¼ constant (the total concentration of Qþ salt inthe organic phase). The rate equation (21) allows a tractable analysis of a rather complexprocess in terms of some limiting cases that can be justified by experimental results. It isclear that simple integral-order kinetics would not be observed when rates of the masstransfer of the anions and the organic phase reaction contribute almost equally to theoverall rate. However, if large concentrations of X�aq and Y�aq ([X��aqi, ½Y��aqi) are presentinitially such that k1½X��aqi þ k�1½Y��aqi � k2½RY�org, then a pseudo-first-order kineticswill be observed:

�d½RY�org=dt ¼ k1k2½Qþ�org½X��aqi½RY�org� �

= k1½X��aqi þ k�1½Y��aqi� �

¼ kobs½Qþ�org½RY�org ¼ k 0obs½RY�orgð22Þ

Equation (22) is justified by the typical displacement of 1-chloro-octane with NaCN(aq)catalyzed by (C16H33ÞBu3PþBr�, performed in a saturated solution of NaCl and NaCN, inwhich the plot of k 0obs versus ½ðC16H33ÞBu3PþBr��org is linear [19,49]. Based on Eq. (21),some limiting cases are analyzed and discussed as follows.

1. If the rate of the organic phase reaction is slow compared to the mass transferrates such that k1½X��aq þ k�1½Y��aq � k2½RY�org, then Eq.(21) reduces to

�d½RY�org=dt ¼ k1k2½Qþ�org½X��aq½RY�org� �

= k1½X��aq þ k�1½Y��aq� � ð23Þ

Since ðk1½X��aq þ k�1½Y��aqÞ remains nearly constant during the reaction, the reactiongenerally follows reasonably good second-order kinetics, as observed in the reaction ofthiophenoxide ion with 1-bromo-octane in benzene/water medium using a variety of PTCcatalysts [122]. In the presence of excess initial concentrations of X�aq and Y�aq, a pseudo-first-order kinetics be observed, which is similar to Eq. (23) [18,48]. Equation (23) can berewritten as

�d½RY�org=dt ¼ k2K1½Qþ�org½RY�org� �

= K1 þ ½Y��aq� � ½X��aq� ð24Þ

where K1 ¼ k1=k�1. Under conditions of constant ½Y��aq and [X��aq and a well-stirredmixture, the ratio of [QþX��org=½QþY��org remains at a constant value of �, then Eq. (25)can be derived:

�d½RY�org=dt ¼ k2½QþX��org½RY�orgÞ ¼ k2 �=ð1þ �Þð Þ½Qþ�org½RY�org ð25ÞEquation (25) is supported by the reaction of 1-chloro-octane with NaCN(aq) catalyzedby various lipophilic quaternary ammonium cations [19,49].

2. If the product anions are also highly organophilic and predominate to pair withthe catalyst cation such that k�1½Y��aq �k1½X��aqþk2½RY�org, then Eq. (21) reduces to

�d½RY�org=dt ¼ k2K1½Qþ�org½RY�org½X��aq� �

=½Y��aq ð26ÞSince in Eq. (26), K1½X��aq=½Y��aq � 1, the reaction could stall after a sufficient amount ofthe product anion is formed, i.e., a catalyst poisoning phenomenon will be observed. Sucha poison effect can be avoided by using a stoichiometric quantity of catalyst. In the PTC


reaction of 1-iodo-octane with NaCN(aq), the reaction essentially came to a halt after 15–25% conversion due to the catalyst poisoning effect caused by iodide ion [19,49]. However,in the reaction of benzyl chloride with sodium benzoate in toluene/water medium, theiodide ion paired with quaternary ammonium cation acts as a cocatalyst rather than a‘‘catalyst poison’’ [127].

3. If both rates of the mass transfer of reactant anion into the organic phase andthe organic phase reaction are fast compared to the rate of the mass transfer of the productanion into the organic phase such that k1½X��aq þ k2½RY�org �k�1½Y��aq, then Eq. (21)reduces to

�d½RY�org=dt ¼ k1k2½Qþ�org½X��aq½RY�org� �

= k1½X��aq þ k2½RY�org� � ð27Þ

This limiting case represents a desirable process since both the rapid steps lead in thedirection of product. However, the reaction is expected to follow nonintegral orderkinetics, except under conditions such as k1½X��aq � k2½RY�org or k1½X��aq � k2½RY�org.The kinetics of the sequential substitution reaction of hexachlorocyclotriphosphazene with2,2,2-trifluoroethanol catalyzed by various quaternary ammonium salts in a chloroben-zene/NaOH(aq) medium were investigated. It was concluded that the reaction rate wascontrolled by both the organic phase reaction and the mass transfer of 2,2,2-trifluoroeth-oxide ion [128].

4. If the organic phase reaction is very fast compared to the mass transfer stepssuch that k2½RY�org �ðk1½X��aqþk�1½Y��aqÞ, then Eq. (21) reduces to

�d½RY�org=dt ¼ k1½Qþ�org½X��aq ð28ÞThe reaction is first order with respect to reactant anion and is zero order with respect toorganic reactant, RY. This limiting case is demonstrated by the hypochloride oxidation ofdi-n-butyl sulfide in CH2Cl2=H2O medium catalyzed by Aliquat 336 [129].

A graphical overview of extraction mechanism limiting cases is presented in aquantitative three-dimensional representation of the two mass transfer rates (k1[X

�]aqand k-1[Y

-]aq) and the rate of organic phase reaction (k2[RY]org) [19]. Gordon andKutina [130] discussed the implications of the interplay between extraction and chemicalreaction. The minimum ratio of [X�]aq/[RY]org that is sufficient for producing pseudo-first-order kinetics was calculated. If the concentration of the phase-transfer cation in theorganic phase ([Qþ]org) is changing during the reaction, the steady-state approximation of[QþX�]org is no longer valid and a more complex nonsteady-state treatment of the kineticsmust be considered [19], as shown in the displacement of 1-bromo-octane and NaCN(aq)catalyzed by Bu4P

þBr� [49]. In this system, no simple rate law is applicable since thereaction starts slowly and proceeds more rapidly with time. Initially, the Bu4P

þBr� saltwas distributed mainly in the aqueous phase of the water/bromo-octane medium.However, as the amount of the more polar product octyl cyanide increased, its distributionin the organic phase also increased, which led to acceleration of the reaction.

(b) Mechanisms of Hydroxide-Promoted Reactions of Organic Acids. Numerous two-phase catalytic reactions such as C-, O-, N-, and S-alkylations, generation of carbenes,isomerization, and H/D isotope exchange, etc., are carried out in the presence of strongalkali metal hydroxides. Nevertheless, much controversy exists in the mechanisticaspects. The transfer of the strong hydrophilic OH� ions into nonpolar medium is ener-getically highly unfavorable even in the presence of a great excess of metal hydroxides.Almost all of the monovalent anions dominate in the competitive extraction with OH�

ion for the quaternary ammonium cations into the organic phase [40]. Therefore, direct


extension of the typical extraction mechanism may not be suitable for all of the hydro-xide-promoted two-phase catalytic reactions. For example, in phenylacetomitrile/50%NaOH(aq) medium, greater than 99% of the benzyltriethylammonium cation formedion pairs with chloride ions. However, a 70% yield of alkylated product could beobtained in the alkylation of phenylacetonitrile with n-butyl iodide and 50% NaOH(aq)in the absence of PTC catalyst [131]. This observation prompted Makosza to suggestthe interfacial mechanism and a general term ‘‘catalytic two-phase systems’’ [15].

(c) Selected Mechanisms for Hydroxide-Promoted PTC Alkylation.

Starks–Brandstrom–Montanari extraction mechanism. The Starks–Brandstrom–Montanari extraction mechanism can be described by the following reaction steps [19]:

ðQþX�mH2OÞorg þOH�aq

k1

Ðk�1

ðQþOH�nH2OÞorg þX�aq ð29Þ

ðQþOH�nH2OÞorg þRHorg

k2

Ðk�2

ðQþR�ðnþ 1ÞH2OÞorg ð30Þ

ðQþR�ðnþ 1ÞH2OÞorg þR 0Xorg

k3!ðQ

þX�mH2OÞorg þRR 0org ð31ÞIn the first step (Eq. (29)], the phase-transfer catalyst cation hydroxide (QþOH�) ion pairis transferred from the aqueous phase through the interfacial region into the organic phase(Starks extraction mechanism) or the (QþOH�) ion pair formed by the exchange reaction(MþOH� þQþX� ! QþOH� þMþX�) at the interfacial region into the bulk organicphase (Brandstrom–Montanari modification). By applying the steady-state approximationto (QþOH�nH2OÞorg and (QþR�ðnþ 1ÞH2OÞorg, the following rate equation can bederived:

d½RR 0�org=dt ¼k1k2k3½QþX��org½OH��aq½RH�org½R 0X�org

k�1k�2½X��aq þ k�1k3½X��aq½R 0X�orgþk2k3½RH�org½R 0X�orgð32Þ

In principle, for this mechansim to be operative the PTC catalyst must have suffi-ciently high organophilicity in order to extract OH� ions into the organic phase. It isexpected that the reaction rate increases with increased organophilicity of catalyst cationand is independent of the agitation rate above a certain value. If the reaction is organicphase reaction limited, such that k�1k�2½X��aq � ðk�1k3½X��aq½R 0X�org þ k2k3½RH�org½R 0X�orgÞ, then Eq. (32) reduces to

d½RR 0�org=dt ¼ k3K1K2 ½QþX��org½OH��aq=½X��aq� �½RH�org½R 0X�org

¼ kobs½RH�org½R 0X�orgð33Þ

where K1 ¼ k1=k�1 and k2 ¼ k2=k�2. The reaction is expected to follow a second-orderkinetics or a pseuso-first-order kinetics (e.g., if initially, ½RH�orgi � ½R 0X�orgi). On the otherhand, if the reaction is mass transfer limited such thatk2k3½RH�org½R 0X�org �ðk�1ðk�2 þ k3Þ½R 0X�orgÞ½X��aqÞ, then Eq. (32) reduces to Eq. (34)and the reaction is expected to follow a zero-order kinetics.

d½RR 0�org=dt ¼ k1 ½QþX��org½OH��aq� ð34Þ


Makosza interfacial mechanism. The Makosza interfacial mechanism can bedescribed by the following steps [15,19]:

RHorg þOH�aq

k1

Ðk�1

ðR�H2OÞif ðif ¼ interfacial regionÞ ð35Þ

ðR�H2OÞif þ ðQþX�Þorgk2

Ðk�2

ðQþR�H2OÞorg þX�aq ð36Þ

ðQþR�H2OÞorg þR 0Xorg

k3!ðQ

þX�H2OÞorg þRR 0org ð37Þ

In this mechanism, the first step involves the deprotonation of organic acid substrate by(MþOH�) at the interfacial region to produce the carbanion (R�), which forms the‘‘anchored’’ ion pair (MþR�) and remains in the interfacial region. The second stepinvolves the detachment of R� ion from the interfacial region into the bulk organicphase under the assistance of catalyst (Qþ) cation. The third step is the reaction of R�

ion with the second reactant (R 0X) in the bulk organic phase. By applying the steady-stateapproximation to (QþR�Þorg and (QþR�Þif , the following rate equation can be derived:


k�1k�2½X��aq þ k�1k3½R 0X�org þ k2k3½RH�org½R 0X�orgð38Þ

It is expected that the reaction rate depends on the agitation rate. The accessibility ofthe Qþ cation plays a key role in the detachment of the carbanion (R�) from its anchoredposition at the interfacial region by forming an ion pair (QþR�). However, the (QþR�)ion pair should be sufficiently organophilic to dissolve itself in the bulk organic phase. Ingeneral, the kinetics of the reaction is complex. In the two-phase catalytic ethylation ofdeoxybenzoin with ethylbromide in (CH2Cl2, C6H6, or p-xylene)/50% NaOH(aq) mediumcatalyzed by various symmetric quaternary ammonium salts [132], in all cases it wasobserved that those catalysts reducing the interfacial tension most markedly were alsothe best catalysts and it was suggested that the Makosza interfacial mechanism bestaccounts for the experimental observations [11,12].

Modified interfacial mechanism. A modified interfacial mechanism is shown by thefollowing steps [19]:

ðQþX�mH2OÞorg þOH�aq

k1

Ðk�1

ðQþOH�nH2OÞif þX�aq ð39Þ

ðQþOH�nH2OÞif þRHorg

k2

Ðk�2

ðQþR�ðnþ 1ÞH2OÞorg ð40Þ

ðQþR�ðnþ 1ÞH2OÞorg þR 0Xorg

k3!ðQ

þX�mH2OÞorg þRR 0org ð41Þ


In the first step [Eq. (39)], the exchange reaction of OH�aq ion with (QþX�) ion pairtakes place at the interfacial region to produce the (QþOH�) ion pair. In the second step[Eq. (40)], the deprotonation of organic acid (RH) by (QþOH�) proceeds at the interfacialregion to produce the (QþR�) ion pair, which is transferred to the bulk organic phase toreact with the second organic substrate (R 0X) to yield the product RR 0 as shown in thethird step [Eq. (41)]. As in the Starks extraction mechanism, the PTC catalyst cation isinvolved in the formation of the carbanion. Based on this argument, it is clear that boththe Starks extraction mechanism and the modified interfacial mechanism are differentfrom the Makosza interfacial mechanism. By applying the steady-state approximationto (QþR�)org and (QþOH�Þif , the following rate equation can be derived:


k�1k�2½X��aq þ k�1k3½X��aq½R 0X�org þ k2k3½RH�org½R 0X�orgð42Þ

It is obvious that the Starks extraction mechanism and the modified interfacialmechanism are kinetically indistinguishable, Eq. (32) versus Eq. (42). The isotopeexchange reaction of fluorene in C6H6=16M NaODðD2O) in the presence ofBuEt3N

þCl� or BuEt3NþBr� was investigated [133]. It was observed that in the absence

of the catalyst no exchange took place, which was contradictory to the Makosza interfacialmechanism. The experimental results demanded the inclusion of the quaternary ammo-nium cation in the deprotonation of organic acid and provided evidence for the operationof the modified interfacial mechanism. In the tri-liquid phase catalysis of the dehydrobro-mination of �-phenylethylbromide to styrene in toluene/40% NaOH(aq) in the presence ofBuEt3N

þBr�, it was suggested that the modified interfacial mechanism best accounted forthe experimental results [134].

The acidity of organic acid may affect the mechanism of these hydroxide-promotedPTC reactions. Since relatively strong acids (e.g., acetylacetone, pKa � 9) can dissolve inNaOH(aq), the effect of the PTC catalyst cation is, therefore, to extract the conjugatebase anion in the form of an ion pair into the organic phase, where C- or O-alkylationoccurs. In other words, the classic Starks extraction mechanism is applicable. For ali-phatic alcohols (pKa � 18), both the uncharged alcohol (ROH) and its conjugate baseanion (alkoxide, RO�) can be extracted into the organic phase, which certainly willcomplicate the kinetics and mechanism of the reaction. The geminal diols (e.g., pinacol)can be extracted more efficiently than simple alcohols. Organic substrates(16 < pKa < 23), with somewhat activated methylene groups, are generally not watersoluble and do not readily dissociate in the absence of strong base, then the transferof OH� ion is usually required as mentioned above [19,57]. Organic substrates(23 < pKa < 38) are very difficult to deprotonate unless the base is very strong. It islikely that the rate of deprotonation is slow compared to the rate of OH� ion transferand predominates in the overall rate expression [19,57]. Organic substrates with pKa >38 are not likely to work in hydroxide-promoted PTC reactions [19,57].

(d) Reverse Transfer Mechanism for Dehydrohalogenation Reaction. An alternativemechanism called the ‘‘reverse transfer mechanism’’ is proposed for those PTC reactionsinvolving hydroxide ion, in which the active base in the organic phase is the quaternaryammonium halide (QþX�) rather than (QþOH�) or (QþR�). For example, in thekinetic study of the dehydrohalogenation of a series of substituted (1-haloethyl)benzeneswith 50% NaOH(aq) in the presence of Bu4N

þX� (X ¼ Cl, Br, I, and HSO4) [135], itwas found that the reactions followed a first-order kinetics and that the catalytic activ-ity of BuEt3N

þ salts followed the order Cl� > Br� > I� as expected. However,


Bu4NþHSO�4 salt showed an initial rapid reaction due to the initial presence of the

(Bu4NþOH�) ion pair extracted into the organic phase caused by the highly hydrophilic

sulfate ions. Nevertheless, as halide ion formed in the elimination reaction, it was pre-ferentially extracted into the organic phase due to its higher organophilicity, and actedas the base instead of hydroxide ion for the remainder of the reaction. Thus, when theextraction of hydroxide ion is inhibited, the reverse transfer mechanism may operate.The reverse transfer mechanism can be described by the steps shown below:

ðQþHX�2 Þorg þOH�aq

k1

Ðk�1

ðQþX�Þorg þX�aq þH2O ð43Þ

ðQþX�Þorg þRCH2CHXR 0orgk2!ðQþHX�2 Þorg þRCH ¼ CHR 0org ð44Þ

After the steady state is established, Eq. (45) can be derived by applying the steady-stateapproximation to (QþX�)org:

d½RCHCHR 0�org=dt ¼k1k2½QþHX�2 �org½OH��aq½RCH2CHXR 0�org

k�1½X��aq þ k2½RCH2CHXR 0�orgð45Þ

If reaction (44) is the rate-determining step such that k�1½X��aq � k2½RCH2CHXR 0�org,then Eq. (45) reduces to Eq. (46) and the reaction follows a first-order kinetics as observed[135]:

d½RCHCHR 0�org=dt ¼ k2K1 ½QþHX�2 �org½OH��aq=½X��aq� �½RCH2CHXR 0�org ð46Þ

(e) Mechanism of Dihalocarbene Generation and Addition Reactions. The method forgenerating dichlorocarbene in the two-phase CHCl3/50% NaOH(aq) medium in the pre-sence of quaternary ammonium salt [15,136] has gained widespread applications andopened a new chapter of carbene chemistry. Competitive reactions demonstrated thatthe dichlorocarbene generated in a PTC system is identical to that generated by othertraditional methods (e.g., by using potassium t-butoxide for the elimination) [5,49,137].In the absence of a reactant, the PTC mixture of CHCl3/concentrated NaOH(aq)/cata-lyst retains its ability to generate dichlorocarbene. In a 0.1 M solution of quaternaryammonium salt (QþX�) in CHCl3/50% NaOH(aq) medium, no evidence was found for(QþCCl�3 ) in the organic phase [137]. A mechanism based on the interfacial mechanismfor the dichlorocarbene addition reaction in a catalytic two-phase system is shownbelow:

HCCl3org þ ðNaþOH�Þaq Ð ðNaþCCl�3 Þif þH2O ð47ÞðNaþCCl�3 Þif þ ðQþX�Þorg Ð ðQþCCl�3 Þorg þ ðNaþX�Þaq ð48ÞðQþCCl�3 Þorg Ð ðQþCl�Þorg þ ð: CCl2Þorg ð49Þð: CCl2Þorg þ alkeneorg ! dichlorocyclopropane derivative ð50ÞStep 1 [Eq. (47)] involves the deprotonation of CHCl3 in the interfacial region to

form trichloromethylide (CCl�3 ) ions, which are anchored at the interfacial region [138].Step 2 [Eq. (48)] involves the detachment of the anchored CCl�3 ion from the interfacialregion into the bulk organic phase under the assistance of Qþ cation. Step 3 [Eq. (49)]


shows the reversible formation of : CCl2 in the organic phase with concomitant formationof a (QþCl�) ion pair, which stabilizes and increases the lifetime of : CCl2 in the organicphase. In contrast, when CHCl3 is treated with t-BuOK in a nonpolar solvent, theKþCCl�3 generated is insoluble and only : CCl2 can dissolve in the solution (i.e.,KþCCl�3 ! KCl # þ : CCl2). However, since the reaction of : CCl2 with alkene cannotcompete effectively with those with t-BuOH or t-BuOK, the irreversible consumption of: CCl2 takes place, which reduces its lifetime. In the presence of a reactant such as alkene,the irreversible addition of : CCl2 to alkene takes place to yield the dichlorocyclopropanederivatives as shown in Step 3 [Eq. (49)]. Since carbenes are usually strongly electrophilicspecies, they are capable of reacting with a variety of nucleophilic species such as alkenes,aromatic compounds, amines, alcohols, and S- and P-containing compounds [15].Reaction (49) competes with two reactions Eqs. (51) and (52), which are relatively slowdue to the phase boundary:

ð: CCl2Þorg þOH�aq! ðHOCCl�2 Þif ð51Þð: CCl2Þorg þH2O! ðHOCHCl2Þif ð52Þ

Reactions (51) and (52) lead to the production of HCOO� ion and CO(g) and in diluteNaOH(aq) they become more competitive and hydrolysis of CHCl3 is observed. In addi-tion, exchange reactions (53)–(55) may also take place, which lead to to the production ofXCCl�2 ion and HCXCl2:

ð: CCl2Þorg þ ðQþX�Þorg Ð ðQþCXCl�2 Þorg ð53Þð: CCl2Þorg þX�aq Ð ðCXCl�2 Þif þ ðQþX�Þorg ð54ÞðCXCl�2 Þif þH2O! ðHCXCl2Þif þOH�aq ð55ÞIn general, all other dihalocarbenes can be generated in a similar catalytic two-phase

system and subsequently add to alkenes. However, difluorocarbene is the only dihalocar-bene being excluded due to its very high rate of formation on deprotonation of theprecursor (CHF2Cl), which inhibits the transfer of CF2Cl

� ion by the Qþ cation [15]. Itwas generally observed that tertiary amines (R3N) catalyze the reactions involving dichlor-ocarbene. It was rationalized by invoking the reaction of R3N with (: CCl2) at the inter-facial region to form an ammonium ylide, which acted as a strong base and generated(: CCl2) in the bulk organic phase as shown in the following reactions [15,139]:

ðR3NÞif þ ðNaþClCCl�2 Þif ! ðR3Nþ � CCl�2 Þorg ð56Þ

ðR3Nþ � CCl�2 Þorg þ CHCl3org Ð ðR3N

þCHCl2CCl�3 Þorg ð57Þ

ðR3NþCHCl2CCl

�3 Þorg Ð ðR3N

þCHCl2Cl�Þorg þ ð: CCl2Þorg ð58Þ

2. Solid–Liquid Phase Transfer Catalysis

A major drawback in liquid–liquid PTC reactions involving transfer of anionic reactantfrom the aqueous phase into the organic phase is the coextraction of hydrated watermolecules. To cope with the problem of anion deactivation caused by the water of hydra-tion, it is reasonable to perform the PTC reactions with solid salts. This methodology iscalled ‘‘solid–liquid phase transfer catalysis,’’ which usually involves the reaction of ananionic reactant originally in a solid salt with a second reactant in the organic phase. Itwas reported that in some systems the liquid–liquid PTC reactions failed while the corre-


sponding reactions using the solid–liquid PTC method were successful [140,141]. It wasfound that the generation of (: CCl2) from sodium trichloroacetate (Naþ�O2CCCl3) undersolid–liquid PTC conditions was superior to that under liquid–liquid PTC conditions. Inanhydrous organic solvents such as absolute dimethoxyethane, (Naþ �O2CCCl3) decom-posed to generate ð: CCl2Þ, i.e. ðNaþ �O2CCCl3Þ ! NaþCl� þ CO2þ : CCl2. However, inthe presence of water, it decomposed to produce HCCl3, i.e.,(Naþ �O2CCCl3Þ þH2O! NaþHCO�3 þHCCl3. It was reported that very satisfactoryyields of dichlorocyclopropanes were obtained by the reactions of alkenes and : CCl2generated in the sodium trichloroacetate/quaternary onium salt/chloroform system[140,141].

The mechanistic description of the simple displacement reactions under solid–liquidPTC is quite similar to that of the liquid–liquid PTC counterpart [142]. However, incontrast to the liquid–liquid PTC system, the first step in the solid–liquid PTC systeminvolves the transport of a reactant anion from the solid phase to the organic phase by aPTC catalyst, which could be an organophilic quaternary onium cation, or an organo-philic complex cation formed by a metal ion such as Kþ with a polydentate ligand such ascrown ether, cryptand, PEGs and their derivatives, and TDA-1, etc. It is expected that thelattice energy plays an important role in the anion exchange of inorganic salt and qua-ternary onium salt. For example, it was observed that KCl salt did not exchange withBu4NBr in toluene, but KBr salt did exchange with Bu4NCl in toluene [143]. Similarly, thesolubilities of potassium salts in acetonitrile in the presence of 0.15 M 18-crown-6 followedthe order of KI > KBr > KCl > KF [68]. Under solid–liquid PTC conditions, the kineticsof displacement reactions of bromide and iodide ions and 1-bromo-octane and the mesy-late of 1-octanol catalyzed by Bu4NBr and 18-crown-6 ether were investigated [144]. Basedon the observed pseudo-first-order rate constants, it was concluded that 18-crown-6 cat-alyzed the reaction more effectively than Bu4NBr.

The effects of added water on the rates of displacement of benzyl bromide andbenzyl chloride with KCN salt in toluene catalyzed by 18-crown-6 were reported [145].It was observed that a small amount of water considerably increased the reaction ratescompared to the anhydrous conditions and that the rate increased sharply to a maximumvalue in the presence of an optimum amount of added water. An important observationwas that under anhydrous conditions, the reaction followed zero-order kinetics while inthe presence of added water it followed first-order kinetics. It was suggested that the initialsmall amounts of added water coated the surface of the salt particle, which extracted thecrown ether from the organic phase to form a new interfacial region called the ‘‘omega (!)phase.’’ It was believed that the catalytic reaction took place mainly in the omega phase,since the quantity of added water corresponding to the maximum quantity of crown etheron the surface of the salt particles correlated well with the optimum quantity of addedwater.

Furthermore, the results of a study on the distribution of 18-crown-6 between thetoluene phase and the omega phase indicated that the amount of crown ether in thetoluene phase remained low and relatively constant even though 3.50–11.45 mmol ofcrown ether were added [146]. It appeared that the omega phase acted like a spongethat was capable of adsorbing the added crown ether. For the 18-crown-6-catalyzed dis-placement of benzyl bromide with KCN salt in toluene [146], it was found that theobserved first-order rate constant was quite independent of the amounts (5.0–12.0mmol) of 18-crown-6, which implied that the displacement reaction probably took placemainly in the organic phase. Mechanistic rationalization of this crown ether-catalyzedtwo-phase reaction is described as follows:


1. In the absence of added water:

ðKþCN�Þs þ Lorg Ð ðKLþCN�Þorg ð59ÞðKþBr�Þs þ Lorg Ð ðKLþBr�Þorg ð60Þ

ðKLþBr�Þorg þ ðKþCN�Þsk1

Ðk�1

ðKLþCN�Þorg þ ðKþBr�Þs ð61Þ

ðKLþCN�Þorg þ PhCH2Brorgk2!PhCH2CNorg þ ðKLþBr�Þorg ð62Þ

Since it was required that KCN and KBr salts and crown ether (L) were stirred together intoluene for about 1 h prior to the addition of benzyl bromide in order to obtain repro-ducible kinetic data, the equilibria of Steps 1 [Eq. (59)] and 2 [Eq. (60)] were establishedand remained practically unchanged during the course of the reaction; in other words, theorganic phase solution was always saturated with (KLþCN�) and (KLþBr�) i.e.,½KLþCN�]org and [KLþBr�]org were constant. Therefore, as long as KCN and KBrsalts are present, the rate equation can be derived by considering mainly Steps 3 [Eq.(61)] and 4 [Eq. (62)]. By applying the steady-state approximation to (KLþCN�)org, thefollowing equation can be derived:

�d½PhCH2Br�org=dt ¼ k1k2½KLþBr��org½PhCH2Br�org=ðk�1 þ k2½PhCH2Br�orgÞ ð63ÞIf k2½PhCH2Br�org �k�1, then Eq. (63) reduces to Eq. (64) and the reaction is expected tofollow zero-order kinetics as observed [146]:

�d½PhCH2Br�org=dt ¼ k1½KLþBr��org ¼ constant ð64Þ2. In the presence of added water:

ðKþCN�Þs þ ðLxH2OÞ! Ð ðKLþCN�nH2OÞ! ð65ÞðKLþCN�nH2OÞ! Ð ðKLþCN�nH2OÞorg ð66ÞðKþBr�Þs þ ðLxH2OÞ! Ð ðKLþBr�mH2OÞ! ð67ÞðKLþBr�mH2OÞ! Ð ðKLþBr�mH2OÞorg ð68Þ

ðKLþBr�mH2OÞorg þ ðKþCN�Þsk1

Ðk�1

ðKLþCN�nH2OÞorg þ ðKþBr�Þs ð69Þ

ðKLþCN�nH2OÞorg þ PhCH2Brorg

k2!PhCH2CNorg þ ðKLþBr�Þorg ð70Þ

It was also required that KCN and KBr salts, crown ether (L), and water were stirredtogether in toluene for about 1 h to allow the equilibria [Eqs (65)–(68)] to be establishedbefore the addition of benzyl bromide. It is reasonable to assume that in the omega phase(!) the solution is always saturated with ðKLþCN�nH2O) and (KLþBr�mH2O), i.e.,


[KLþCN�nH2O�! and [KLþBr�mH2O�! are essentially constant so long as KCN andKBr salts are present. Thus, the rate equation can be derived based mainly on Steps 9 [Eqs.(69) and 10 (70)]. By applying the steady-state approximation to (KLþCN�nH2OÞorg, thefollowing equation can be derived:

�d½PhCH2Br�org=dt ¼ k1k2½KLþBr�mH2O�!½PhCH2Br�org=ðk�1 þ k2½PhCH2Br�orgÞð71Þ

If k�1 � k2½PhCH2Br�org, Eq. (71) reduces to Eq. (72) and the reaction is expected tofollow first-order kinetics as observed [146]:

�d½PhCH2Br�org=dt ¼ k2K1½KLþBr�mH2O�!½PhCH2Br�org ð72Þ

where ðK1 ¼ k1=k�1). This mechanistic interpretation is most applicable to the system inwhich an optimum amount of water is added. Since it was also observed that the quantityof water added was greater than the optimum value, the reaction rate decreased withincreased quantity of water and approached that of the reaction in toluene/H2O mediumand in the absence of crown ether [145]. Therefore, under these circumstances both thecrown-catalyzed solid–liquid PTC reaction and the uncatalyzed two-liquid-phase reactiontook place concomitantly.

B. Reversed Phase Transfer Catalysis

Besides the typical (normal) PTC reactions involving nucleophilic reactant anions andcationic catalyst, it is reasonable to believe that the PTC technique can be applied toreactions involving electrophilic reactant cations such as aryldiazonium and carboniumcations and anionic catalysts. In such ‘‘reversed phase transfer catalysis’’ (RPTC), acationic reactant in the aqueous phase is continuously transferred into the organicphase in the form of a lipophilic ion pair with a lipophilic, non-nucleophilic anioniccatalyst, and reacts with the second reactant in the organic phase.

Ellwood et al. [147] investigated the coupling reactions of 4-nitrobenzenediazoniumchloride with N-ethylcarbazole and N,N-dimethylaniline, etc., in H2O=CH2Cl2 mediumcatalyzed by sodium dodecylbenzenesulfornate and found that a 50-fold increase in thereaction rate was observed. Iwamoto et al. [148] reported coupling reactions of 4-nitro-benzenediazonium cation (generated in situ) with N-ethylcarbazole and 1-methoxy-naphthalene catalyzed by sodium tetrakis-[3,5-bis(trifluoromethyl)phenyl]borate(NaþTFPB�) in CH2Cl2=0:5M H2SO4ðaqÞ medium containing sodium nitrite [148].

They also investigated the Friedel–Crafts-type alkylation reactions of carboniumcations with m-methylanisole, o-cresol, and m-dimethoxybenzene catalyzed by(NaþTFPB�) in CH2Cl2=0:5M H2SO4ðaq) medium. The carbonium cations are generatedin situ by protonation of triphenylmethanol, diphenylmethanol, p-methoxybenzyl alcohol,and �-methylbenzyl alcohol [149]. Although the Friedel–Crafts-type reversed PTC appearsto be a promising methodology, its application is however, somewhat limited due to thegeneration and stability of the carbonium cation. Although relatively stable carboniumcations can be generated in dilute aqueous H2SO4, they can react only with active nucleo-philic aromatic compounds. On the other hand, less stabilized carbonium cations shouldbe generated in concentrated H2SO4 or other strong protic or Lewis acids. However, undersuch conditions, the reaction is interfered with by protonation of the aromatic substrateand the PTC catalyst.


C. Inverse Phase Transfer Catalysis

In contrast to the normal and reversed PTC methodologies, in which the chemical trans-formation takes place in the organic phase, it is reasonable to expect that PTC reactionscan also be performed by transferring the organic reactants from the organic phase intothe aqueous phase for reaction with a second reactant. Such a complementary methodol-ogy is named as ‘‘inverse phase transfer catalysis’’ (IPTC) by Mathias and Vaidya [124].Recently, the application of IPTC in organic synthesis has been reviewed by Li et al. [150].

1. Transition Metal Complexes

Cuprous chloride tends to form water-soluble complexes with lower olefins and acts as anIPTC catalyst, e.g., in the two-phase hydrolysis of alkyl chlorides to alcohols with sodiumcarboxylate solution [10,151] and in the Prins reactions between 1-alkenes and aqueousformaldehyde in the presence of HCl to form 1,3-glycols [10]. Similarly, water-solublerhodium-based catalysts (4-diphenylphosphinobenzoic acid and tri-C8-10-alkylmethylam-monium chlorides) were used as IPTC catalysts for the hydroformylation of hexene,dodecene, and hexadecene to produce aldehydes for the fine chemicals market [152].Palladium diphenyl(potassium sulfonatobenzyl)phosphine and its oxide complexes cata-lyzed the IPTC dehalogenation reactions of allyl and benzyl halides [153]. Allylic sub-strates such as cinnamyl ethyl carbonate and nucleophiles such as ethyl acetoactate andacetyl acetone catalyzed by a water-soluble bis(dibenzylideneacetone)palladium or palla-dium complex of sulfonated triphenylphosphine gave regio- and stereo-specific alkylationproducts in quantitative yields [154]. Ito et al. used a self-assembled nanocage as an IPTCcatalyst for the Wacker oxidation of styrene catalyzed by (en)Pd(NO3) [155].

2. Cyclodextrins

Cyclodextrins (cyclic oligosaccharide/polyalcohols of �-D-glucose with six to eight mono-meric units) form cyclindrical-like structures in aqueous solution having organophilicinteriors and hydrophilic exteriors and form complexes with a large number of compoundsand ions via the various intermolecular forces between host and guest molecules [156].Cyclodextrins can solubilize various organic compounds in aqueous phase solutions viaformation of host–guest complexes within the interior of the cyclodextrin structure; there-fore, they are expected to be good candidates of IPTC catalysts. Trifonov and Nikifornov[157] studied cyclodextrin-catalyzed IPTC nucleophilic substitution reactions of 1-bromo-octane and cyanide, iodide, and thiocyanate ions and found that both �- and �-cyclodex-trins could catalyze the reaction and that �-cyclodextrin was considerably more activethan �-cyclodextrin. �-Cyclodextrin has also been used as an IPTC catalyst in the follow-ing reactions:

1. The isomerization of 4-allylanisole with iridium(III) chloride to cis- and trans-anethol, in which a ternary allylanisole–cyclodextrin–iridium(III) chloride com-plex was proposed as an intermediate [158].

2. The selective oxidation of olefins, MeðCH2ÞnCH ¼ CH2 (n ¼ 5, 6, 7, 9, and 11),to ketones catalyzed by PdCl2=CuCl2 [159,160].

3. The epoxidation of alkenes such as styrene, cis-cyclo-octene, trans-hept-2-ene,and norbornene with iodosobenzene catalyzed by a water-soluble diaquo-N,N 0-ethylbenzenebis(salicyclideneaminato)chromium(III) complex [161].

4. The reductions of bromoanisoles with sodium formate in the presence of solid-phase (Pd/C) catalyst [162].


5. The hydrolysis of phthalic acid ester in 10% NaOH(aq) [163].6. The oxidation of methyl ketones by hypochlorite (the haloform reaction) [164].

An enhanced IPTC activity was observed for water-soluble �-cyclodextrin–epichlor-ohydrin copolymers in the nucleophilic substitution reactions of alkyl bromides andsodium iodide [165]. However, in the hypochlorite-induced oxidation of 1-phenyl-1-pro-panol or benzyl alcohol in the presence of �-cyclodextrin, the reactions were enhanced bylowering the pH of the aqueous phase rather than by the IPTC catalyst [166]. In contrast,the secondary alcohol was inert in aqueous hypochlorite solution maintained at high pH,even in the presence of the cyclodextrin.

3. Surfactants

Boyer and coworkers [167–170] have investigated the following IPTC reactions usingsurfactants as the phase transfer catalysts: (1) the reduction of ketones by sodium bor-ohydride in the presence of dodecenylsulfonate (monomer and polymer species) [167]; and(2) the epoxidation of �; �-unsaturated ketones (such as chalcone, carvone, citral, mesityloxide, and methyl cinnamate) by H2O2 in heptane/0.5 M NaOH(aq) medium and in thepresence of cationic surfactants (e.g., dedecylenyltrimethylammonium bromide) [168–170].The results indicated that the reaction was catalyzed by water-soluble micellar aggregatesof the surfactant and the catalytic effects depended strongly on the hydrophobicity of thesubstrate. Interesting results were observed in the study of the effect of surfactant con-centration on the epoxidation of chalcone by H2O2. It appeared that under slow agitation(100 rpm), the reaction occurred mainly via IPTC, while under vigorous agitation (1200rpm) it took place mainly at the interface due to the formation of an emulsion [170].

4. Tetramethylammonium Salts

Due to its low organophilicity (high hydrophilicity), the tetramethylammonium cation isnormally a poor PTC catalyst for transferring reactant anions into the organic phase.However, for certain systems where the reaction in the organic phase was not feasible,these salts could act as the IPTC catalysts as shown in the following reactions: (1) thefluorination of chlorobenzaldehydes [171] and the preparation of 1,2,2,2-tetrafluoroethyldifluoromethyl ether [172] with alkali metal fluorides, (2) the acetalization of sorbitol withbenzaldehyde to produce dibenzalsorbitol [173], and (3) the oxidation of benzyl alcohol byNaOCl(aq) to produce benzaldehyde, in which the catalyst was the trimethylammoniumgroups bound to resins [174].

5. Dimethylaminopyridine, Pyridine-1-Oxide, and Sulfide

An important class of IPTC reactions involves the conversion of a reactant and the IPTCcatalyst in the organic phase to an ionic intermediate that is transported into the aqueousphase for reaction with the second reactant to yield the organic product and to regeneratethe catalyst. This class of IPTC catalysts includes 4-(dimethylamino)pyridine (DMAP), 4-pyrrolidinopyridine, pyridine-1-oxide (PNO), tetrahydrothiophene, and diethylsulfide, etc.Mathias and Vaidya studied the first acylation reaction of alanine with decanoyl- or p-chlorobenzoyl chloride in H2O=CH2Cl2 medium catalyzed by DMAP [124]. In this system,the acid chloride reacted with DMAP in the organic phase to form the ionic intermediate,1-acyl-4-(dimethylamino)pyridinium ion, which was highly water soluble and sufficientlystable and was transported into the aqueous phase to react with the carboxylate ion ofalanine to yield the amide product. DMAP was also used as an IPTC catalyst to improve


the tosylation of alcohols and amines with tosyl chloride [175]. Similarly, Fife and Xin[176] reported the IPTC reaction of acid chloride with carboxylate ions catalyzed by PNOin H2O=CH2Cl2 medium to produce acid anhydride, in which the active ionic intermedi-ate, 1-(acyloxy)pyridinium ion, was formed by acid chloride and PNO in the organicphase. In the IPTC reaction of benzoyl chloride and phenols in H2O=CH2Cl2 mediumcatalyzed by PNO, it was observed that the IPTC reaction was more efficient than thenormal PTC reaction catalyzed by quaternary ammonium salts [177].

The pyridinyl- and 1-oxypyridinyl-substituted silanes and siloxanes were patented asIPTC catalysts in transacylation reactions [178]. In the IPTC nucleophilic substitutionreaction of benzoyl chloride with KSCN catalyzed by cyclic and acyclic sulfides such astetrahydrothiophene and diethyl sulfides, etc., the active ionic intermediate, benzylsulfo-nium ion, formed by benzyl chloride and sulfide in the organic phase, transferred into theaqueous phase to react with thiocyanate ion to produce benzylthiocyanate [179]. In thefollowing discussion, selected IPTC systems are presented, focusing on the kinetic andmechanistic aspects.

(a) DMAP-Catalyzed IPTC Reactions Involving �-Amino Acids. Asai et al. [180] stu-died the DMAP-catalyzed IPTC reaction of benzoyl chloride with glycine inH2O=CH2Cl2 medium in the absence of NaOH(aq), which produced high yields (up to94%) of hippuric acid, a precursor for the synthesis of aromatic amino acids such astryptophan and phenylalanine, etc., and the raw material of azlactone dyes. Themechanism of this reaction can be described as follows:

DMAPaq Ð DMAPorg ð73ÞDMAPorg þ PhCOClorg Ð DMAPCOPhþCl�org ð74ÞDMAPCOPhþCl�org Ð DMAPCOPhþCl�aq ð75ÞDMAPCOPhþCl�org þH2NCH2CO2Horg! PhCOONHCH2CO2Horg

þDMAPHþCl�org ð76ÞDMAPCOPhþCl�aq þH2NCH2CO2Haq! PhCOONHCH2CO2Haq

þDMAPHþCl�aq ð77ÞThe DMAPCOPhþCl� ion pair is the active ionic intermediate, formed by the reac-

tion of benzoyl chloride and DMAP in the organic phase. It was observed that the overallreaction rates were proportional to the interfacial concentration of DMAPCOPhþCl� inthe aqueous phase. In the absence of DMAP, the reaction was about three to four orders ofmagnitudes slower than that of the DMAP-catalyzed reaction. The yield of hippuric aciddecreased with increasing amounts of NaOH added, due to the hydrolysis of benzoylchloride. The overall rates could be rationalized by theoretical calculations based on theproposed model of this IPTC system including the consideration of the mass transferresistance of relevant reaction species. In contrast, Wang et al. [181] examined the feasibilityof the DMAP-catalyzed reaction of benzoyl chloride and the sodium salt of glycine in H2O(7 < pH < 10Þ=CH2Cl2 medium (Fig. 3). It was observed that the rates of both the unca-talyzed and DMAP-catalyzed reactions were fast and the yields of hippuric acid were veryhigh (up to 100%). These results were in contrast to those performed in the absence ofNaOH, in which both the reaction rate and the yield of hippuric acid were very low for theuncatalyzed reaction mentioned above [180]. It was observed that the reaction ratedepended on the agitation rate below 1200 rpm and on the shape of the reaction vessel


[181]. Both the uncatalyzed and DMAP-catalyzed reactions followed pseudo-first-orderkinetics in the initial presence of excess amount of the sodium salt of glycine (sodiumaminoacetate). Both the observed apparent pseudo-first-order rate constants increasedwith the initial concentrations of sodium aminoacetate and DMAP in the aqueousphase. The mechanism of the uncatalyzed reaction can be described by the followingreactions:

H2NCH2CO�2 aq þH2OÐ H2NCH2CO2Haq þOH�aq ð78Þ

H2NCH2CO2Haq Ð H2NCH2CO2Horg ð79ÞH2NCH2CO2Horg þ PhCOClorg! PhCONHCH2CO2Horg þHClorg ð80ÞH2NCH2CO

�2 ifPhCOClif ! PhCONHCH2CO2Hif þ Cl�if ð81Þ

The hippuric acid can be generated via Step 3 [Eq. (80)] in the organic phase and Step 4[Eq. (81)] in the interfacial region (if). The mechanism of the DMAP-catalyzed reactioncan be described by Eqs (73)–(83):

DMAPCOPhþClorg þH2NCH2CO2Horg! PhCOONHCH2CO2Horg

þDMAPHþCl�org ð82ÞDMAPCOPhþCl�aq þH2NCH2CO

�2 aq ! PhCOONHCH2CO2Haq

þDMAPaq þ Cl�aq ð83ÞIn the uncatalyzed reaction, the reaction rate was determined by Eqs. (80) and (81)

and in the DMAP-catalyzed reaction it was controlled by Eqs (74), (82), and (83). It wasdemonstrated that the reaction rates were similar in parallel experiments in which DMAPwas present initially in the organic and in the aqueous phase, respectively, which impliedthat the mass transfer of DMAP between the two phases was extremely rapid. Since thepKa values relative to water are 10–11, 4–5, and �1:74 for RNHþ3 , RCOOH, and H2O,respectively [182], the nucleophilicity of RNH2 is considerably higher than that of theRCCO� ion. Therefore, the reaction of PhCOCl with H2NCH2CO

�2 to yield

PhCOOCOCH2NH2 is negligible, as observed [181]. Since no benzoic acid was detected,the hydrolysis of PhCOCl was also negligible. Similar results were observed for othersodium salts of �-amino acids (RNHCHR 0COOH). These reactions proceeded rapidlyto produce PhCONRCHR 0COOH with high yields (85–100%). The order of reactivities ofamino acids was (N-methylglycine, l-prolineÞ � glycine� dl-alanine > 2-methylalanineð� acetic acid) [183]. The reactivities of these amino acids depended on their nucleopholi-cities and organophilicities (solubilities in CH2Cl2) and on the steric hindrance, e.g., thelow reactivity of 2-methylglycine was due to both the low solubility in CH2Cl2 and the

FIG. 3 Inverse phase transfer catalysis: the dimethylaminopyridine-catalyzed reaction of benzoyl

chloride and sodium salt of glycine.


steric hindrance of the 2-methyl group. An attractive application of the IPTC techniquewas demonstrated in the protection of the amino group of dl-serine with carbobenzoxychloride (benzyl chloroformate) in H2O=CH2ClCH2Cl medium catalyzed by DMAP [184].This method is useful for preparing the precursor for synthesizing the peptide containingthe serine moiety, since the protection of amino acids by the carbobenzoxy group isgenerally made in the alkaline solution, which is not applicable to dl-serine due to itsdecomposition in the alkaline solution to produce byproducts such as glycine.

(b) PNO-Catalyzed IPTC Reactions Involving Carboxylate Ions. Fife and coworkers[176,185] reported a similar IPTC process in which PNO was used instead of DMAP asthe IPTC catalyst in the two-phase reactions of acid chlorides and carboxylate ions tosynthesize the acid anhydrides (Fig. 4), which, being less reactive than acyl chlorides,are very important intermediates for the synthesis of esters, amides, and peptides. Jwoand coworkers [186–196] have carried out a systematic study on the kinetics andmechanism of the two-phase substitution reactions of benzoyl chlorides and carboxylateions using PNO as the IPTC catalyst, focusing on the substituent effects of benzoylchlorides, the structural effects of carboxylate ions, and the solvents, etc. Based on thekinetic results, a detailed mechanism was proposed for the PNO-catalyzed substitutionreaction of benzoyl chloride and benzoate ion in H2O=CH2Cl2 medium [186]. The mainreaction steps are shown as follows:

PNOaq Ð PNOorg ð84ÞPhCOClorg þ PNOorg ! PhCOONPþCl�org ð85ÞPhCOONPþCl�org Ð PhCOONPþCl�aq ð86ÞPhCOONPþaq þ PhCOO�aq! ðPhCOÞ2Oaq þ PNOaq ð87ÞPhCOONPþCl�org þH2O! PhCOOHaq þ PNOHþCl�aq ð88ÞPhCOClþH2O! PhCOOHþHCl ð89ÞReaction (89) can take place in both the organic and aqueous phases and in the

interfacial region. It was generally observed that without agitation the reaction rate wasslow and it increased with increasing agitation speed. However, the reaction rate wasindependent of the agitation speed beyond 1100 rpm in H2O=CH2Cl2 medium. ThePNO-catalyzed IPTC reactions of benzoyl chloride and benzoate ion produced a substitu-tion product (benzoic anhydride) and a hydrolysis product (benzoic acid). A high yield(> 95%) of benzoic anhydride could be obtained if a polar solvent like CH2Cl2 was used.Under suitable reaction conditions, the reaction followed pseudo-first-order kinetics asshown in Eq. (90):

FIG. 4 Inverse phase transfer catalysis: the pyridine 1-oxide-catalyzed reaction of benzoyl chloride

and sodium benzoate.


�d½PhCOCl�org=dt ¼ kobs½PhCOCl�org ð90Þ

The observed pseudo-first-order rate constant (kobs) depended linearly on the initial con-centration of PNO in the aqueous phase ð½PNO�iaq) and could be expressed as

kobs ¼ kh þ kc½PNO�iaq ð91Þ

In Eq. (91), kh and kc were the uncatalyzed (or hydrolysis) rate constant and cata-lyzed rate constant, respectively. Therefore, the reaction of PhCOCl and PNO in theorganic phase to yield the ionic intermediate, 1-(benzoyloxy)pyridinium chloride, [reaction(85)] was the rate-determining step in the PNO-catalyzed reaction path, which led mainlyto the production of benzoic anhydride. The value of kh obtained from the linear plot ofkobs versus ½PNO�iaq was generally consistent with that obtained in the uncatalyzed reac-tion. Therefore, reaction (89) was the main step in the uncatalyzed (hydrolysis) path,which led to the production of benzoic acid. In the following discussion, the main featuresof this IPTC system are described.

Solvent effects. In the PNO-catalyzed IPTC reaction of PhCOCl and benzoate ion,the order of the reaction rate in different two-phase media was H2O=CH2Cl2 >n-C6H14

=H2O > C6H6=H2O and the yield of benzoic anhydride in H2O=CH2Cl2 was considerablyhigher than those in the other two media. Similar results were generally observed for otherbenzoyl chlorides and carboxylate ions [191,192,194–196]. For example, for½PhCOCl�iorg ¼ 0:01M, ½PhCOONa�iaq ¼ 0:5M, and ½PNO�iaq ¼ 6� 10�4 M, the valuesof kobs at 22�C are (2.50, 2.25, and 0:417Þ � 10�3 s�1 for H2O=CH2Cl2, n-C6H14=H2O,and C6H6=H2O media, respectively. Although the reaction rate was fast in C6H6=H2Omedium, the reaction generated mainly the hydrolysis product, benzoic acid.Thermodynamically, the distribution of PNO in the organic phase is favored by thepolarity of the organic solvent. Kinetically, the reaction is also more favorable to takeplace in polar organic solvent as mentioned in Section II.B. Kinetic aspects, since thetransition state formed by PhCOCl and PNO (the rate-determining step [Eq. (85)] ismore ionic than both PhCOCl and PNO. These arguments were also strongly supportedby the PNO-catalyzed IPTC reaction of PhCOCl and acetate ion [187]. It was observedthat the order of relative reaction rates with respect to the effect of organic solvents wascyclohexanone > CH2Cl2 � CHCl3 > CCl4, which was consistent with the order of pola-rities. It was also found that in the H2O=CH2Cl2 medium (keeping the volume of organicphase constant), the reaction rate increased with the addition of an inert organic substancehaving larger polarity than CH2Cl2 such as nitrobenzene and benzonitrile whereas itdecreased with increasing amounts of added CCl4 [187]. Selected values of kobs areshown in Table 1.

Effects of carboxylate ions. The effects of carboxylate ions on the PNO-catalyzedIPTC reactions of PhCOCl and sodium carboxylates in H2O=CH2Cl2 medium were inves-tigated for selected carboxylate ions including formate, acetate, propionate, 2-methylpro-panoate, pentanoate, hexanoate, heptanoate, and octanoate ions [189]. It was found thatthe values of kobs depended somewhat on the type of the carboxylate ion under similarreaction conditions. For example, for ½PhCOCl�iorg ¼ 0:0100M, and½RCOONa�iaq ¼ 0:500M, the values of kc in kobs ¼ kh þ kc½PNO�iaq at 188C were (3.50,3.55, 3.52, 3.77, 3.83, 3.75, 3.83, and 3:35Þ �M�1 s�1 for RCOONa ¼ HCOONa,CH3COONa, C2H5COONa, ðCH3Þ2CHCOONa, n-C4H9COONa, n-C5H11COONa, n-C6H13COONa, and n-C7H15COONa, respectively. These results were rationalized bythe good correlations of the distribution of PNO in the CH2Cl2 phase and the carboxylate


ions in the aqueous phase [189,193]. The peculiar effect of the butanoate ion is described ina subsequent subsection.

The effects of dicarboxylate [RðCOONaÞ2] ions on the PNO-catalyzed IPTC reac-tions of PhCOCl and sodium dicarboxylates in H2O=CH2Cl2 medium were investigated onselected dicarboxylate ions including oxalate, malonate, maleate, fumarate, succinate,adipate, nonanedioate, phthalate, isophthalate, and terephthalate [190]. In general, theobserved products included mono- and bis-(benzoyloxycarbonyl) compounds, benzoicanhydride, and benzoic acid, which depended on the molecular structure of the dicarbox-ylate ion. Four types of dicarboxylate ions were classified according to the distribution ofproducts shown as follows:

1. Type I dicarboxyltes: the main product was PhCOOH (70–80%) and the minorproduct was ðPhCOÞ2O. Neither mono- nor bis-(mixed anhydride) productswere detected. They included oxalate, malonate, maleate, and succinate.

2. Type II dicarboxylates such as phthalate: the main product was the mono-(benzoyloxycarbonyl) compounds (PhCOOCORCOOH) and the minor pro-ducts were (PhCOÞ2O and PhCOOH.

3. Type III dicarboxylates: the main product was bis-(mixed anhydride)[RðCOOCOPhÞ2� with 70–88% yield. The minor products were (PhCOÞ2O,PhCOOH, or PhCOOCORCOOH. They included fumarate, isophthalate,and nonanedioate.

4. Type IV dicarboxylates such as adipate: the main products were PhCOOH andRðCOOCOPhÞ2; the minor products were (PhCOÞ2O and PhCOOCORCOOH.

Similar to the effects of monocarboxylates, the reaction rates depended significantlyon the type of dicarboxylates. For ½PhCOCl�iorg ¼ 0:0100M and½RðCOONaÞ2�iaq ¼ 0:500M, the values of the catalyzed rate constant (kc) at 18

�C were(4.10, 4.02, 3.83, 3.03, 4.27, 4.08, 3.80, 2.73, and 2:72Þ �M�1 s�1 for malonate, succinate,maleate, fumarate, adipate, nonanedioate, phthalate, isophthalate, and terephthalate,respectively. For ½PhCOCl�iorg ¼ 0:0100M, ½ðCOONaÞ2�iaq ¼ 0:200M, and½NaNO3�iaq ¼ 0:300M, the value of kc at 18

�C was 2:67M�1 s�1 for oxalate. These resultswere also rationalized by the good correlations of the distribution of PNO in CH2Cl2 andthe dicarboxylate ions, with the exception of the nonanedioate ion, due to interference by

TABLE 1 Effect of Composition of Organic Solvent on PNO-Catalyzed

Substitution Reaction of Benzoyl Chloride and Sodium Acetate in Two-Phase

H2O/Organic Solvent Medium

Organic solvent kobs ð10�4 s�1Þ Organic solvent kobs ð10�4 s�1Þ

Cyclohexanone 17.7 CH2CL2 (0.5M PhCN) 10.1

CHCl3 3.25 CH2Cl2 (0.5M PhNO2) 9.50

CCl4 2.70 CH2Cl2 (1.5M PhNO2) 10.1

CH2Cl2 8.08 CH2Cl2 (0.5M CCl4) 7.08

CH2Cl2 (0.5M PhCH2CN) 10.2 CH2Cl2 (1.5M CCl4) 4.75

CH2Cl2 (1.5M PhCH2CN) 12.0

½PhCOCl�iorg ¼ 0:0100M, ½PhCOONa�iaq ¼ 0:500M, and ½PNO�½iaq¼ 2:00� 10�4 M, at 18�C.Source: Ref. 187.


the emulsion phenomenon [189]. Reaction steps for the generation of RCOOCOPhCOOHand RðCOOCOPhÞ2 were proposed as follows:

Aqueous phase reaction:

PhCOONPþaq þRðCO�2 Þ2 aq ! PhCOOCORCO�2 aq þ PNOaq ð92ÞPhCOONPþaq þ PhCOOCORCO�2 aq ! RðCOOCOPhÞ2 aq þ PNOaq ð93ÞOrganic phase reaction:

PhCOONPþorg þRðCO2HÞ2org! PhCOOCORCO2Horg þ PNOorg ð94ÞPhCOONPþorg þ PhCOOCORCO2Horg ! RðCOOCOPhÞ2org þ PNOorg ð95ÞInterfacial reaction:

PhCOONPþif þRðCO�2 Þ2if ! PhCOOCORCO�2 if þ PNOif ð96ÞPhCOONPþif þ PhCOOCORCO�2 if ! RðCOOCOPhÞ2 if þ PNOif ð97ÞType I dicarboxylates tend to exist in the aqueous phase due to their low organo-

philicities. Reactions (92) and (93) or (96) and (97) were inhibited by the steric effect ofthe nearby second carboxylate group. As a consequence, the reaction was dominated bythe hydrolysis path [reactions (88) and (89)] to produce PhCOOH. Since the conjugateacids of phthalate (Type II dicarboxylate) ion and PhCOOCOC6H4CO

�2 ion had higher

organophlicities than those of the Type I dicarboxylates, the observed main product,PhCOOCOC6H4CO2H could be generated by reactions (92), (94), and (96). However,reactions (93), (95), and (97) were inhibited by the steric effect of the second carboxylatogroup at the ortho-position, since no C6H4ðCOOCOPhÞ2 was detected. In contrast, themain products were the bis(benzoyloxycarbonyl) compounds [RðCOOCOPhÞ2] for TypeIII dicarboxylates due mainly to the release of the steric hindrance of the second car-boxylato group. For isophthalate and terephthalate systems, reactions (92–97) wereinvolved in the generation of C6H4ðCOOCOPhÞ2. For the fumarate system, trans-C2H4ðCOOCOPhÞ2 was generated mainly via reactions (92) and (93) and (96) and(97), which was in contrast to its cis isomer, maleate (Type I). For the nonanedioatesystem, ðCH2Þ7ðCOOCOPhÞ2 was produced mainly by reactions (96) and (97) due to itssurfactant property. The propertities of succinate (Type IV dicarboxylates) ion seemedto occur at an intermediate position in these series and a wide distribution of products[(PhCOOH, ðCH2Þ4ðCOOCOPhÞCOOHÞ > ðPhCOÞ2O > ðCH2Þ4ðCOOCOPhÞ2] wasobserved.

Effects of substituents. In the PNO-catalyzed reaction of benzoyl chloride withbenzoate ion in H2O=CH2Cl2 medium, it was observed that the reaction of benzoylchloride and PNO in the CH2Cl2 phase to form the intermediate, 1-(benzoyloxy)pyridi-nium chloride, was the rate-determining step. Therefore, it was worthwhile investigatingthe effects of substituents on this system. The substituents included CH3, ðCH3Þ3C, CH3O,F, Cl, Br, and I groups. Similar to the PhCOCl/PhCOONa system, these reactions fol-lowed pseudo-first-order kinetics with the observed pseudo-first-order rate constant, kobs¼ kh þ kc ½PNO�iaq, Eq. (91). The values of the catalyzed rate constant (kc)[186,191,192,194,196] for XC6H4COCl are summarized in Table 2. The values of kc at22�C for the PNO-catalyzed reactions of Cl2C6H3COCl and the correspondingCl2C6H3COONa in H2O=CH2Cl2 medium to produce symmetric (Cl2C6H3COÞ2O were(15.6, 11.1, 15.4, and 57:3Þ �M�1 s�1 for, 2,3-, 2,4-, 3,4-, and 3,5-C6H3COCl, respectively[195]. The values of kc for the PNO-catalyzed reactions of Cl2C6H3COCl and PhCOONa


in H2O=CH2Cl2 medium to produce mixed PhCOOCOC6H3Cl2 were 11:6M�1 s�1 (22�C),

12:4M�1 s�1 (20�C), 7:98M�1 s�1 (20�C), and 10:5M�1 s�1 (22�C) for 2,3-, 2,4-, 3,4-, and3,5-C6H3COCl, respectively [195]. Good Hammett corelations were obtained for the meta-and para-substituents in the plot of logðkc=kcH) versus , where was the substituentconstant and kcH was the catalyzed rate constant of the parent compound (PhCOCl)(Fig. 5) [196]. The reaction constant (�) of the Hammett equation logðkc=kcHÞ ¼ �] soobtained for this reaction series was þ1:3, which implied that this reaction was a nucleo-philic substitution reaction and was expected to be accelerated by the electron-withdraw-ing substituent and retarded by the electron-donating substituent as observed in thesereactions. It is well known that the application of the Hammett equation to the ortho-substituent is usually poor mainly due to the steric effect. However, besides the inductiveand resonance effects, the electron-withdrawing ortho-substituent (F, Cl, Br, or I) alsofacilitates the reaction considerably by complexing with the positively charged nitrogenatom of the pyridinium moiety. In contrast, the electron-donating ortho-substituent (CH3

or CH3O) also retards the reaction via the steric effect.Reversible PNO-catalyzed benzoyl chloride / carboxylate systems. In contrast to

the other carboxylates (see earlier subsection), a peculiar phenomenon was observed in thePNO-catalyzed IPTC reaction of PhCOCl and butanoate (PrCOO�) ion in H2O=CH2Cl2medium, which led to an equilibrium with the PNO-catalyzed reaction of butanoylchloride (PrCOCl) and benzoate ion and vice versa [188]. It was observed that thePNO-catalyzed reaction of PrCOCl and PhCOO� ion reached equilibrium much morerapidly than that of PhCOCl and PrCOO� ion. For the PhCOCl/PrCOONa system, themain product was PrCOCl and the expected mixed benzoic butanoic anhydride

TABLE 2 Effects of Substituents on Catalyzed Rate Constant

(kc) for PNO-Catalyzed Reaction of Benzoyl Chloride

(XC6H4COCl) and Benzoate Ion (YC6H4COONa) in

H2O=CH2Cl2 Medium

X Y

kc(M�1 s�1) Ref. X Y

kc(M�1 s�1) Ref.

H H 3.60 186 2-Cl 2-Cl 8.10 191

2-CH3 2-CH3 1.49 196 2-Cl H 10.1 191

3-CH3 3-CH3 2.53 196 3-Cl 3-Cl 6.43 191

4-CH3 4-CH3 1.53 196 3-Cl H 6.37 191

4-ðCH3Þ3 H 1.87 194 4-Cl 4–Cl 5.37 191

3-CH3O 3-CH3O 3.40 196 4-Cl H 5.43 191

2-CH3O H nega 196 2-Br 2-Br 7.10 192

3-CH3O H 1.83 196 2-Br H 7.37 192

4-CH3O 4-CH3O 0.712 196 3-Br 3-Br 6.10 192

4-CH3O H 0.640 196 3-Br H 6.21 192

2-F 2-F 9.10 194 4-Br 4-Br 5.80 192

2-F H 10.4 194 4-Br H 5.61 192

3-F 3-F 6.10 194 2-I 2-I 17.5 196

3-F H 6.80 194 2-I H 10.9 196

4-F 4-F 3.40 194 4-I H 6.83 196

4-F H 3.93 194

a Negligible (mainly hydrolysis).


(PhCOOCOPr) was not observed. However, both PhCOOH and ðPhCOÞ2O (trace) wereobserved. The equilibrium conversion (Xeq) of PhCOCl depended on the concentrations ofPNO and PrCOO� ion for a given concentration of PhCOCl. For example, for½PhCOCl�iorg ¼ 0:0100M and ½PNO�iaq ¼ 6:00� 10�4 M, the values of Xeq at 18�C were0.536 and 0.552 for ½PrCOONa�iaq ¼ 0:500 and 0.100M, respectively. For½PhCOCl�iorg ¼ 0:0100M and ½PrCOONa�iaq ¼ 0:500M, the values of Xeq at 18�C were

0.494 and 0.519 for ½PNO�iaq ¼ 2:00� 10�4 and 4:00� 10�4 M, respectively. The value ofXeq depended insignificantly on the concentration of PhCOO� ion, the pH value(6:5 < pH < 10:7), the Cl� ion (by adding benzyltriethylammonium chloride), and thetemperature. The value of Xeq and the yield of ðPhCOÞ2O depended on the concentrationof PhCOO� ion, e.g., for ½PhCOCl�iorg ¼ 0:0100M, ½PNO�iaq ¼ 2:00� 10�4 M and½PrCOONa�iaq ¼ 0:500M, the values of [Xeq, ðPhCOÞ2O yield] at 18�C were 0.494 and2.78% and 0.554 and 25.7% for ½PhCOONa�iaq ¼ 0 and 0.2M, respectively. In contrast,in the PrCOCl/PhCOONa system, the reaction rapidly reached the equilibrium state withmuch smaller equilibrium conversion (< 0:1) to yield PhCOCl and no PrCOOCOPh beingdetected. PNO exhibited a great effect on the equilibrium yield of PhCOCl. Even in theabsence of PNO, a small amount of PhCOCl was observed. For example, for½PrCOCl�iorg ¼ 0:0100M and ½PhCOONa�iaq ¼ 0:500M, at 18�C, the values of the equili-brium concentration of PhCOCl were (1.16, 4.73, 7.09, and 10:3Þ � 10�4 M for½PNO�iaq ¼ ð0, 2.00, 4.00, and 8:00Þ � 10�4 M, respectively. In the uncatalyzed reaction,PhCOCl could be produced via the following reaction:

PrCOClorg þ PhCOOHorg Ð PhCOClorg þ PrCOOHorg ð98Þ

FIG. 5 Inverse phase transfer catalysis: Hammett plot for the pyridine 1-oxide-catalyzed reactions

of benzoyl chlorides and benzoate ions.


For ½PhCOCl�iorg ¼ 1:00� 10�3 M, the measured values of the equilibrium constantof reaction (98) at 18�C were (7.92 and 7:73Þ � 103 for ½PrCOOH�iorg ¼ 0:500 and 1.00M,respectively. The equilibrium concentration of PhCOCl was increased considerably by thepresence of a relatively small amount of Cl� ion (added as PhCH2Et3N

þCl�), in contrastto the insignificant effect of Cl� ion in the PhCOCl/PrCOONa system. The experimentalresults indicated that the mechanism of this system was very complicated. A simplifiedmechanistic description is shown in the following reaction steps:

PhCOClorg þ PNOorg Ð PhCOONPþCl�org ð85ÞPrCOClorg þ PNOorg Ð PrCOONPþCl�org ð99ÞPhCOONPþCl�aq þ PrCOO�aq Ð PhCðO�ÞðOCOPrÞðONPþÞCl�aq ð100ÞPrCOONPþCl�aq þ PhCOO�aq Ð PrCðO�ÞðOCOPhÞðONPþÞCl�aq ð101ÞPhCðO�ÞðOCOPrÞðONPþÞaq Ð PrCðO�ÞðOCOPhÞðONPþÞaq ð102ÞPhCðO�ÞðOCOPrÞðONPþÞaq Ð PhCOOCOPraq þ PNOaq ð103ÞPrCðO�ÞðOCOPhÞðONPþÞaq Ð PrCOOCOPhaq þ PNOaq ð104ÞPhCOONPþaq þ PhCOO�aq Ð ðPhCOÞ2Oaq þ PNOaq ð87ÞPrCOONPþaq þ PrCOO�aq Ð ðPrCOÞ2Oaq þ PNOaq ð105ÞReactions (100)–(104) play an important role in this reversible reaction. The beha-

vior of the reaction of mixed benzoic butanoic abhydride, PhCOOCOPr, and PNO issimilar to that of the acylation reaction of benzene catalyzed by AlCl3 [197].Furthermore, it is generally believed that the exchange reaction of acyl halide (RCOX)and carboxylic acid (R 0COOH) in a homogeneous organic medium takes place via a mixedacid anhydride intermediate:

RCOXþR 0COOHÐ ðRCOOCOR 0 þHXÞ Ð RCOOHþR 0COX ð106ÞThe reactivity of RCOCl is increased by an electron-withdrawing substituent and

decreased by an either electron-donating or a steric-hindered substituent. Similar argu-ments are applicable to acid anhydride (RCOOCOR 0). Acid anhydrides are generallymore stable than the related acyl chloride. As reported by Ugi and Beck [198], the relativereactivities of RCOCl toward hydrolysis in 89% aqueous acetone at �20�C were Cl3C(9200), ClCH2 (1.9), CH3 (1.0), C2H5 (0.69), n-C3H7 (0.54), (CH3Þ2CH (0.41), (CH3Þ3C(0.068), PhCH2 (0.33), and Ph (0.0038). As reported by Bunton et al. [199], the relativereactivities of RCOOCOR 0 toward hydrolysis in dioxane/water at 25�C were (CH3COÞ2ð1:0Þ > CH3COOCO Ph ð0:74Þ > ðPhCOÞ2O (0.033). In general, acid anhydrides withsmall alkyl groups are unstable and those with phenyl groups are considerably morestable. Thus, the order of relative reactivities is PrCOCl > PhCOCl > ðPrCOÞ2O >PhCOOCOPr > ðPhCOÞ2O, which is supported by experimental results [188]. Mixedacid anhydrides are unstable and prone to disproportionation and/or decomposition inthe presence of carboxylic acids and carboxylates. Wong and Jwo [200] studied theexchange reaction of symmetric benzoic and 2-chlorobenzoic anhydrides in CHCl3 toproduce mixed benzoic 2-chlorobenzoic anhydride. It was found that the reactionrate was slow and varied abnormally with the concentration ratio of½ðPhCOÞ2O�=½ð2-ClC6H4COÞ2O]. The reaction was promoted substantially by PNO andbenzoate salts. When 2-(ClC6H4COÞ2O was the limiting reactant, the order of reactivities


for promoting the exchange reaction was (PhCOOLi, PhCOONBu4Þ > PhCOONa> PhCOOH. Unexpectedly, the exchange reaction did not follow simple second-orderor pseudo-first-order kinetics. However, in the presence of PNO or benzoate salt, thereaction did follow pseudo-first-order kinetics under pseudo-order reaction conditions.Therefore, the mechanism of this exchange reaction was more complicated than expectedand the complex formation between two acid anhydrides could play a key role [200].

An interesting reversible phenomenon was also observed in the PNO-catalyzed reac-tion of nitrobenzoyl chlorides and the corresponding nitrobenzoate ions in H2O=CH2Cl2medium [196]. In the absence of PNO and carboxylate salt, a complete hydrolysis reactionwas observed for 2-, 3-, or 4-NO2C6H4COCl, whereas it reached an equilibrium in thepresence of PNO. The PNO-catalyzed reactions of 2-, 3-, and 4-NO2C6H4COCl andPhCOONa to synthesize mixed acid anhydride were unsuccessful. However, symmetric4-(NO2C6H4COÞ2O could be obtained with low yield, e.g., for [NO2C6H4COCl�iorg ¼0:010M, NO2C6H4COONa�iaq ¼ 0:50M, and ½PNO�iaq ¼ 4� 10�4 M. The reactionrapidly reached an equilibrium state with the yield of 4-(NO2C6H4COÞ2O being about40% [196].

D. Two-Phase Wittig Reactions

The Wittig reaction is one of the most important reactions in organic chemistry for thesynthesis of alkenes with unambiguous positioning of the C––C double bond. A compre-hensive review was made by Maryanoff and Reitz [201]. Maerkl and Merz [202] demon-strated that the Wittig reactions could be carried out in organic solvent/NaOH(aq)medium, in which ylides were generated by the reactions of quaternary alkyltriphenylpho-sphonium salts and NaOH in the aqueous phase, and then transferred into the organicphase to react with aldehydes to produce alkenes. One drawback of this two-phase Wittigreaction was the decomposition of quaternary phosphonium salts by NaOH(aq) to tri-phenylphosphine oxide, which depended on the solvent [CH2Cl2 � ðC6H6, n-C6H14Þ > nosolvent] and seemed to be catalyzed by Bu4N

þX� salts (X ¼ Cl > Br > I) [203]. Typicaltwo-phase Wittig reactions were performed in the following system: K2CO3ðsÞ=C6H6,Kþtert-BuO�(s)/C6H6, 50%NaOH(aq)/CH2Cl2, NaOH(s)/C6H6, and KF(s)/C6H6 orCH2Cl2 [204].

Based on the mechanistic aspect, two-liquid phase Wittig reactions cannot becounted as phase transfer catalyzed reactions, since it has been argued that phosphoniumsalts themselves are known to be PTC catalysts and the resulting ylenes are neutral speciesthat can diffuse into the organic phase without the assistance of a catalyst. However, theclosely related two-liquid phase Wittig–Horner and Horner–Emmons reactions are cata-lyzed by quaternary ammonium salts or crown ethers and are considered as PTC reac-tions. Therefore, it is useful to extend the concept of PTC to include two-phase Wittigreactions [10,18]. The two-phase Wittig reaction with NaOH(aq) is generally limited toaldehydes. Most of the studies on Wittig reactions were carried out homogeneously inorganic solvents such as THF, C6H6, CCl4, CHCl3, DMF, and CH3OH. In contrast, lesswork has been reported for the heterogeneous Wittig reactions. Jwo and coworkers[205,206] investigated the two-phase Wittig reactions of various benzyltriphenylphospho-nium salts (Ph3P

þCH2Ph0X�) and benzaldehydes (Ph 00CHO) in various organic solvent/

NaOH(aq) media (Fig. 6), focusing on the effects of substituents and organic solvents.This reaction system was chosen for study because of the convenience for two-liquid phasereactions and the versatility of varying the organic solvents and the substituents on the


ylide and benzaldehyde for studying their effects on the Z/E ratio of the product stilbene.These systems can be described by the following main reactions:

Ph3PþCH2Ph

0aq þOH�aq! ðPh3Pþ �CHPh 0 $ Ph3P ¼ CHPh 0Þaq ð107Þ

ðPh3Pþ �CHPh 0 $ Ph3P ¼ CHPh 0Þaq Ð ðPh3P ¼ CHPh 0Þorg ð108ÞðPh3P ¼ CHPh 0org þ Ph 00CHO! Ph 0CH ¼ CHPh 00org þ Ph3POorg ð109ÞThe mechanism of the homogeneous Wittig reaction [Eq. (109)] was generally

expressed in terms of two main steps: (1) the nucleophilic addition of the phosphorusylide to the carbonyl group to give intermediates (threo-betaine ¼ E form oxaphosphe-tane; erythro-betaine ¼ Z form oxaphosphetane), and (2) the irreversible decomposition ofthe intermediates to yield Z and E forms of alkene and phosphine oxide. The stereo-selectivity of the Wittig reaction is highly dependent on the substituents bonds to theylidic carbon and to the phosphorus atom, and on the reaction conditions, especiallythe organic solvent. In general, three categories of phosphonium ylides, namely, nonsta-bilized, semistabilized, and stabilized ylides, are classified. The Wittig reaction has beenshown to produce preferentially the thermodynamically stable E alkenes for stabilizedylides having strongly conjugating substituents such as COOMe or CN group; mixturesof the E and Z alkenes for semistabilized ylides bearing mildly conjugating substituentssuch as phenyl, vinyl, or allyl groups, and mainly contrathermodynamic Z alkenes for

FIG. 6 (a) Two-phase Wittig reaction mechanisms; (b) Organic phase reaction of

triphenylphosphonium ylide and benzaldehyde.


nonstabilized ylides lack such conjugating functionalities such as an alkyl group. In astudy of the two-phase Wittig reaction of Ph3P

þCH2Ph0X� salt and benzaldehydes

(Ph 00CHO) in organic solvent/NaOH(aq) medium [206], the substituents chosen forstudy included CH3, F, Cl, Br, CH3O, NO2, and CF3 and the organic solvents includedpolar solvents (CHCl3 and CH2Cl2) and nonpolar solvents (n-C6H14, C6H6, and CCl4).The main conclusions are summarized as follows:

1. The reaction rate was fast and independent of the agitation speed.2. The reaction of the intermediate, benzylidenetriphenylphosphorane

(PhP3 ¼ CHPh 0) and Ph 00CHO in the organic phase, was the decisive step responsiblefor the stereoselectivity.

3. In general, the yield and the Z/E ratios depended insignificantly on the concen-trations of phosphonium salt, Ph 00CHO, and NaOH, or agitation speed and temperature.

4. The substituents of Ph 00CHO exhibited considerably greater effects on the Z/Eratios of the product stilbene than those on the Ph3PCH2Ph

0þ ions. Therefore, the Z/Eratios of stilbene could change substantially by interchanging the substituents on thebenzyl group of the phosphorus atom and on the phenyl group of Ph 00CHO, even thoughthe product stilbene was the same. For example, the Z/E ratios were 1.4 and 3.3 for the (2-ClC6H4CH2PPh

þ3 -3-ClC6H4CHO) and (3-ClC6H4CH2PPh

þ3 -2-ClC6H4CHO) reactions in

NaOH(aq)/CH2Cl2 medium, respectively. The Z/E ratios were 4.5 and 1.8 for the (2-CH3C6H4CH2PPh

þ3 -2-BrC6H4CHO) and (2-BrC6H4CH2PPh

þ3 -2-CH3C6H4CHO) reac-

tions in NaOH(aq)/CH2Cl2 medium, respectively. The Z/E ratios were 6.8 and 1.5 forthe [2,5-(CH3Þ2C6H3CH2PPh

þ3 -2-ClC6H4CHO] and [2-ClC6H4CH2PPh

þ3 -2;5-ðCH3Þ2

C6H3CHO] reactions in C6H6/NaOH(aq) medium, respectively.5. In contrast to the meta- and para-substituted Ph 00CHO and the ortho-substituted

benzylidene ylide (Ph3P––CHPh 0), the ortho-substitued Ph 00CHO bearing heteroatom sub-stituent exhibited a pronounced enhancement for the Z selectivity with the order of effec-tiveness of substituents being CF3 > ðCl; BrÞ > CH3O > F > NO2. For example, for thereactions of 2,5-(CH3Þ2C6H3CH2PPh

þ3 ion and Ph 00CHO, the Z/E ratios were 0.93, 1.2,

2.3, 3.6, 0.71, 0.75, 4.0, 1.1, 3.6, 5.7, and 0.08 in NaOH(aq)/CH2Cl2 medium; and 0.63,0.84, 3.4, 6.8, 0.43, 0.41, 6.0, 2.0, 5.2, 9.6, and 0.04 in C6H6/NaOH(aq) medium forPhCHO, 2,5-(CH3Þ2C6H3CHO, 2-FC6H4CHO, 2-ClC6H4CHO, 3-ClC6H4CHO, 4-ClC6H4CHO, 2-BrC6H4CHO, 2-NO2C6H4CHO, 2,3,4-(CH3OÞ3C6H2CHO, 2-CF3C6H4CHO, and 2,6-Cl2C6H3CHO, respectively. This abnormal ortho effect was gen-erally rationalized by invoking the through space 2p–3d overlap effect. To avoid stericrepulsion, the phenyl group of the aldehyde should point away from the ylide and theC–P–O–C dihedral angle could then be varied freely. Assuming other things being equal,the complex would be expected to render a near 1 : 1 mixture of Z- and E-ozapho-sphetane, leading to a near 1 : 1 mixture of Z- and E-stilbenes. However, for an ortho-substituted Ph 00CHO bearing substituent such as F, Cl, Br, CH3O, or CF3, the Z selectivityof the oxaphosphetane could become more favorable due to chelate stabilization since thephosphorus atom (adopting a hypervalent octahedral structure) would co-ordinate to two-electron donating atoms, the carbonyl oxygen atom and the heteroatom of the ortho-substituent. However, in a 2,6-Cl2C6H3CHO system, the steric effect of two ortho-chlorosubstituents lowered the Z/E ratio substantially.

6. The effects of solvents depended somewhat on the substituent on the benzylgroup of the phosphonium ion. For XC6H4CH2PPh

þ3 (X ¼ H, CH3, F, Cl, Br,) ions,

the more polar solvents (CHCl3 and CH2Cl2) generally exhibited more favorable Z selec-tivity (CHCl3 > CH2Cl2). In contrast, for the ðCH3Þ2C6H3CH2PPh

þ3 ion, the nonpolar


solvents (CCl4, C6H6, and n-C6H14) could become more favorable for Z selectivity. Forexample, theZ/E ratioswere 1.2, 1.5, 1.2, 1.8, and 4.0 for the 2-ClC6H4CH2PPh

þ3 -2;5-ðCH3Þ2

C6H3CHO reaction system and 7.4, 6.8, 5.1, 3.6, and 5.8 for the 2;5-ðCH3Þ2C6H3CH2PPhþ3

-2-ClC6H4CHO reaction system with the organic phases being CCl4, C6H6, n-C6H14,CH2Cl2, and CHCl3, respectively.

7. The concerted asynchronous cycloaddition mechanism involving a four-centeredtransition state was suggested to be operating in these systems.

E. Asymmetric and Thermoregulated Phase Transfer Catalyses

Two novel methodologies termed ‘‘assymmetric phase transfer catalysis’’ and ‘‘thermo-regulated phase transfer catalysis’’ have been developed readily in the past decade andhave broadened greatly the scope of application of PTC. Therefore, it is worthwhile brieflydiscussing these two techniques.

1. Asymmetric Phase Transfer Catalysis

The use of optically resolved PTC catalysts for the synthesis of enantiomerically purecompounds is no doubt an attractive field. Asymmetric PTC has become an importanttool for both laboratory syntheses and industrial productions of enantiomerically enrichedcompounds. Recently, Lygo and coworkers [207–216] reported a new class of Cinchonaalkaloid-derived quaternary ammonium PTC catalysts, which have been applied success-fully in the enantioselective synthesis of �-amino acids, bis-�-amino acids, and bis-�-amino acid esters via alkylation [207–213] and in the asymmetric epoxidation of �=�-unsaturated ketones [214–216].

(a) Asymmetric �-Amino Acids. Chiral �; �-dialkyl-�-amino acids are an importantclass of noncoded amino acids in the design and the synthesis of modified peptides.Naturally occurring bis-�-amino acids such as dityrosines, isotyrosine, and meso-diami-nopimelic acid may act as cross-linking agents for stabilizing structural polymer ele-ments in plants and bacteria, and iodityrosine is a key structural subunit in a large classof bioactive peptides. O’Donnell et al. [217] first reported the use of chiral quaternaryammonium salts derived from Cinchona alkaloids as PTC catalysts for the asymmetricalkylation of amino acid imine esters to promote enantioselectivity. Lygo andWainwright [207] synthesized a class of Cinchona alkaloid-derived PTC catalysts viaquaterization of cinchonine, cinchonidine, dihydrocinchonine, dihydrocinchonidine, qui-nidine, and quinine using 9-chloromethylanthracene (Fig. 7). It was found that for theasymmetric phase transfer catalyzed alkylation of glycineimine in toluene/50%NaOH(aq), the quinidine- and quinine-derived catalysts were the least effective andthose derived from dihydrocinchonidine gave the best selectivity [94% enantiomericexcess (ee)]. N-Anthracenylmethylcinchonidinium chloride catalyzed (1) the PTC reac-tion of the enantio- and diastereo-selective synthesis of a series of bis-amino acids andesters with high enantioselectivity (> 95% ee) in toluene/50% NaOH(aq) medium [208–209]; (2) the PTC reactions of the alkylation of a series of alanine-derived imines withup to 87% ee in solid K2CO3=KOH medium [210]; and (3) the PTC alkylation of a ser-ies of benzophenone-derived glycineimines in toluene/50% KOH(aq) with up to 95% ee[213].

For environmental considerations (green chemistry), the organic solvent in thesesystems was generally toluene rather than CH2Cl2. However, the PTC alkylation of aseries of benzophenone-derived glycineimines catalyzed by N-anthracenylmethylcinchoni-


dinium chloride showed similar results using toluene of CH2Cl2 as the organic solvent[212]. In these systems, the alkylation reaction proceeded via ion-pair formation of thecarbanions and the chiral cinchona alkaloid-derived quaternary ammonium salts, whichrelied on the structure of the catalyst to promote the enantioselectivity. Lygo et al. [211]probed the role of key structural elements of a series of chiral cinchona alkaloid-derivedquaternary ammonium catalysts and concluded that the N-anthracenylmethyl substituentwas the key structural element that led to substantially enhanced enantioselectivity oversmaller N-alkyl substituents, which also suggested that the 1-quinonlyl group present inthe parent alkaloid played a key role in enantioselectivity.

Belokon and coworkers [218,219] reported a novel class of chiral metal complexesfor the asymmetric synthesis of �-amino acids under PTC conditions. The use of (4S,5S)-2,2-dimethyl-�; �; � 0; � 0-tetraphenyl-1,3-dioxane-4,5-dimethanol (TADDOL) promotedthe asymmetric PTC C-alkylation of Schiff’s bases of alanine esters with up to 82% ee[218], in which TADDOL functioned as a chelating agent for the alkali metal ions andmade the ion pair of the metal-ion complex and carbanion soluble in the organic solvent.Recently, Belokon et al. [219] have tested a series of chiral metal complexes of (1R,2R or1S,2S)-[N,N 0-bis-(2 0-hydroxylbenzylidene)-1,2-diaminocyclohexane (salen) as catalystsfor the C-alkylation of Schiff’s bases of alanine and glycine esters with alkyl bromidesunder PTC conditions in toluene/50% NaOH(aq) medium (Fig. 7) and found that theoptimal catalyst, (salen)Cu(II) complex gave �-amino and �-methyl-�-amino acids with eeof 70–96%.

(b) Asymmetric �; �-Epoxy Ketones. Recently, the enantioselective epoxidation of�; �-unsaturated ketones has received much attention. Lygo and coworkers [214–216]have investigated the enantioselective epoxidation of various �; �-unsaturated ketonesutilizing chiral Cinchona alkaloid-derived quaternary ammonium salts (e.g., N-anthrace-nylmethylcinchodinium salts) as PTC catalysts in conjunction with sodium hypochlorite,in which up to 90% ee could be obtained. A study on the factors affecting the rate ofthis reaction system suggested that ion exchange between the catalyst and sodium hypo-chlorite is the rate-determining step [216].

2. Thermoregulated Phase Transfer Catalysis

Recently, efforts to achieve facile catalyst/product separation in two-liquid phase transfercatalyzed systems have received considerable attention. Horvath and Rabai [220] devel-

FIG. 7 Asymmetric phase transfer catalysis: alkylation of glycine imine esters.


oped a fluorous two-phase system, based on the limited miscibility of partially or fullyfluorinated compounds with a nonfluorinated parent compound. Bianchini et al. [221]reported another method that is based on the solubility gap of metal–sulfur complexesin a two-phase methanol/hydrocarbon system. Both of these systems could become one-phase systems at appropriate higher reaction temperatures. However, after completion ofthe reaction, the reaction solution was cooled down to room temperature and then sepa-rated into two phases again, which facilitated the recovery of the catalyst.

Jin et al. [222] reported the synthesis of a series of novel polyether-substituted tri-phenylphosphines [4-HOðCH2CH2OÞn-C6H4�m-PPh3�m, m ¼ 1; 2 or 3] (PETPPs). PETPPsexhibited inverse temperature-dependent solubility in water and their Rh(III) complexescould act as PTC catalysts in thermoregulated PTC, which was successfully applied to thetwo-phase hydroformylation of higher alkenes (C6–C12) such as 1-dodecene in toluene/H2O medium (Fig. 8) with about 95% conversion and 85% aldehyde selectivity. Thisprocess can generally be described as follows. At room temperature, the Rh(III)–PETPP catalyst remains mainly in the aqueous phase. However, at a temperature higherthan the cloud point (or the critical solubility temperature), the catalyst precipitates fromwater and transfers into the organic phase, where it catalyzes the hydroformylation reac-tion of (CO=H2) and alkenes to produce aldehydes. After the reaction is complete, thesystem is cooled down to room temperature and the catalyst returns to the aqueous phase.Therefore, a simple phase separation allows continuous reuse of the catalyst. The inversetemperature-dependent solubility phenomenon of Rh(III)–PETPP catalyst in water isattributed mainly to the cleavage of the hydrogen bonds between the polyether chainsand water molecules on heating. Jin and coworkers [223–228] have also developed a seriesof nonionic water-soluble phosphine ligands bearing polyethylene moieties and appliedthem successfully in the hydroformylation of higher alkenes via the attractive thermore-gulated PTC.

V. POSTSCRIPT

In this chapter, an overview of fundamentals and selected systems of PTC is presented.The development of PTC has followed the scientific trend that a successful PTC applica-tion frequently stimulates further research that in turn leads to more applications andimproved processes. The growth of PTC is also accelerated by its applications in thechemical industry. Today, PTC has grown to become a very important and widely applied

FIG. 8 Thermoregulated phase transfer catalysis: hydroformylation of higher olefins (C6–C12).


methodology in organic syntheses. No doubt numerous novel catalysts, methodologies,and new applications based on PTC wait for discovery and exploration.

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