Polyethylene glycol and solutions of polyethylene glycol as green reaction media

Abstract

In this review, we examine the concept that aqueous biphasic reactive extraction (ABRE) can successfully integrate the solvent properties of polyethylene glycol (PEG) and its phase-transfer characteristics into a single efficient system which can additionally be manipulated to facilitate the separation of reactants and/or catalysts from products. We also suggest that the properties of these systems may recommend them as being relatively environmentally benign in comparison to the current use of organic solvents in extraction and in reactive extraction. In developing this concept, we review a number of the physical and chemical properties of PEG and aqueous solutions of PEG in the context of recent applications to chemical reaction engineering. Thus, we cover the interesting physical properties of PEG solutions in water, their unique solvent properties, and finally the metal cation coordination ability of PEG solutions. These properties are important in the application of low molecular weight liquid PEG as a solvent in chemical reactions; in the use of PEG as an alternative phase-transfer catalyst (PTC); and in the application of ABRE in the development of alternative pulping processes, catalytic chemistry, and enzymatic catalysis.

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1. Introduction

Regulatory pressure is increasingly focusing on the use, manufacture, and disposal of organic solvents, and thus the development of nonhazardous alternatives (one of several goals of green chemistry and engineering) is vitally important for the continued and sustainable development of the chemical enterprise.^1,2 There are many potential advantages to replacing volatile organic compounds (VOCs) with water or various types of aqueous solutions. The most obvious are low cost, reduced flammability, reduced toxicity, and reduced environmental risk as a result of discharges of the supporting phase. Water and aqueous-based solvent systems may represent an increasingly significant choice for the replacement of traditional solvents in synthetic chemistry. Other leading VOC solvent alternatives include supercritical fluids, ionic liquids, immobilized solvents, solventless conditions, and the use of fluorous solvents.¹

A recent special edition of Chemical Reviews and a recent American Chemical Society Symposium volume highlighted some aspects of the use of water and aqueous solutions in green chemistry,^3,4 however, relatively few articles have focused on the use of aqueous PEG solutions and related materials in chemical reactions. This is despite the fact that, unlike several of the ‘neoteric solvents’ such as ionic liquids (ILs) where toxicity and environmental burden data are for the most part unknown, complete toxicity profiles are available for a range of polyethylene glycol (PEG) molecular weights and indeed, many are already approved for internal consumption by the US FDA.^5,6

Table 1 lists a number of recent reviews of organic reactions conducted in water and aqueous solutions including the use of high temperature water, soluble polymer supports, micellar solutions, and PEG derivatives. In this context, PEG has been used as a solvent and phase-transfer catalyst (PTC) in organic synthesis.

Table 1 Selected reviews of water and aqueous solutions used as green reaction media

Medium and main reaction type	Ref.
High temperature water as reaction medium	5,7
Organometallic reactions performed in water	8–11
Reactions mediated by soluble polymers as catalysts and supports including PEG	12,13
Micellar solutions as catalysis and reaction media	14–19
PEG and its derivatives as PTC and solvents for organic synthesis	20,21

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A number of recent reviews have also covered PEG chemistry and its applications in biotechnology and medicine,^22,23 PEG and PEG-supported catalysis,²⁴ PEG-based aqueous biphasic systems (ABS) as alternative separation media,²⁵ aqueous two-phase systems (ATPS) in bioconversion,^26–28 and PEG and its derivatives as solvent and PTC in organic synthesis.^20,21 However, none of these articles has focused on PEG solutions as alternative reaction media. Here we present a comprehensive review and analysis of the role of aqueous solutions of PEG in the development of alternative reaction media, an area of green chemistry which seems to have been rather overlooked in comparison to other solvent systems such as, for example sc-CO₂ and ILs.^4,29,30

Our interest in PEG solutions as green reaction media was spurred by several factors including; the present high interest in green separation chemistry,^31–38 our long-term study of PEG–metal ion coordination,^39–44 our studies of ABS solvent properties,^45–49 and our application of aqueous biphasic reactive extraction (ABRE) in the development of alternative processes for wood pulping and green catalytic oxidation systems.^50–57 In this review, we draw together five strands of the current literature: (1) the interesting physical properties of aqueous PEG solutions; (2) the unique solvent properties and cation coordination ability of PEG solutions; (3) the application of low molecular weight liquid PEG as a solvent in chemical reactions; (4) PEG as an alternative PTC; and (5) the application of ABRE in the development of green pulping processes, catalytic chemistry, and enzymatic catalysis.

2. Aqueous PEG solution properties

Polyethylene glycol, PEG: HO–(CH₂CH₂O)_n–H, is available in a variety of molecular weights from 200 to tens of thousands. At room temperature, the water soluble and hygroscopic polymer is a colorless viscous liquid at molecular weight <600 and a waxy, white solid at molecular weights >800.⁵⁸ The numerical designation of PEGs generally indicates the number average molecular weight (e.g., PEG-2000), although typically they are not monodisperse polymers. Liquid PEG is miscible with water in all proportions, and solid PEG is highly soluble in water, for example, PEG-2000 has a solubility of about 60% in water at 20 °C. Lower molecular weight liquid PEGs can be used as solvents in their own right with or without addition of water. These we define loosely here as low molecular weight PEG.

PEG has a number of benign characteristics that underlie, for example, its application in bioseparations.⁵⁹ PEG is on the FDA's GRAS list, (compounds Generally Recognized as Safe) and has been approved by the FDA for internal consumption.^60,61 PEG is weakly, if at all, immunogenic, a factor which has enabled the development of PEG–protein conjugates as drugs.^62–65 Aqueous solutions of PEG are biocompatible and are utilized in tissue culture media and for organ preservation.⁵⁹

Unlike VOCs, low molecular weight liquid PEGs are nonvolatile. The vapor density for low molecular weight PEG is greater than 1 relative to air according to available MSDS data,⁶⁶ and this is consistent with the industry standard for selection of alternative solvents to VOCs.¹ PEG also has low flammability, and is biodegradable.

PEG has been found to be stable to acid, base, high temperature,^50,56,57,67 O₂, H₂O₂ high oxidation systems,⁶⁸ and NaBH₄ reduction systems,^69,70 although partial oxidation of the PEG terminal –CH₂OH group to –COOH may occur in such systems as H₂O₂–Na₂WO₄.⁵⁶ In addition, PEG may be recovered from aqueous solution by extraction with a suitable solvent or by direct distillation of water or solvent.⁷¹

2.1. Phase separation

Aqueous solutions of PEG display a miscibility gap characterized by lower and upper critical solution temperatures (LCST and UCST, respectively) in which the polymer and water segregate into polymer-rich and polymer-poor phases.⁴⁵ The physical basis of this behavior is dependent upon the amphipathic nature of the polymer chain with its hydrophobic methylene groups interspersed with ether groups which can compliment the hydrogen bonded structure of water.^72–76 Hydration/dehydration of these groups promotes the observed behavior.

Similar phase incompatibility may be found in a number of different polymers such as PEG–PPG co-polymers, poly-vinylpyrrolidone, poly-N-isopropylacrylamide, and in the clouding of non-ionic surfactants.^25,59,77 Additionally, aqueous solutions of PEG phase separate in the presence of other, incompatible, but still water soluble polymers. The exact nature of phase separation here is incompletely understood, but appears to be an UCST phenomenon perhaps based on incompatible hydrogen bonded structures, or on an excluded volume mechanism.^25,59,78

PEG-based biphasic systems are generally formed by the addition of PEG and other water soluble polymers such as Dextran, above critical concentrations, however, many other pairs of polymers show incompatibility (and not only in aqueous solution);²⁵ the phase separation of Ficoll and Dextran is an important example.^59,77,79 Alternatively, 1-butyl-3-methylimidazolium chloride may be combined with a kosmotropic salt such as K₃PO₄, above critical concentrations in aqueous solution resulting in two distinct aqueous phases.⁸⁰ This is simply an extension of the temperature induced phase separation of PEG as a result of the lowering of the cloud point brought about by the salting-out effects of the salts.⁸¹ These effects follow the Hofmeister series.⁴⁵

Thus, aqueous PEG solutions may display phase separation under controlled conditions. Such phase separated solutions are known as ABS (Aqueous Biphasic Systems) or alternatively, ATPS (Aqueous Two-Phase Systems), and have been exploited in bioseparation for nearly fifty years since their discovery by Albertsson.⁵⁹

A typical phase diagram for the system, PEG-2000–NaHSO₄ in 50% H₂O₂–H₂O at room temperature is shown in Fig. 1. Mixture compositions lying to the left of the binodal curve are monophasic, whereas mixture compositions to the right of the binodal curve are biphasic. Tie lines (e.g., A–B in Fig. 1) connect mixture compositions to points on the binodal curve (the nodes A and B) representing the compositions of the two phases in equilibrium. All mixture compositions lying on the same tie line give identical compositions of the equilibrium phase. Only the relative volume of the phase changes, and this may be used as a means to manipulate recovery of products. The length of the tie line is called Tie Line Length (TLL).⁵⁹ Increasing PEG or salt concentration results in longer TLL and increasing phase divergence. The phase divergence has been shown to be proportional to the chemical potential difference between the phases. Thus, solute preference for one phase over another increases with increasing phase divergence.⁴⁵

Fig. 1 The phase diagram for PEG-2000–NaHSO₄ in 50% H₂O₂ at room temperature used for catalytic oxidation of cyclic olefins.^56,57

Differences in phase preference between species can be adjusted by controlling the ABS system composition. The fact that PEG, and other polymers, form biphasic systems, having tunable phase properties is an important advantage that allows the development of versatile reactive extraction systems; a property of PEG solutions which has yet to be fully exploited.^56,57

2.2. Solution polarity

The poor solubility of organic reactants and their intermediates in water is the main limitation to the widespread application of water as a reaction solvent. Enhancement of the solubility of organic solutes in aqueous solutions, including the use of supercritical water, surfactants, co-solvents, and complexants,^7,82–84 is an important aspect of the application of aqueous solutions as alternative solvents. For example, supercritical water is characterized by a reduced dielectric constant and a weaker hydrogen bonded network, which greatly increases the solubility of organic compounds.^7,82 Eckert et al. have pointed out that this unusual combination of physical properties can provide environmentally benign separation and reaction processes.⁸²

Similarly, surfactants with polar and non-polar regions orient themselves into micelles with a hydrophobic solvent-like interior and a polar water-exposed surface. Organic solutes become localized in the interior or within the surface of the micelle, and this is believed to be responsible for the success of organic and enzyme catalyzed reactions in micellar media.^14–16 A significant application of micellar catalysis lies in the field of homogeneous catalysis. In such systems, aqueous micellar solutions serve, not only as the reaction medium, but also to improve reaction selectivity and to facilitate catalyst recycling.^9,17–19 In metal-mediated carbonyl additions, the allylmetal intermediate complexes are formed as a result of the action of a wide variety of intermolecular forces, and as a result can effectively “activate” the metal center of some organometallic reagents and enhance allylation and other organometallic reactions in water.^11,85

The water soluble polymer PEG can be considered a co-solvent in water which leads to an apparent decrease of the aqueous solution polarity.^77,84 The consequent increase in solubility of organic molecules has led to the application of PEG as a solvent and a PTC in organic synthesis.^20,21

PEG, in aqueous solution, acting as a co-solvent, significantly changes many of the properties of water.⁸³ Solutions of PEG in water may be viewed as monophasic, consisting of two homogeneously mixed components, or as biphasic, having large hydrated polymer molecules separated by regions of free water.⁷⁷ Zaslavsky has made the argument that the latter viewpoint invites comparison of the resultant solution properties to the effects ascribed to vicinal water, i.e. water adjacent to solid interfaces, which has significantly different properties from pure water.⁷⁷ In comparison to bulk water, vicinal water shows a decrease in density and dielectric relaxation, and an increase in viscosity and ionic conductance.⁷⁷

Perhaps of even more significance to a discussion of PEG solutions as reaction media, is the effect of PEG on the polarity of aqueous solutions. Solution polarity is frequently measured by reference to the solvatochromatic properties of certain polarity sensitive dyes, in particular to Reichardt's betaine, from which is derived the E_T scale of polarity.²⁵ Zaslavsky found that the E_T(30) values of PEG-6000–Dextran-500 were very close to, but somewhat less than those of pure water and the values decreased with increasing polymer concentration.⁸⁶

We have found in the PEG-2000–K₃PO₄ system, that values of E_T(30) are considerably lower than water at the critical point, and decrease in the PEG-rich phase with increasing phase divergence.⁴⁶ However, for the lower salt-rich phase, the apparent polarity as measured by E_T(30) increases with increasing TLL and distance from the critical point until it is virtually indistinguishable from that of water. Thus, there is an increasing difference in the polarity of the two phases as measured by this technique.

The polarity difference in PEG–Dextran and PEG–K₃PO₄ ABS with TLL is shown in Fig. 2. PEG–Dextran shows a small difference in polarity between the phases, whilst the greatest difference is found for PEG–K₃PO₄ ABS and this difference increases with TLL. In broad terms, the polarity of the PEG-rich phase could be described as being similar to a short chain alcohol when measured on the E_T(30) scale.⁴⁶

Fig. 2 Solvent polarity scale for PEG-6000–Dextran-500⁸⁶ and PEG-2000–K₃PO₄⁴⁶ ABS systems: (○) Dextran-rich bottom phase in PEG–Dextran ABS, (●) PEG-rich top phase in PEG–Dextran ABS, (□) K₃PO₄-rich bottom phase in PEG–K₃PO₄ ABS, (■) PEG-rich top phase in PEG–K₃PO₄ ABS.

The relative affinity of the solvent medium for a non-polar CH₂ group, ΔG_CH2, has also been used to measure the solvent properties of different organic solvents, and various aqueous polymer solutions.⁴⁶ This scale is not related to the polarity of the medium, but to the free energy of cavity formation or the cohesive energy density. The polarity of the separated top and bottom phases of a PEG-2000–K₃PO₄ ABS have been thoroughly investigated.⁴⁸ The relationship between −ΔG_CH2 and the degree of phase separation of the co-existing phases of the ABS, expressed in terms of the difference in concentration of the total number of ethylene oxide monomers (ΔEO) or the TLL between the phases, was investigated in various PEG–salt ABS differing in salt type (K₃PO₄, K₂CO₃, (NH₄)₂SO₄, NaOH, Li₂SO₄, MnSO₄, ZnSO₄) and PEG molecular weight.⁴⁸ No matter the salt type, the concentration, or the molecular weight of PEG, −ΔG_CH2 was the same at the same degree of phase divergence (expressed as ΔEO, ΔPEG, or TLL). That is the free energy of transfer of a methylene group in all PEG–salt systems investigated was the same at the same degree of phase divergence. The difference in concentration of the polymers between the phases at a given temperature has been shown to be a measure of the chemical potential difference between the phases.⁴⁵

Fig. 3 shows both the E_T(30) and −ΔG_CH2 relative solvent hydrophobicity scales as applied to PEG-based ABS and some organic solvents and surfactant solutions.⁴⁶E_T(30) is given for the organic phase (PEG in the case of ABS), and −ΔG_CH2 represents the free energy of transfer from the aqueous to the organic phase. The E_T(30) values of both PEG-6000–Dextran-500 and PEG-2000–K₃PO₄ aqueous polymer solutions are closer to that of pure water than most of the organic solvents shown in Fig. 3. However, it is possible to construct ABS, such as the PEG–K₃PO₄ system mentioned previously, having phase compositions such that −ΔG_CH2 may range from zero to about 0.85 kcal mol⁻¹. Not only does this mean that the hydrophobicity of the system is controllable, but in some cases the free energy of transfer may approach and exceed that of many organic solvents. It may thus be possible to achieve considerable solubility of some organic solutes in such systems, and this may allow certain organic reactions to be carried out in these relatively hydrophobic aqueous solutions.

Fig. 3 Relative solvent polarity E_T (■) and −ΔG_CH2 (□) for selected PEG-based ABS solutions and for some organic solvents.

The molar transition energy, E_T, however, taken from the wavelength of absorption of the long wavelength absorbance band of Reichardt's betaine dye,⁸⁷ includes not only the effect of molecular dipole and induced dipole interactions, but also the ability of the solvent to interact with the betaine by hydrogen bond donation.⁸⁷ Also, the free energy of transfer of a methylene group is only a measure of the energy associated with cavity formation, ignoring the contribution of molecular interactions between solute and solvent to the overall free energy of transfer for all solutes beyond simple alkyl chains.

Huddleston et al. have characterized the phases of selected polymer–polymer and polymer–salt systems in terms of their polarity using the Kamlett and Taft π* parameter (relative polarity/polarizability),⁴⁶ and extended these studies to include α (hydrogen bond acidity) and β (hydrogen bond basicity)⁴⁹ contributions to solute selectivity in these systems using a suite of solvatochromatic indicators. The parameters π* and β were found to show little difference between the two phases in PEG-2000–(NH₄)₂SO₄ or K₃PO₄ ABS, but a big difference was found for the α value.⁴⁹ At 37% w/w TLL, the α value between the PEG-2000-rich top phase and K₃PO₄ salt-rich phase could be as low as 0.3. The hydrogen bond donation ability was greatly depleted in the PEG-rich top phase. The solvatochromatic study of π*, β, and α lends support to later conclusions, derived from the application of linear free energy relationships (LSER),⁴⁸ that polarity and solvent basicity play little part in solute distribution in ABS.

Other studies using solvatochromatic probes and the solvation model of Kamlett and Taft, have found that low molecular weight PEG, such as pure PEG-300, has a polarity value (π* = 0.94) greater than methanol (0.63), a hydrogen bond acceptor ability (β = 0.60) similar to methanol (0.62), and a hydrogen bond donor ability (α = 0.45) less than methanol (0.93).⁸⁸ In the Hansen three component description of solubility behavior, the solubility parameters for tetraethylene glycol have been determined in terms of a dispersion component (δ_d² = 16.6), polarity component (δ_p² = 5.7) and a hydrogen bonding component (δ_h² = 16.8) and these parameters were found to be similar to those of n-propanol.⁸⁹

Linear solvent free-energy relationships (LSERs or LFERs) based on chemical equilibria and Gibbs energy relationships, have been applied to the investigation of the solvent properties of ABS.^46,48 The general solvation equation of Abraham is usually given as in eqn. 1:

log SP = c + rR₂ + sπ₂^H + a∑α₂^H + b∑β₂^H + vV_x (1)

where c is a constant, R₂ is the solute excess molar refraction, π₂^H is the solute dipolarity/polarizability obtained from partition measurements, and ∑α₂^H and ∑β₂^H are the effective solute hydrogen bond acidity and basicity, respectively. V_x is the McGowan volume of the solute. The coefficients c, r, s, a, b, and v obtained by linear regression of the partitioning data of a suitable solute set, may be used to characterize the properties of the solvent. For a PEG-2000–(NH₄)₂SO₄ ABS these were found to be −0.05, 0.65, −0.21, 0.21, −1.31, and 1.71, respectively.⁴⁸

LSERs are useful in the determination of the solute–solvent interactions that govern solute partitioning in ABS, and it is also possible to compare ABS to, for instance, aqueous micellar systems and traditional organic–aqueous biphasic systems.⁹⁰ Such comparisons may greatly aid the selection of suitable solvent systems in a search for replacements for VOC systems. The solvent properties which were found to be of prime importance in driving solute partitioning in ABS, were solvent hydrogen bond acidity (donation ability) and the free energy of cavity formation.

2.3. PEG–metal ion complexes

PTCs are usually used to transport an aqueous reagent into an organic phase in an activated state, so that the reaction can proceed as a consequence of bringing the aqueous reagent and organic reagent together.⁶⁷ PEG has the ability to serve as a PTC since the polyethylene oxide chains can form complexes with metal cations, similar to crown ethers.²¹ To maintain electroneutrality, such PEG–metal cation complexes must bring an equivalent anion into the organic phase, thus making the anion available for reaction with the organic reactants. Many factors affect phase catalytic activity, such as PEG molecular weight, chain end effects, and the nature of the associated cations and anions.

Fig. 4 shows that the stability constants, log K, for PEG complexes with Na⁺ in ethanol (using a Na⁺ electrode with Ag⁺/AgCl as the reference electrode) depend on both the PEG molecular weight and the end-group substituents.^91–93 The degree of complexation of solid alkali metal salts by PEG-400 is strongly dependent on both the salt anion and cation as shown in Fig. 5.^94,95 For the Na⁺ and K⁺ salt–PEG complexes, commonly used in phase-transfer reactions, there is a greater dependency on the nature of the anion than the cation. The anions OH⁻, F⁻, HSO₄⁻, and HCO₃⁻ were found (by conductimetric and refractive index measurements) to be ion paired with the PEG cation complex, and assumed to be relatively naked anions, while Cl⁻, Br⁻, I⁻, SCN⁻, NO₃⁻, NO₂⁻, and HF₂⁻ were assumed to be disassociated anions with significant solvation shells.⁹⁵

Fig. 4 The stability constants of PEG–Na⁺ complexes with various PEG molecular weights and functional group substituents.^91–93 PEG terminal groups were symmetrically substituted (see legend) and the molecular weight was set as that of the unsubstituted PEG.

Fig. 5 The metal ion (K⁺ and Na⁺) transfer ratio (mol%) from solid alkali metal salts of different anions to PEG-400.^94,95

The binding constants of Na⁺ with PEG, with PEG monomethyl ethers (PEG-MME), with PEG dimethyl ethers (PEG-DME), and with crown ethers have been measured in anhydrous MeOH solutions.⁹⁶ The binding constants (K) of one PEG chain containing 3–312 EO units with the sodium cation show a linear relationship with the number of binding sites available.⁹⁶ It has also been proposed that for some alkoxylation reactions, several catalytic centers exist in a single PEG molecule.⁹⁷ Dramatically reduced costs of PEG compared to crown ethers are a considerable incentive for investigating the properties of these “crown-like” PTCs.

PEG–cation complex structures have been analyzed by a variety of methods (Table 2) such as single crystal X-ray structure analyses, mass spectrometry, NMR, IR and Raman spectroscopy, powder X-ray diffraction, and electrochemistry. X-Ray analyses have shown that low molecular weight PEG (expressed as (EO)_n) can usually form single crystal complexes with metal cations in acetonitrile, methanol, and their mixtures. For example, Sr²⁺ will typically organize 3–6 EO units into a pseudocyclic crown ether-like equatorial array. Thus (EO)₃ or (EO)₄ chains complex Sr²⁺ in a 2 ∶ 1 fashion, whereas longer chains (EO)₉–(EO)₁₀ are able to helically wrap the Sr²⁺ ion.⁴⁴ Because Sr²⁺ can be completely wrapped by (EO) units, the complex is given a hydrophobic exterior, effectively dehydrating the metal cation, and allowing Sr(EO)_n²⁺ complexes to be transferred to an organic phase. This is the basis for the synergistic extraction of Sr²⁺ from aqueous solution using a mixture of cobalt dicarbollide and PEG.⁹⁸

Table 2 Structural analyses of PEG–metal cation complexes

Analysis method	Metal ions
X-Ray crystal structure	Hg,^39 Bi,^40 Pb,^41 Ln,^42 U,^43 Sr^44
Mass spectrometry	Li, Na,^99,100 Cs^101
NMR	Na, Ca, K, Sr,^102,103 Li^104
IR and Raman spectroscopy	Li,^105,106 Na^107
X-Ray powder diffraction	Li,^108,109 Na,^110 K,^111 Rb^112
Electrochemistry	Li^113

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Compared with crown ether complexation, the same PEG can coordinate different sizes of metal cations such as Sr²⁺ (1.12 Å)⁴⁴ and Li⁺ (0.76 Å),¹¹⁴ thus, PEG presents a more flexible structure for metal cation complexation. Extraction by PEG polymer complexation also represents a considerable cost saving over crown ether complexation.

Pb²⁺ and (EO)₅ can form Pb(EO)₅ chelate rings, and the six oxygen donors arrange themselves in a nearly hexagonal equatorial plane, so that the anion can approach the two axial sites.⁴¹ Lanthanides have important applications in organic synthesis in protic solvents, and the crystal structures of dozens of LnX₃ (X = Cl⁻, SCN⁻, NO₃⁻) complexes formed with a range of small PEGs ((EO)₃ to (EO)₇) have been investigated by Rogers et al.⁴² These results showed that different EO chain lengths result in differences in the coordination sphere and can, in some cases, require additional inner-sphere ligands, such as an anion, water, or solvent molecules. These results have been the subject of extensive review.⁴²

The complexation of metal ions with PEG has also been investigated by ¹H NMR spectroscopy. There is a strong ion–dipole binding affinity with metals, and the preferred coordination numbers for Na⁺ and Ca²⁺ of 6 EO, and for Sr²⁺ of 7 EO, have emerged using the ion radius concept.^102,103 Mass spectrometry has shown that the lowest energy structure Na⁺(EO)₉ results from the Na⁺ ion being “solvated” by seven nearest neighbor atoms, and thus, the cation is completely encased by the (EO)₉.⁹⁹

IR and Raman spectroscopic studies of a PEG–Na⁺ complex in the context of the development of polymer electrolytes, (EO)_nNaCF₃SO₃, have shown that free ions, ion pairs, and aggregates exist due to the interaction of Na⁺ with (EO)_n and CF₃SO₃⁻ at different concentrations.¹⁰⁷ The electrochemical characterization of the Li⁺/Li redox electrode reaction in solid polymer electrolytes (SPEs) of PEG-10000–LiClO₄ shows higher conductivity than polyethylene oxide (PEO) electrolytes due to the increase in the number of carriers and the facilitation of the formation of the conduction pathways.¹¹³ A powder X-ray diffraction study shows that Li⁺–EO₃ forms isolated and helical EO chains with Li⁺ inside the helix,¹⁰⁸ which is similar in conclusion to the results of X-ray crystallographic studies. In the case of Li⁺–EO₆ complexation, double helical EO chains were shown to surround the Li⁺ cations, so that the anions were left outside the helical structure unpaired with Li⁺ ions.¹⁰⁹ The conclusions were supported spectroscopically by FT-IR and Raman studies that showed that Li⁺ is completely surrounded by the two EO₆ chains forming a cylindrical structure without significant anion coordination in the EO₆∶LiAsF₆ complex.¹⁰⁵

PEGs certainly have the ability to form complexes with metal cations. This property may be of some importance in the application of PEGs as alternative PTCs and in ABRE processes. Crown ether metal ion complexation depends on the fixed size of the cavity in the center of the crown. However, fixed molecular weight PEGs show more flexible selectivity in the binding of different size metal cations due to changes in helical conformation. During the phase-transfer process, PEG may transfer metal cations from the aqueous phase to the organic phase by complexation and partition. The corresponding anion is also forced to transfer to maintain electroneutrality, thus the inorganic or organic solvated anion may be activated in the organic phase for participation in the chemical reaction.

3. Liquid PEG as reaction solvent

PEG and its aqueous solutions represent interesting solvent systems for solvent replacement, and may stand comparison to other currently favored systems such as ionic liquids, supercritical carbon dioxide, and micellar systems. Recently, Sheftel has reviewed the general toxicological action of PEG such as acute toxicity, the mean lethal doses of all molecular weights of PEG, short and long-term, reproductive toxicity, and the mutagenicity in vitro or vivo.¹¹⁵ Additionally, relevant laws or regulations governing use in the European Union and from the US FDA were also included. One important difference between using PEG and other ‘neoteric solvents’ is that all of the toxicological properties, the short and long-term hazards, and the biodegradability, etc., are established and known. For many of the other alternative solvent systems, lengthy investigations will be required to establish the necessary background safety and toxicological information.

PEG is a hydrophilic polymer, easily soluble in water and many organic solvents including: toluene, dichloromethane, alcohol, and acetone, but it is not soluble in aliphatic hydrocarbons such as hexane, cyclohexane, or diethyl ether.⁵⁸ The non-polar and hydrophobic hexane, slightly polar 2-octanone, and mildly polar heptanol, all showed some solubility in 70% PEG-300(aq), giving solutions of 0.01, 0.1, and 0.8 M, respectively.⁸⁸ Solubilities of 1.7 M and 0.5 M were found for 2,3-dimethyl-1,3-butadiene in PEG-300 and its 90% PEG aqueous solution, and 4.5 M and 1.2 M for 1-bromobutane in these two media, respectively.⁸⁸ This solubility enhancement has been applied to aqueous synthesis in both Diels–Alder and S_N1 reactions.^88,116,117

Of particular interest, is the high solubility of some salts in PEG-400, such as 1.8 M CH₃COOK, 2.1 M KI, 1.1 M KNO₃, 0.25 M KCN, and 0.16 M K₂Cr₂O₇. This has enabled the use of this medium in some homogeneous oxidation and substitution reactions resulting in high yields.¹¹⁸ The solubility of these salts in PEG is comparable with their solubility in dimethylsulfoxide (DMSO). PEG-1500 used in a phenoxide allylation reaction was claimed to effectively enhance the solubility of the reactant allyl chloride in PEG aqueous solution.¹¹⁹

Low molecular weight liquid PEGs can be regarded as protic solvents with aprotic sites of binding constituted by the EO units. A few inorganic salts and many organic substrates are soluble in low molecular weight liquid PEG, and thus, they have been proposed as solvents for organic reactions.^{71,88,116,117} PEGs have been termed “host” solvents⁷¹ due to their ability to form complexes with metal cations as illustrated in Figs. 4 and 5.

Three main types of reactions have been investigated: substitution, oxidation, and reduction. However, application of liquid PEG is not limited to these reactions, polymerization of methyl methacrylate and styrene has been reported in PEG-400, and a higher rate of polymerization of methyl methacrylate was found than that in toluene, but the rate was slower for styrene in PEG-400 than that in xylene. Moreover, the easy removal of the copper catalyst following the reaction is comparable with the performance of other solvent alternatives such as 1-butyl-3-methylimidazolium hexafluorophosphate and fluorinated biphasic systems.¹²⁰ Other types of liquid PEG have been used in substitution and reduction reactions such as high molecular weight PEGs including molecular weights of 900, 1000, 2000, and 3400 in conjunction with sc-CO₂ above the melting point of the PEG.^121–123 The similar small molecular weight liquid polypropylene glycols (PPG) 425 and 1000 have also found application in solvent substitution.^{88,116,117,124,125}

3.1 Substitution reactions

Table 3 provides examples of substitution reactions performed using liquid PEG as the solvent. Potassium thioacetate in PEG-400 has been used as a nucleophilic reagent to substitute alkyl halides, tosylates, or mesylates, and the product yields were about 92–98%.¹²⁷ The hydrolysis rate constant for the synthesis of 2-chloro-2-methylpropane in PEG-300–H₂O has been compared to those found for acetic acid, methanol, ethanol, and acetone as co-solvent with H₂O, and rate constants were found to increase by 1–3 orders of magnitude at high mass% PEG(aq) over those found for the above organic co-solvents. The Diels–Alder reaction rates of 2,3-dimethyl-1,3-butadiene with nitrosobenzene in PEG-300 showed a 3.3 fold increase compared to the same reactions in dichloromethane, and a 2.5 fold increase over that found in ethanol. 2,3-Dimethyl-1,3-butadiene in reaction with acrolein showed a 14 fold increase in rate constant in 70 mass% PEG-300(aq) over that in methanol.^88,116 PPG-425 showed a similar enhancement of reaction rate, but this was lower than that of PEG-300.^88,116

Table 3 Substitution reactions in PEG solvent media

Substrate (RX)	Substitution (Y)	PEG	Product	Ref.
R-CH2Br	CH3COO^−, I^−, C6H5O^−, CN^−	PEG-400	R–CH2Y	126
R = C6H5, C3H7, C9H19, C7H15				118
R1-CHX-R2	CH3COS^−	PEG-400	R1-CHY-R2	127
R1 = C7H15, C9H19, C11H23, C10H21, C6H5
R2 = H, CH3
X = CH2C6H4SO2, CH2SO2, Cl, Br, I
(CH3)3CCl	H2O	PEG-300	(CH3)3COH	88
(CH3)2C=CHCl		PPG-425	(CH3)2C(OH)CH3,	117
			(CH3)2CHCH2OH
CH2CH(CH3)CH(CH3)CH2	CH2=CH-CHO	PEG-300	OCH-C6H7-(CH3)2	88
	C6H5-N=O	PPG-425	C6H5-NOC4H4-(CH3)2
R′X	RSO2^−	PEG-400	R-SO2-R′ + S2O2R′	128
R′ = C6H5CH2Cl, BrCH2Br		PEG-400-C2H5
R″-Br
R″ = C2H5, n-C4H9, n-C8H17, CH2=CHCH2
R1-(SO3-R2)n	F^−	PEG-400	R1-(F)n	129
R1 = n-C8H17, n-C6H13-CH, (CH3)3CCH2, C6H5(CH2)2
R2 = CH3, 4-CH3C6H4, 2-C10H10, 2,4,6-(CH3)3C6H5
ArNH2	Cl^−, Br^−, I^−, CN^−	PEG-200-CH2Cl2	ArY	130
Ar = C6H5, p-PhCOC6H4, 1-C10H9, p-ClC6H4, p-CH3OC6H4,
o-CH3OC6H4, m-CH3OC6H4, p-C6H5C≡CC6H4
R-C6H4Br	C6H5-B(OH)2	PEG-400	R-C6H4-C6H5	131
(C6H5)2CNCH2CO2PEG	R2X	PEG-3400	(C6H5)2CNCHR2CO2PEG	121
R-C6H4-Br	CH2=CHX	PEG-2000	R-C6H4-CH=CHX	122
R = Cl, OCH3, CH2O2	X = C6H5, CO2C2H5, n-CH3(CH2)3O	(Pd(CH3OAc)2 catalyst)

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The reaction of sodium p-toluenesulfonate monohydrate with various alkyl halides in PEG-400 or its diethyl ether have been investigated, and it has been shown that sulfones can be obtained in good to excellent yields, while the alkylation of sodium p-toluenesulfinate and N, N′-dimethylformamide in methanol gives only moderate yields.¹²⁸ The reaction of KF with the mesylates and tosylates of alcohols has been found to provide good yields of fluoro derivatives in PEG-400 compared to methanol and apolar crown ethers.¹²⁹ The diazotization and Sandmeyer reactions of arylamines in PEG-CH₂Cl₂ were found to be effective for the preparation of halogenoarenes and cyanoarenes even in 10 mM dilute substrate. This is still comparable with these reactions in various organic solvents (e.g., xylene, DMSO, 18-crown-6, chloroform, and tetrahydrofuran (THF)), giving high yields only in high concentrations of substrate (≥73 mM)).¹³⁰ The ordinary aqueous Sandmeyer reactions reported in Organic Synthesis gave only very poor yields.¹³⁰

A Schiff base protected glycine modified by end functionalized PEG-3400 reacted readily with various electrophiles without the need for other organic solvents under microwave activation. PEG served as both polymer support and solvent in this reaction. The reaction was comparable with that in acetonitrile.¹²¹ The microwave-assisted Suzuki cross-coupling of arylboronic acids with aryl halides using PdCl₂ as catalyst and KF as base in PEG-400 was found to offer ease of operation and the ability to recycle the catalyst. The recyclability of the PdCl₂ and PEG-400 solvent by ether extraction makes the reaction more economic and thus, increases its viability for commercial exploitation.¹³¹

Molten liquid PEG-2000 at 80 °C was used as reaction solvent for Heck coupling reactions and gave a fast reaction rate and high yield.¹²² The reaction rate, yield, and regio- and stereoselectivities in this solvent system are comparable with the conventional organic solvents dimethyl formamide (DMF), DMSO, CH₃CN, and the ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate. The recyclability of both PEG-2000 and Pd(OAc)₂ can be achieved by simple ether extraction of the product, and the higher yield can be sustained even after four subsequent experiments.

Raston and co-workers have shown that PPG-425, HO–(CH(CH₃)CH₂)_n–H, can be a solvent for aldehyde synthesis from 4-hydroxybenzaldehyde, K₂CO₃, and the corresponding bromo- or dibromoalkane at 60 °C.¹²⁴ PPG-1000 was also successfully used in indium metal mediated synthesis of homoallylic amines.¹²⁵ Yields and reaction times were better than and comparable with aqueous reactions and those employing traditional organic solvents. In addition, the product was easily isolated.

PPG is a viscous liquid with a negligible vapor pressure, stable under these reaction conditions, and is easily recovered. However, in contrast to PEG used as a solvent, most commercially available PPG, such as Dow PPGs from molecular weight 250 to 4000, are viscous liquids. Low molecular weight PPG-250 and 425 are in fact water soluble, but PPG shows an inverse temperature–solubility relationship, along with a rapid decrease in water solubility as the molecular weight increases. PPG-2000 has only 0.012% w/w solubility in water at 25 °C, and this may invite exploitation as a relatively more hydrophobic phase in comparison to PEG. These physical properties may limit the wide use of PPGs as reaction media.

3.2. Oxidation reactions

Oxidation reactions conducted in PEG-200 and PEG-400 are given in Table 4. Among the few oxidants examined, K₂Cr₂O₇, which is relatively soluble in PEG-400, can oxidize benzyl bromide with good yields.⁷¹ This is similar to the reaction of Na₂Cr₂O₇ in hexamethylphosphoramide (HMPA) and crown ether using the same substrate. Aerobic oxidations catalyzed by a polyoxometalate, H₅PV₂Mo₁₀O₄₀, in PEG-200 or 400 solvents showed wider application to alcohols, cyclic dienes, sulfides, and in the Wacker reaction.⁶⁸ Only 5% weight loss during benzyl alcohol oxidation after three recycles was observed in a solvent recycling process due to PEG degradation, resulting from a 1.7% weight loss for each cycle. No oxidation of the terminal hydroxyl of PEG occurred.

Table 4 Oxidation reactions in PEG solvent media

Substrate	Oxidant	PEG	Product	Ref.
C6H5CH2Br	K2Cr2O7	PEG-400	C6H5CHO	71
R-CH2OH	Aerobic oxidation (catalyzed by H5PV2Mo10O40)	PEG-200	R-CHO	68
R = R′-C6H4		PEG-400
CnH2n−4 (cyclic dienes)	Same as above	PEG-200	CnH2n−6	68
R-S-R (sulfide)	Same as above	PEG-200	R-SO2-R (sulfoxides and sulfones)	68
CH3CH=CH2	Aerobic oxidation (catalyzed by H5PV2Mo10O40 and palladium)	PEG-200	CH3COCH3	68
R1CH=CHR2	N-Methylmorpholine (NMO) (catalyzed by OsO4)	PEG-400	R1CH(OH)CH(OH)R2	132
R1 = CnH2n+1, C6H5
R2 = H, CnH2n+1, C6H5

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The dihydroxylation of olefins has been conducted using PEG-400 as solvent and OsO₄ as catalyst,¹³² and high yields of diols were achieved in a short time (2–3 h). The PEG-400 and OsO₄ were easily reused by simple extraction of product diols using ether, and more than 90% yield was sustained even after 5 recycles. Additionally, the reaction was suitable for asymmetric dihydroxylation (Sharpless reaction) with high yield and good enantioselectivity.

3.3. Reduction reactions

Table 5 lists some important reduction reactions which have been demonstrated utilizing PEG as solvent. In PEG-400, carbonyl compounds could be reduced by NaBH₄ more efficiently than by slow reaction in THF.⁷¹ It was also found that the reduction of alkyl and aryl esters to the corresponding alcohols by NaBH₄ in PEG-400 was enhanced, where these compounds had been considered inert toward reduction in other organic solvents.¹³⁴ The halide reduction by NaBH₄ in PEG-400 is comparable to that in a variety of polar protic solvents such as DMSO, sulfone, HMPA, and DMF, and the acyl chloride reduction can effectively occur in PEG-400 as a substitute for the inert solvent dioxane.¹³⁵ Lindlar's catalyst, Pd–CaCO₃ poisoned with PbO, is found to partially reduce triple bonds in alkynes to cis-olefins in PEG-400,¹³³ and PEG and the catalyst can be used 3–5 times without loss of activity or yield.

Table 5 Reduction reactions in PEG solvent media

Substrate	Reductant	PEG	Product	Ref.
CH3COC6H13	NaBH4	PEG-400	CH3CHOHC6H13	71
R1-COO-R2	NaBH4	PEG-400	R1-CH2OH	134
R1 = alkyl, aryl
R2 = CH3, C2H5
R1-CHX-R2	NaBH4	PEG-400	R1-CH-R2	135
R1 = alkyl, aryl
X = Cl, Br, I
R2 = H, CH3, C4H9
R-COCl	NaBH4	PEG-400	R-COH	135
R = C15H31, C9H19, C6H5, p-BrC6H4
C6H5-CH=CH2	H2	PEG-900	C6H5-CH2CH3	123

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The waxy solid PEG-900 at 155 bar pressure in sc-CO₂ at 40 °C, showed liquid solvent characteristics, and was successfully used as the solvent for hydrogenation of styrene.¹²³ The RhCl(PPh₃)₃-catalyzed hydrogenation of styrene to ethyl benzene in PEG-900 at 155 bar, 55 °C in sc-CO₂ was conducted as a homogeneous catalysis reaction. Ethyl benzene was extracted into sc-CO₂, and the catalyst-containing PEG phase was reused without loss.¹²³

4. PEG as phase-transfer catalyst (PTC)

PEGs and their many derivatives have been extensively investigated as PTCs, and are used in many commercial processes to replace expensive, and environmentally-harmful PTCs.^{20,21,24,136,137} Of the commonly used PTCs, linear PEGs are much cheaper than analogous macrocyclic crown ethers and cryptands.¹³⁸ PEGs are also more stable at high temperatures, up to 150–200 °C, and show higher stability to acidic and basic conditions than quaternary onium salts.⁶⁷

4.1. Free phase-transfer catalysts

4.1.1. Williamson ether synthesis. The novel Williamson reaction has been successfully conducted in a liquid–solid or liquid–liquid biphasic system using PEG as PTC with or without organic solvent as shown in Table 6. Williamson ether synthesis is an important nucleophilic substitution reaction (S_N2) and involves the synthesis of an ether using an alkyl halide and an alkoxide in an alcoholic solvent. The yield of decan-1-ol during etherification using PEG-2000 as PTC is 84%, which is equal to that found by using 18-crown-6, and higher than the 72% yield found using Kryptofix222 (cryptand).¹³⁹ The crown ether and cryptand are very expensive, may constitute toxins or irritants, and are sensitive to humidity.¹³⁹ On the other hand, in PEG-300 or PEG-1000, the etherification is also sensitive to H₂O content. A 15% ratio of H₂O/KOH is the optimum H₂O content, and a 30% ratio of H₂O/KOH results in a great decrease in yield. Excess H₂O is presumed to limit the formation of the intermediate alcoholate, and thereby decrease the yield of ether.¹⁴⁸ Both 5% PEG and etherified PEG as PTC are able to enhance the alkyl alcohol etherification reaction with high yield.¹³⁹ Catalytic activity is attributed to the presence of sufficient oxygen atoms in the EO units. The hydroxyl group weight percent of 5% PEG-2000 is about 0.085% in this reaction, and the consumption of electrophilic halogenated reactant is very small.¹⁴⁸

Table 6 PEGs as free PTCs in Williamson ether syntheses in bases

R1 of substrate (R1OH)	Substrate (R2X)	PEG and solvent	Product	Ref.
a Furfuryl alcohol.
CnH2n+1	CnH2n+1X	PEG-350–2000	R1-O-R2	139–141
n = 10, 12	n = 4, 8	PEG-(C2H5)2
	X = Br, Cl, I	No solvent
C6H5, 4-Cl-C6H4, 3,5-(CH3)2-C6H3,	CnH2n+1X	PEG-400, 1500, 6000	R1-O-R2	119
4-OH-C6H4, C6H5-C6H4	CnH2nX	No solvent		142–145
	C6H5CH3X
	n = 1, 2, 3, 4, 8
	X = Cl, Br, I
OC4H4-CH2,^a or	XRX	PEG-400, 600, 800–C6H6 or CH2Cl2	(OC4H4CH2O)2R	146
Ar = CH3C6H4, Cl-C6H4,	X = Br, Cl		or	147
NO2-C6H4, HO2CCH2-C6H4,	R = (CH2)n, C2H5OC2H5		Ar-ORO-Ar
OHC-C6H4, C6H5-C6H4	n = 1, 4, 5
PEG-300, PPG-425, 1000	RBr	PEG-300	PEG-OR	148
	R = CnH2n+1	PPG-425, 1000	or
	n = 2, 4, 6	KOH/no solvent	RO-PEG-OR

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4.1.2. Substitution reactions. One of the most common areas for the application of PEGs as PTCs is in nucleophilic substitution reactions. As listed in Table 7, typical anionic nucleophilic reagents are hydroxides, halides, sulfides, cyanides, cyanamides, carboxylates, sulfonates, and others. The diaryl 1,4-phenylenedioxydiacetic acid and diaryl 1,4-phenylenedioxydiacetate synthesis using PEG-400 as PTC showed good to excellent yields under mild conditions, with short reaction times and simple operation.¹⁴⁹N-Acylation reactions, normally considered difficult, could be conducted using PEG-400 as PTC with high yield.¹⁵² Although 3–6 fold more PEG was needed to achieve the same yield as obtained using 18-crown-6 during p-dibromobenzene synthesis, the much lower cost of PEG is an important compensating factor.¹⁵³ Ultrasound has been found to be effective in enhancing N-alkylation of a variety of amines by alkyl halides using PEG-350 methyl ether.¹⁵⁴

Table 7 PEGs as free PTCs in substitution reactions

Substrate	Nucleophilic reagents	PEG/solvent and base	Product	Ref.
Cl-CH2CO2H	OH-C6H4-OH	PEG-600/CH3C6H5	HO2CCH2-O-C6H4-O-CH2CO2H	149
p-ClOCCH2-O-C6H4-O-CH2COCl	R-C6H4-OH	PEG-400/CH2Cl2	R-C6H4-OCCH2-O-C6H4-O-CH2CO-C6H4-R	149
m-(ClCOCH2O)2-C6H4	ArOH	PEG-400/NaOH	(ArO2CCH2O)2-C6H4	150
	Ar = X-C6H5			151
	X = Cl, NO2, C6H5, CH3
C6H4-N2HC-R	ArOCH2COCl	PEG-400/	C6H4-N2HC (COCH2OAr)R	152
R = H, C6H5OCH2, 2,4-Cl2C6H3OCH2, 2,4,5-Cl3C6H2OCH2	Ar = C6H5, 4-ClC6H4, 4-CH3C6H4	CH3CN, K2CO3
p-Y-C6H4-N2^+BF4^−	CCl3Br	PEG-1000/	p-Y-C6H4-Br	153
Y = Br, NO2	CH3I	CH3COOK, CHCl3	p-Y-C6H4-I
p-Y-C6H4-N2^+BF4^−		PEG-1000/	p-Y-C6H4-C6H5	153
Y = Br, NO2		CH3COOK/C6H6
C6H4-C2H2NHR1	R2X	PEG-OCH3/	C6H4-C2H2NR1R2	154
R1 = H, C6H5	R2 = CH3, C6H5, C12H25	NaOH/C6H5CH3
	X = Br, I
C6H5CH2Cl	KSCN	PEG w/o sc-CO2	C6H5CH2SCN	142,155
p-CH3-C6H4-SO2Cl	MF	PEG-115–40000/	p-CH3-C6H4-SO2F	156
	M = Li, Na, K, Rb, Cs	CH3COCH3
p-X-C6H4-Y	MOR	PEG-150–20000000/	p-Y-C6H4-OR	97
X = Br, Cl	M = alkali metal	KOH
Y = Br, Cl, H	R = alkyl, aryl
2-OC4H4-CO2H	C6H5-SO2Cl	PEG-400	2-C4H4O-CO2-SO2-C6H5	157
R-CO-Cl	NH4SCN	PEG-400/CH2Cl2	RCOSCN	158
R = Ar-C4H4O, 2-ClC6H4				159
POCl3	ArONa	PEG/CHCl3	(ArO)3PO	160
	Ar = RC6H4, 2,4-Cl2C6H3
	R = CH3, C4H8, Cl, C6H5
C8H17Cl	NaCN	PEG/C10H22	C8H17CN	96
CH2Br2	R-C6H4-CO2K	PEG-600/CH3CN	R-C6H4-CO2-CH2-CO2-C6H4-R	161
C6H5-CH2Br	CH3CO2K	PEG/CH3CN	C6H5-CH2OCH3	162

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PEG as PTC has been employed in a sc-CO₂ solvent to convert benzyl chloride with potassium cyanide to form phenylacetonitrile, although the yield is lower than a similar reaction employing tetraheptylammonium cyanide. Nevertheless, this is a promising beginning for the development of a low cost, green reaction process.¹⁵⁵ The effect of PEG molecular weight on catalytic effectiveness in the reaction of mono- and di-halobenzenes with alkoxide ions to form monoalkoxybenzenes has been examined.⁹⁷ The yield of product was found to increase with primary, secondary, and tertiary alkoxide ions, and high molecular weight PEG was more effective than low molecular weight PEG. The synthesis of N-phenyl-N′-2-chlorobenzoyl-thiourea from 2-chlorobenzoyl chloride and ammonium thiocyanate using PEG-400 as PTC is more effective than with most quaternary ammonium salts and crown ethers.¹⁵⁹

4.1.3. Oxidation and reduction reactions. PEG as PTC has been used successfully in many conventional redox reactions. A variety of autoxidation and reduction reactions examined in this solvent are listed in Table 8. The cobalt-catalyzed carbonylation of benzyl halide using PEG-400 proved to be cheaper than using quaternary ammonium salts or crown ethers, and more stable than the use of quaternary ammonium salts, which suffer from irreversible degradation under the same conditions.¹⁶³ An acceptable yield can be achieved even without organic solvent for the oxidation of benzyl chloride under the above conditions.¹⁶³ A combination of ultrasound with PEG as PTC can effectively change base-catalyzed autoxidation of alkylnitrobenzenes from a dimeric product to a carboxylic acid.¹⁶⁴ PEG-400 and inexpensive CoCl₂ in KCN–BF₃·Et₂O–FeCl₂ have proved to be useful for the production of carboxylic acids of iodoarenes and iodoalkanes under mild conditions, compared to the use of a catalyst involving a platinum complex.¹⁶⁵

Table 8 Oxidation and reduction reactions using PEG as PTC

Substrate	Oxidant or reductant/catalyst	PEG/solvent and base	Product	Ref.
C6H5-CH2OH	KOCl	PEG-6000/CH3COOC2H5	C6H5-CHO	142
R-C6H4-CH2X	Air/Co2(CO)8	PEG-400/2-CH3-C4H9OH	R-C6H4-CO	163
X = Cl, Br
p-NO2-C6H4-CH3	O2	PEG-400/C6H5-CH3/KOH	p-NO2-C6H4-CO2H	164
RI	Air/CoCl2	PEG-400/KCN/KOH	RCO2H	165
R = CH3-C6H4CH3(CH2)n
C6H5-CH2-C6H5	O2	PEG-6000	C6H5-CO-C6H5	166
RCH=CBr2	Air/Pd(diphos)2	PEG-400/NaOH	RCH2COOH	167
R = CH3C6H4, C6H4, CH3, CH3OC6H4, CH3CH=CH
C6H5-C≡CH	Mn(CO)3Br	PEG-400/NaOH	C6H5-C5H6O2	168
R1COR2	NaBH4	PEG-400/C6H6	R1CH(OH)R2	169
R1 = C6H5, C6H5CH2				69
R2 = CH3, C6H5
RCOY	PEG–Li(Na, K)BH4	PEG-350	RC(OH)Y	70
Y = H, R′, OR″, RCH2Br			RCH3

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PEG with NaBH₄ and PEG–NaBH₄ complexes have been used in the reduction reactions of ketones and aldehydes.^69,70,169 Free PEG can catalyze ketone reduction by NaBH₄,¹⁶⁹ while the PEG–NaBH₄ derivative can selectively reduce aldehydes in the presence of ketones without concurrent reduction of the ketone group.⁶⁹ Base-catalyzed autoxidation of picoline showed that PEG-6000 in benzene was more effective than the use of crown ethers or quaternary ammonium salts,¹⁶⁶ and the reaction can replace previously used expensive aprotic polar solvents such as DMF, Me₂SO, and HMPA. The conversion of vinyl dibromides to 1-bromoalkyne in PEG-400 has been shown to be superior to the same reaction using benzyltriethylammonium.¹⁶⁷ The conversion of aldehydes to homologous acids by a simple two-step procedure using PEG is also considered more practical than the widely used conversion of p-anisaldehyde to p-methoxyphenylacetic acid.¹⁶⁷ The conversion of alkylene to lactone by manganese carbonyl under PEG-400 has been shown to perform almost as well as the more expensive reaction employing benzyltriethylammonium chloride.¹⁶⁸

PEG as PTC has also been investigated in the form of a liquid–gas phase reaction in the isomerization of allylbenzene by diffusion and adsorption.¹⁷⁰ The results showed remarkably higher activity for dehydrohalogenation of 2-bromoethyl benzene than the use of benzyltriethylammonium and 18-crown-6.¹⁷¹

4.2. PEG-supported PTC

In addition to its own phase-transfer activity, PEG has also been employed as a polymer support for other PTCs. PEG has been modified with some typical PTCs such as crown ethers, ammonium salts, cryptands, and polypodands to enhance phase-transfer in two-phase reactions. 16-Crown-5, 19-crown-6, and 18-crown-6 ethers have been attached to PEG-3400 and PEG-6800 and demonstrated effective transfer of metal picrates into CH₂Cl₂ from H₂O, which were able to catalyze the reaction of CH₃COOK with benzyl bromide.¹⁶² The quantitative recovery of these crown–PEG polymers from CH₂Cl₂ and acetonitrile can be achieved by ether precipitation.

The covalent attachment of quaternary ammonium salts to PEG-600 resulted in higher reaction rates for dehydrobromination of 2-bromoethylbenzene at 85 °C than those of PEG and quaternary salts alone.¹⁷² In the dehydrohalogenation of 4-bromo-1-chloroethylbenzene to 4-bromostyrene, the catalytic activity of PEG-600–ammonium salt depended on both the PEG end hydroxyl substitution and ammonium salt structure.¹⁷² The PEG-5000–quaternary ammonium salt complex was also easily recovered by precipitation using hexane, diethyl ether, and tert-butyl methyl ether, in which PEG is not soluble, and by filtration, without activity loss.^12,173,174

PEG monoalkyl ether ((EO)_n, n = 3, 4, 5) has been attached to hexachlorophosphazene to form cyclophosphazenic polypodands, and these compounds were found to have higher phase-transfer catalytic activity for nucleophilic substitution and alkylation reactions,^175,176 especially when commercial Brij 30 (polyoxyethylene-4-lauryl ether) was used as the reactant. The reaction may be competitive with most commonly used PTCs because of the high catalytic activity and low price.¹⁷⁶ The use of PEG of molecular weights from 2000 to 20000 as soluble polymer supports for catalysts and reagents has been reviewed by Janda and co-workers.¹²

5. Aqueous biphasic reactive extraction (ABRE)

The term aqueous biphasic reactive extraction (ABRE) has been used to describe the use of ABS as biphasic reaction media in which controlled partitioning of reactants, catalysts, and products, by choice of phase systems and manipulation of TLL, can be used to enable higher reaction yields, greater product selectivity, and simultaneous separation of reactants, products, and catalysts.⁵⁰

ABS have been used for separations primarily relating to biological solutes and particles for almost half a century.^{31,59,79,177,178} Recent extension of this technology has been directed toward application as green separation media²⁵ including, separation of organic hydrocarbon species^32,33,45 and metal ions.^34–38 However, both PEG and ABS have been largely ignored as “green reaction media” until recent papers indicated their application as new solvents for delignification of cellulose,^50–55 cyclic olefin oxidation,^56,57 polyoxometalate catalyzed aerobic oxidation,⁶⁸ S_N1, Diels–Alder, and enzymatic reactions,^88,116,117 and olefin catalytic oxidation to diols.¹³²

ABRE has three main characteristics: (1) phase separation benefiting separation of reactants and products, and providing a reaction driving force; (2) the PEG-rich top phase in PEG–salt ABS has organic solvent-like properties as a medium for reaction; (3) ABS components, PEG and metal salts, may be included in the form of PTCs^56,57 and metal-catalysts.⁵⁰ Two types of ABRE have been noted. One takes the form of a three-phase reaction,^{56,57,179–181} and the other a two-phase reaction.^50–55 The three-phase reaction results from adding organic reactants with or without corresponding supporting organic solvent into an ABS, thus, the system forms three phases initially as shown in Scheme 1. The three phases are usually composed of the light organic phase, and the typical PEG–salt ABS made of the PEG-rich top phase and salt-rich bottom phase. The two-phase reaction results from the chemical or enzyme catalyzed reaction supported only by the normal ABS biphases as demonstrated in Scheme 2.

Scheme 1 Three-phase ABRE: Ro = organic reactant; Ra = aqueous reactant; Po = organic product; Pa = aqueous product; S = PTC.

Scheme 2 Typical enzyme hydrolysis reaction in ABS: S = substrate; E = enzyme; P = product.

5.1. Three-phase reactions

In order to enhance reaction rate and yield, PEG–salt ABS were formed to increase the organic reactant solubility and PEG concentration in the PEG-rich top phase, which has been described as an ABRE process applied to catalytic oxidation,^56,57 substitution, and isomerization reactions.^179–181 The currently rather limited number of investigations of ABRE processes listed in Table 9, suggest that the role of ABS may be very important for increasing the reaction yield, however, the underlying mechanism is still largely unexplored. For the reactions shown in Scheme 1, ABS formation results in a PEG-rich top phase, which facilitates an increase in the solubility of some organic reactants.^56,57,119 Secondly, phase separation is useful for reactant and product separation, and thirdly, alteration of the reactant, product or catalyst distribution may be used to manipulate the reaction rate. In three-phase reactions, many solvophilic and solvophobic reactants may display some solubility in and partition, at least to some extent, to the PEG-rich top phase and the reaction may occur in this phase.^56,57,180

Table 9 Three-phase ABRE: ABS and organic solvent

ABS and PEG	Organic phase	Product	Ref.
C4H9ONa + PEG + NaOH	C6H5-CH2Cl	C6H5-CH2-OC4H9	179
(PEG-600, 3000)	(in C6H6 or C12H26)		181–183
(Hex)4NBr + PEG + KOH	2-C8H17Br	C8H16	184
(PEG-200)	(in C12H26)
KOH + PEG	CH3O-C6H4-CH2-CH=CH2	CH3O-C6H4-CH=CH-CH3	180
(PEG-400–6000)	(in C6H5-CH3)
H2O2 + PEG + NaHSO4	C6H10	HOOC-(CH2)4-COOH	56
(PEG-600–20000)	C5H8	HOOC-(CH2)3-COOH	57

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In the synthesis of n-butyl phenyl ether by three-phase catalysis,¹⁸¹ addition of NaOH resulted in a higher reaction rate than the addition of other kinds of salts such as NaCl, KBr and NaBr. PEG and OH⁻ easily form ABS due to the more negative Gibbs free energy of hydration (ΔG_hyd) of the hydroxide anion than that of Cl⁻ and Br⁻. In the three-phase reaction, the mechanism shown in Scheme 1 is supposed to be that of organic reactant diffusion into the PEG-rich top aqueous phase^56,57 (or PEG as PTC carrying aqueous reactant into the organic phase¹⁸¹), with subsequent reaction resulting in product precipitation (or dissolution) in the bottom phase, or alternatively, organic product partition into the organic phase.¹⁷⁹ For the above reaction, in an ABS made up of PEG-3000, tetrahexylammonium bromide/KOH and dodecane as organic phase, the production rate of the three-phase system was seven times higher than a corresponding aqueous–organic two-phase system, however when toluene was added as the organic phase, no ABS was formed, because PEG-3000 is soluble in toluene. The yield in toluene was about 10% lower than that in dodecane under the same experimental conditions. The ether production rate and its selectivity are dependent on the initial concentration of n-butanol.¹⁸¹

Synergistic effects of PEG and (Hex)₄NBr in the form of a third phase for dehydrohalogenation of 2-bromooctane, and butylphenyl ether have been studied.¹⁸⁴ The amount of quaternary ammonium salt can be reduced to one-nineteenth of the original amount and easily recycled without any loss in catalytic activity in the 2nd and 3rd recycle.¹⁸⁴

The mechanism of base-catalyzed three-phase reactions with PEG has been studied using the isomerization of allylanisole as a model reaction.¹⁸⁰ The kinetically controlled reaction is successful only under three-phase conditions due to the phase separation of NaOH–PEG aqueous solutions. A potential advantage lies in the fact that PEG is more stable under the experimental conditions, under which quaternary ammonium salts undergo Hoffmann elimination and deactivation.

Recently, we have developed a new green catalytic oxidation of cyclic olefins (e.g., cyclohexene, cyclopentene, and 1,2,3,6-tetrahydrophthalic anhydride (THPA)) to dicarboxylic acid (e.g., adipic acid, glutaric acid, and 1,2,3,4-butanetetracarboxylic acid (BTCA)) in a PEG-2000–NaHSO₄ 50% H₂O₂ ABS and in the absence of organic solvent and specific PTC. Phase separation in PEG–NaHSO₄ was found to be essential to enhance reaction yield.^56,57 The ABS selection, and effect on adipic acid yield were carefully investigated, and in this ABRE process, the results showed that phase compositions, TLL, and PEG molecular weight can all affect the reaction yield. This model reaction demonstrated the potential “green” characteristics of the use of organic solvent-free, inexpensive, low toxicity PEG and NaHSO₄ ABS components, combined with an ecologically benign and clean oxidant (50% H₂O₂).

5.2. Biphasic reactions

5.2.1. Chemical reactions. ABS have been used as alternative delignification processes for hardwood and softwood paper pulping analogous to organosolv pulping. The reactions of delignification in alkaline medium during organosolv pulping are the α-ether cleavage of the free phenolic hydroxyl to quinone methide, and β-ether cleavage of associated phenolic hydroxyl groups combined with condensation reactions.¹⁸⁵ ABS have been proposed as similar in process concept to organosolv pulping,⁵¹ but without the involvement of an organic solvent. ABRE has some obvious advantages compared with the organosolv process: (1) it utilizes a wholly aqueous medium; (2) some of the phase forming components, e.g., Li₂SO₄, can serve as highly effective metal-catalysts for the delignification reaction;⁵² (3) reaction enhancement can be achieved by cellulose and lignin partitioning to opposite phases;^53,54 (4) solubility of lignin in the polymer solutions is improved; and (5) the activation energy for the reaction is reduced by improving reagent access through swelling of the fibers.⁵⁰ The ABRE pulping process has been shown to compare favorably with the best organosolv practice.⁵⁵

Hydrogel microspheres of methylacrylate bound Dextran polymer can be obtained from the polymerization of methylacrylate bound Dextran in PEG-10000–methacrylated Dextran (Dextran-40000 or 220000) ABS without using organic solvent.¹⁸⁶ A 90% yield can be obtained within short times at relatively low concentrations of radical initiators potassium peroxydisulfate (KPS) and tetramethylethylenediamine (TEMED). Comparison of microspheres from ABS with a macroscopic hydrogel product with a system confined to one aqueous phase, showed a higher reaction rate. With the macroscopic hydrogel process in one phase, the KPS concentration decreased gradually with time, whereas for the microspheres in ABS, the KPS concentration remained constant due to the partition equilibrium between KPS in the PEG-rich top phase and the Dextran-rich bottom phase.

5.2.2. Enzyme reactions. Aqueous two-phase systems have been widely studied for protein purification and immobilization, and also to remove product during biotranformations catalyzed by free cells or enzymes.^26,28,187 Several important enzyme catalyzed biomass hydrolyses and biosyntheses, including processes applicable to cellulose, antibiotics, starch, cyclodextrin, and fermentation processes, have been examined. These ABRE systems for enzymatic hydrolysis can lead to enhanced reaction rates, as well as cost and energy savings, all achieved without the involvement of any organic solvent in the process.

The enzyme hydrolysis and biomass bioconversions in ABS listed in Table 10, represent important applications of ABRE in bioengineering.^26,28 Compared with one-phase reactions, several important characteristics are illustrated in Scheme 2. (1) The ABS must selectively distribute enzyme and substrate to one phase (the bottom phase was assumed in Scheme 2), while the desired product should be partitioned to the other phase (the top phase was assumed in Scheme 2). This can be achieved through differences in molecular weight or molecular structure. The un-hydrolyzed biomass, such as cellulose or starch, is macromolecular, while products, such as glucose or cellobiose, are much smaller. Transformation of substrate to product by an enzyme confined in the bottom phase can effectively enhance reaction by distribution of product to the top phase. Even if the low molecular weight product is evenly partitioned between the phases, the reaction can still be conducted by continuous removal of product from one phase. (2) Product inhibition can effectively be avoided by separation of enzyme and product into two different phases. (3) In some cases, product hydrolysis can be effectively prevented due to partition in the high concentration PEG phase.¹⁹⁹

Table 10 Enzyme hydrolysis in ABS

Substrate	Enzyme	PEG and ABS	Product	Ref.
Cellulose (C6H10O5)n	Endo-β-glucanase	PEG-40000, 200000	Glucose (C6H12O6)	189–194
	Exo-β-glucanase	Dextran (MW = 1, 4, 11, 50, 200 × 10^4)
	β-Glucosidase
Starch or native starch	α-Amylase;	PEG-6000, 20000	Maltose, glucose	195–198
	Glucoamylase	Dextran (MW = 5–7 × 10^4)
	Amyloglucosidase	PEO-PPO-2500
		MgSO4, (NH4)2SO4
p-Nitrophenyl α-mannoside	α-Mannosidase	PEG-8000	Oligosaccharides	199
p-Nitrophenyl β-galactoside		Dextran-500000
Bovine hemoglobin	Papain	PEG-6000	Soluble peptides	195
		Dextran (MW = 5–7 × 10^4)
		Ultra fine silica particles (Snowtex 30)
N-Acetyl-L-methionine	Acylase	PEG-600	Acetic acid and L-methionine	200,201
		K3PO4
Penicillin G	Penicillin acylase	PEG-6000, 20000	6-Aminopenicillanic acid (6-APA)	202–204
Potassium salt		K3PO4
Benzylpenicillin (BP)
7-amino-deacetoxicephalosporanic acid (7-ADCA)	Penicillin G acylase	PEG-400	Cephalexin	205,202
Phenylglycine methyl ester (PGME)		MgSO4
C21H30O5 (Hydrocortisone)	Bacterium	PEG	Prednisolone	187
		Reppal-PES

---

In the bioconversion of cellulose to ethanol, the enzymes for hydrolysis, and enzyme recycling constitute the major portion of the process costs.¹⁸⁹ Biphasic systems can be used in cellulose pretreatment, hydrolysis, and fermentation. Both the cellulose substrate and cellulolytic enzyme may be partitioned to the bottom phase, while the hydrolysis product, glucose and some soluble reducing sugars, will be partitioned to the top phase.^189–192 Use of ultra filtration technology¹⁹³ and an attrition bioreactor¹⁹⁴ in combination with ABRE, have been found to enhance the reaction rate and improve the yield.^193,194

Various crude starches have been hydrolyzed by the synergistic action of α-amylase and glucoamylase in PEG–Dextran and PEG–starch ABS.¹⁸⁸ The main advantage in the use of starch is that the starch serves as one of the phase forming polymers, which markedly decreases the cost of the reaction.¹⁸⁸ The enzyme hydrolysis of corn starch in ABS using α-amylase immobilized on ultra fine silica particles by covalent cross linking with glutaraldehyde has been studied,¹⁹⁵ and the enzyme showed high activities. The immobilized enzyme was partitioned to the PEG-rich top phase in PEG–Dextran ABS, and the products were recovered from the bottom phase. Bovine Hb and papain immobilized on ultrafine silica particles by covalent crosslinking with glutaraldehyde have been studied in PEG-6000–Dextran-60000.¹⁹⁵ The immobilized papain was totally partitioned to the top PEG-rich phase, and the soluble peptide product was found in the bottom phase.

Conversion of native waxy maize starch to glucose by α-amylase and glucoamylase has also been conducted in a PEG-20000–crude Dextran ABS in combination with membrane ultra filtration.¹⁹⁶ A continuous stream of glucose could be produced, and PEG, Dextran, and the starch-degrading enzymes could be recycled. It was possible to cut the starch bioconversion time almost in half by employing a PEO-PPO-2500–MgSO₄ ABS compared to a single phase process.^197,198 (PEO-PPO-2500 is a random copolymer of ethylene oxide and propylene oxide with an average molecular weight of 2500.)

PEG-8000–Dextran-500000 ABS have also been applied to the synthesis of oligosaccharides by reverse action of Jack bean α-mannosidase.²⁰⁵ The reaction and whole yields were similar in two-phase systems and one-phase aqueous buffer systems, but the yield of product per unit of enzyme increased ten fold when using the ABS. This is likely to become a rapidly developing area of the application of ABRE systems since the availability of carbohydrate enzymes in high purity and modest cost has increased with the advent of the wide application of genetic manipulation (GM) techniques.²⁰⁶

Cephalexin has been synthesized in ABS by using penicillin G acylase (PGA) as a catalyst and 7-amino-deacetoxicephalosporanic acid (7-ADCA) and phenylglycine methyl ester (PGME) as substrates. A 60% yield of cephalexin was achieved in ABS compared to 21% in an entirely aqueous single phase reaction.²⁰² The deacylation of penicillin G has been studied using penicillin acylase in a PEG–K₃PO₄ ABS. In this system, the cells partitioned to the bottom phase and the products to the top phase.²⁰³ Cephalexin synthesis from 7-ADCA and PGME catalyzed by PGA, which is covalently immobilized inside a glyoxyl-agarose porous support, can be conducted in PEG-600–(NH₄)₂SO₄ ABS. The yield of 90% in the biphasic reaction was higher than that of 55% found in the monophasic reaction.¹⁹⁹

Chirally selective enzymatic acylase hydrolysis of N-acetyl-L-methionine into acetic acid and L-methionine was carried out in PEG–K₃PO₄ ABS in liquid–liquid centrifugal partition chromatography (CPC), and the products and reactants were obtained separately in the same process.^200,201

Enzyme-biocatalysts are often considered to be inherently green, clean, and nontoxic as opposed to traditional catalysts, which are often toxic metal compounds. Enzymatic syntheses are capable of providing high stereo- and regio-selectivities without using chemical protection-deprotection.²⁰⁷ ABS may have an important contribution to make in this area. ABS allow manipulation of product and reactant distributions allowing the possibility of separation and yield enhancements. ABS also provide a benign non-denaturing environment for enzymes in contrast to classical solvent media.

6. Conclusions

In recent years PEG aqueous solutions have been widely used in many different kinds of reaction systems. Their low-toxicity, low volatility, and biodegradability represent important environmentally benign characteristics, which are particularly attractive when combined with their relatively low cost as a bulk commodity chemical. In addition, aqueous PEG solutions may often substitute for expensive and often toxic PTCs. The developed state of knowledge with regard to the toxicological properties of PEG is of considerable current advantage compared to the paucity of knowledge for many other potential alternative solvent systems.

The wide range of reactions conducted in pure liquid PEG demonstrates its resilience to degradation and the low occurrence of unwanted side reactions. The role of PEG as a cheap substitute PTC supports the idea that it can assist in promoting the molecular proximity of reactants and catalysts. ABRE combines many of the above advantages along with a measure of process integration and intensification in which chemical synthetic steps are combined with extractive steps. Aqueous solutions of polymers, and in particular PEG, can profoundly affect water structure, reducing cohesivity and some aspects of hydrogen bonding and thereby increasing the solubility of relatively less polar species.

The critical phase formation phenomena associated with PEG aqueous solutions are uniquely important in ABRE, since this brings together phases having different properties and which may be described as having different degrees of hydrophobicity. These phases are uniquely tunable and thus, taken together, ABRE systems can cover a large range of relative difference in chemical potential difference between the phases. In order to achieve this, ABRE systems need to be thought of as a continuum of self-similar systems ranging from Dextran–Ficoll and similar systems, through to PEG–Dextran, and ultimately, PEG–salt ABS. In all of these systems, the polymer molar concentration difference between the phases is proportional to the chemical potential difference engendered across the interface. Metal salts and metal-catalysts may be expected to benefit from solubility in the lower salt-rich phase and yet continued solubility in the more hydrophobic phase may provide for intimate contact with less polar species.

Phase separation can also provide a driving force for chemical reaction through the law of mass action by separation of reactants and products at the moment of formation. Phase separation in ABRE processes may also significantly aid in catalyst and product recovery by providing means of distribution to different phases. In turn, this can aid in the efficient use of reactants and the recycling of catalysts.

Solute distribution is controllable to a much greater extent than with conventional extraction systems. With careful design, this can result in enhanced reaction rates and improved yields in specific reactions. It is also possible to achieve the result that expensive and inefficient recycling and recovery steps can be minimized.

On the other hand, ABRE processes represent complex systems with a large number of variable reaction parameters, requiring optimization and analysis, such as temperature, pH, the addition of particular reactants, or the formation of products or soluble intermediates. All these factors will need to be carefully considered in the design of ABRE processes.

In the course of our recent studies on ABRE processes, we have identified two-types of ABRE process. The first is a three-phase system which includes insoluble liquid organic reactants. The second type is a biphasic process in which the reactants are completely soluble. In the former case, as for example in the oxidation of cyclic olefins in a PEG–NaHSO₄–H₂O₂–H₂O ABS, the solubility of the cyclic olefins in the PEG-rich phase is of prime importance. Successful design of the ABS, including selection of PEG molecular size and salt type, depends on an understanding of ABS phase behavior and phase polarity. Such reactions may be applicable in many organic synthetic processes.

Pure biphasic processes may be widely applicable where most components are more soluble. However, even here the existence of a third phase may be noted in some cases, for example a phase of residual solid wood pulp in alternative delignification processes for hardwood and softwood paper pulping in PEG–salt ABS. Such ABRE pulping processes were shown to compare favorably with Kraft type processes and with current organosolv practice. Another example may be given in the form of enzyme hydrolysis reactions, for example the degradation of cellulose in PEG/polymer ABS has shown these ABRE systems can lead to enhanced reaction rates, and cost and energy savings.

It may be anticipated, given the greater availability, higher purity, and reduced cost of enzymes resulting from the impact of rDNA technology, combined with the exquisite specificity of these enzymes and our increasing ability to engineer their properties, that the use of enzymatic synthesis in synthetic chemistry will greatly expand in the years to come. In this context, ABRE processes provide a compatibility with macromolecular stability unmatched by any other extractive solvent systems. Thus, the application of ABRE in the development of controlled enzymatic synthesis, for example of complex carbohydrates, is very promising.

It is to be hoped that this review will further stimulate interest in the extension of ABS applications to yet more novel catalytic processes and reactive extractions. The application of ABRE in synthetic organic chemistry represents both an opportunity and a challenge, and the wide availability of PEG at low cost may give such processes a promising future in green chemistry and green engineering.

Abbreviations

ABRE	Aqueous biphasic reactive extraction
ABS	Aqueous biphasic systems
7-ADCA	7-Amino-deacetoxicephalosporanic acid
ATPS	Aqueous two-phase systems
BTCA	1,2,3,4-Butanetetracarboxylic acid
CPC	Centrifugal partition chromatography
DMF	Dimethyl formamide
DMSO	Dimethyl sulfoxide
GM	Genetic manipulation
GRAS	Generally recognized as safe
HMPA	Hexamethylphosphoramide
IL	Ionic liquid
KPS	Potassium peroxydisulfate
LCST	Lower critical solution temperature
PEG	Polyethylene glycol
PGA	Penicillin G acylase
PGME	Phenylglycine methyl ester
PPG	Polypropylene glycol
PTC	Phase-transfer catalyst
sc-CO2	Supercritical carbon dioxide
TEMED	Tetramethylethylenediamine
THF	Tetrahydrofuran
THPA	1,2,3,6-Tetrahydrophthalic anhydride
TLL	Tie line length
UCST	Upper critical solution temperature
VOC	Volatile organic compound

Acknowledgements

Our work with PEG is supported by the Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Research, US Department of Energy (Grant DE-FG02-96ER14673).

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Footnote

† Current address: Key Lab. of Rare Earth Chemistry and Physics, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Renmin Street 5625, Changchun, 130022, People’s Republic of China.

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