Metal-Catalyzed Reactions in Water E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Water is abundant in nature, non-toxic, non-flammable and renewable and could therefore be safer and economical for the chemical industry
wherever it is used as a solvent. This book provides a comprehensive overview of developments in the use of water as a solvent for metal
catalysis, illustrating the enormous potential of water in developing new catalytic transformations for fi ne chemicals and molecular materials
synthesis. A group of international experts cover the most important metalcatalyzed reactions in water and bring together cutting-edge results
from recent literature with the first-hand knowledge gained by the chapter authors. This is a must-have book for scientists in academia
and industry involved in the fi eld of catalysis, greener organic synthetic methods, water soluble ligands and catalyst design, as well as for teachers and students interested in innovative and sustainable chemistry.
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Veröffentlichungsjahr: 2013
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Table of Contents
Related Titles
Title Page
Copyright
Preface
List of Contributors
Chapter 1: Metal-Catalyzed Cross-Couplings of Aryl Halides to Form C–C Bonds in Aqueous Media
1.1 Introduction
1.2 Aqueous-Phase Cross-Coupling Using Hydrophilic Catalysts
1.3 Cross-Coupling in Aqueous Media Using Hydrophobic Ligands
1.4 Heterogeneous Catalysts in Aqueous Media
1.5 Special Reaction Conditions
1.6 Homogeneous Aqueous-Phase Modification of Biomolecules
1.7 Conclusion
References
Chapter 2: Metal-Catalyzed C–H Bond Activation and C–C Bond Formation in Water
2.1 Introduction
2.2 Catalytic Formation of C–C Bonds from spC–H Bonds in Water
2.3 Activation of sp2C–H Bonds for Catalytic C–C Bond Formation in Water
2.4 Activation of sp3C–H Bonds for Catalytic C–C Bond Formation in Water
2.5 Conclusion
Acknowledgments
References
Chapter 3: Catalytic Nucleophilic Additions of Alkynes in Water
3.1 Introduction
3.2 Catalytic Nucleophilic Additions of Terminal Alkynes with Carbonyl Derivatives
3.3 Addition of Terminal Alkyne to Imine, Tosylimine, Iminium Ion, and Acyl Iminium Ion
3.4 Direct Conjugate Addition of Terminal Alkynes
3.5 Conclusions
Acknowledgments
References
Chapter 4: Water-Soluble Hydroformylation Catalysis
4.1 Introduction
4.2 Hydroformylation of Light C2–C5 Alkenes in the RCH/RP Process
4.3 Hydroformylation of Alkenes Heavier than C5
4.4 Innovative Expansions
4.5 Conclusion
References
Chapter 5: Green Catalytic Oxidations in Water
5.1 Introduction
5.2 Examples of Water-Soluble Ligands
5.3 Enzymatic Oxidations
5.4 Biomimetic Oxidations
5.5 Epoxidation, Dihydroxylation, and Oxidative Cleavage of Olefins
5.6 Alcohol Oxidations
5.7 Sulfoxidations in Water
5.8 Conclusions and Future Outlook
References
Chapter 6: Hydrogenation and Transfer Hydrogenation in Water
6.1 Introduction
6.2 Water-Soluble Ligands
6.3 Hydrogenation in Water
6.4 Transfer Hydrogenation in Water
6.5 Role of Water
6.6 Concluding Remarks
References
Chapter 7: Catalytic Rearrangements and Allylation Reactions in Water
7.1 Introduction
7.2 Rearrangements
7.3 Allylation Reactions
7.4 Conclusion
Acknowledgments
References
Chapter 8: Alkene Metathesis in Water
8.1 Introduction
8.2 Examples of Applications of Olefin Metathesis in Aqueous Media
8.3 Conclusions and Outlook
Acknowledgments
References
Chapter 9: Nanocatalysis in Water
9.1 Introduction
9.2 Nanocatalysis
9.3 Effects of Size of Nanocatalysts
9.4 Transition-Metal Nanoparticles
9.5 Catalytic Applications of Transition-Metal-Based Nanomaterials
9.6 Pd Nanoparticles in Organic Synthesis
9.7 Nanogold Catalysis
9.8 Copper Nanoparticles
9.9 Ruthenium Nanocatalysts
9.10 Magnetic Iron Oxide Nanoparticle
9.11 Cobalt Nanoparticles
9.12 Conclusion
References
Index
Related Titles
Li, C.-J., Perosa, A., Selva, M., Boethling, R., Voutchkova, A. (eds.)
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Series: Handbook of Green Chemistry (Set III)
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The Editor
Prof. Dr. Pierre H. Dixneuf
CNRS-Université de Rennes 1
Catalyse et Organométalliques
Campus de Beaulieu, Bat10c
35042 Rennes Cedex
France
Dr. Victorio Cadierno
Universidad de Oviedo
Departamento de Química
Orgánica e Inorgánica
Instituto Universitario de
Química Organometálica
“Enrique Moles” (Unidad Asociada al CSIC)
Facultad de Química
Julían Clavería 8
33006 Oviedo
Spain
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Preface
Metal catalysis represents a frontier field of research. The ability of metal complexes to catalyze organic reactions, and to selectively create new ones, is now the basis of the most powerful strategies leading to new synthetic methods. Homogeneous catalysis has brought a revolution in fine chemical synthesis, drug and cosmetic discovery, in the preparation of molecular materials and polymers, and it is more active than ever before.
Catalysis, one of the twelve principles of Green Chemistry, is offers selective processes with energy and atom economy and is an essential partner for sustainable manufacturing in the chemical industry. Within this context, the use of a safe, nontoxic, eco-friendly, and cheap solvent is also advised. Water is probably the most appealing candidate as an easily available, noninflammable, nontoxic, and renewable solvent. Consequently, the use of water as a solvent in synthetic organic chemistry and materials science has spread throughout the chemical community at a staggering pace during the last two decades.
The combination of metal catalysis and water has led in recent years to the development of a huge number of new and greener synthetic methodologies. Although the hydrophobic character of most organic compounds has been for long time considered as a major drawback, it is nowadays well documented that even when the reaction medium is heterogeneous, “on water” conditions, an enhancement on the catalyst activity and/or selectivity can be observed by using water as solvent. The low solubility and inherent instability of organometallic compounds in water is another limitation that has also been largely surpassed in recent years by designing new hydrophilic ligands and more robust, air- and water-stable catalysts. Moreover, the use of metal catalysts in water or in a two-phase system offers other advantages versus more classical organic solvents, that is, it simplifies the separation of the products, and that of catalyst, thus favoring water recycling, a very important aspect for large-scale chemical processes. New discovered techniques in nanofiltration and in recovery of metal ions from water contribute to this field. All these facts make catalysis in aqueous systems a very active field of research today, both from an academic and an industrial point of view. In fact, metal catalysis in water is now in the heart of the main fields of contemporary chemical research.
The content of this volume gathers the main aspects and potentials of metal catalysis in water, including C-C cross couplings (Chapter 1), C-H bond activations (Chapter 2), nucleophilic additions of alkynes (Chapter 3), hydroformylations (Chapter 4), oxidation processes (Chapter 5), hydrogenations (Chapter 6), rearrangements and allylations (Chapter 7), olefin metathesis reactions (Chapter 8), and nanocatalysts in water (Chapter 9).
The aim of this book is to introduce the readers to this topic through cutting-edge results from the recent literature, and the know-how shared by the chapter authors. This volume should be helpful to academic and industrial researchers involved in the fields of catalysis, new greener organic synthetic methods, water-soluble ligands, and catalysts designing and also to teachers and students interested in innovative and sustainable chemistry.
We are grateful to the Wiley-VCH team who made this project practical and to all the contributors to this volume for their effort and enthusiasm in sharing their expertise to join this aquatic editorial enterprise.
Pierre H. Dixneuf
Victorio Cadierno
List of Contributors
Chapter 1
Metal-Catalyzed Cross-Couplings of Aryl Halides to Form C–C Bonds in Aqueous Media
Kevin H. Shaughnessy
1.1 Introduction
Metal-catalyzed cross-coupling reactions have developed into a standard component of the synthetic chemist's toolbox [1–4]. These reactions date to the work of Ullmann and Goldberg in the early 1900s on copper-promoted C–C and C–heteroatom bond formations. Copper remained the catalyst of choice for these reactions until the pioneering work of Heck, Suzuki, Stille, Negishi, and others on palladium-catalyzed cross-coupling reactions. Palladium-catalyzed reactions, which can be generally carried out under milder conditions and with a wider range of substrates than reactions catalyzed by copper or other metals, have become standard methods for formation of carbon–carbon and carbon–heteroatom bonds.
Cross-coupling reactions are characterized by the metal-catalyzed coupling of an organic electrophile, typically an organic halide, with an organic nucleophile (Scheme 1.1). The organic halide can be an sp-, sp2-, or sp3-hybridized carbon with any halogen or pseudohalogen leaving group. The majority of research has focused on sp2 carbon–halogen bonds. A variety of name reactions have been developed using organometallic carbon nucleophiles. Examples with nearly every metal in the periodic table have been demonstrated, but the most common organometallic species used include organotin (Stille), organoboron (Suzuki), Grignard reagents (Kumada), organosilicon (Hiyama), organozinc (Negishi), and in situ generated acetylide anions (Sonogashira). Key steps in these cross-coupling reactions include oxidative addition of the organic halide, transmetalation of the nucleophilic carbon, and reductive elimination to form the product. The Heck coupling of aryl halides and alkenes also falls into this class of reactions, although it involves a migratory insertion/β-hydride elimination sequence in the key bond-forming step rather than reductive elimination.
Scheme 1.1 Major classes of metal-catalyzed cross-coupling reactions.
Organic synthetic methodology has largely developed using organic solvents. Homogeneous-metal-catalyzed reactions have similarly largely relied on the use of traditional organic solvents. Organic solvents have a number of advantages: they are good solvents for organic compounds, there are a range of properties (polarity, protic/aprotic, boiling point, viscosity) that can be chosen, and certain organic solvents are inert toward highly reactive reagents. Disadvantages of organic solvents include flammability, toxicity, and lack of sustainability. Because of these latter issues, there has been an interest in moving away from organic solvents to safer and more renewable solvent systems. Water is a particularly attractive alternative solvent [5–9]. Water is a renewable, although limited, resource that is nontoxic, nonflammable, and relatively inexpensive. The unusual properties of water, such as its strong hydrogen bonding ability, can lead to unusual reactivity that is not seen in traditional organic solvents. Although water is an attractive solvent, it presents a number of challenges in synthetic organic chemistry. Water is a poor solvent for most organic compounds. Although this can limit the use of water as a reaction medium, it also provides opportunities for alternative reactivity and simplified product isolation compared to organic solvents. Water is also highly reactive with many useful reagents, particularly many organometallic reagents. This can limit the types of reactions that can be performed in water. Late transition metal–carbon bonds as well as many of the common organometallic reagents used in cross-coupling reactions, such as organotin, organoboron, and organosilicon compounds, are tolerant of water, however.
The primary motivations to carry out cross-coupling reactions in aqueous solvents have been economic and environmental. For the reasons described above, water is potentially safer than organic solvents. Although water is often considered an environmentally benign solvent, water contaminated with organic materials must still be treated as hazardous waste. Recycling of water and decreased solvent demand in purification may still make water a better choice economically and environmentally. Another motivation to use water is to allow for simple separation of the catalyst from the product stream. The simplified separation can significantly decrease cost and waste output for a given process. The palladium catalysts most commonly used in these reactions are expensive. The ability to recover and reuse the palladium catalyst is critical for the application of these methodologies in large-scale fine chemical synthesis. Because the catalysts are often homogeneous, separation of the metal from the product stream can also be quite challenging, particularly to the low levels required in pharmaceutical synthesis [10]. The use of a water-soluble catalyst in an aqueous–organic biphasic system helps in potentially constraining the catalyst to the aqueous phase, allowing for simple separation of the catalyst from the organic product stream. Recently, a number of researchers have shown that water can have promoting effects on cross-coupling reactions of hydrophobic substrates [11, 12].
In this chapter, the use of water as a reaction medium for metal-catalyzed coupling of organic halides and carbon nucleophiles is reviewed. Reactions catalyzed by hydrophilic catalysts, hydrophobic catalysts, and heterogeneous catalysts are discussed. A number of previous reviews have been published in this area, including reviews specifically on aqueous-phase Suzuki couplings [13–17] and more general reviews of aqueous-phase cross-coupling reactions [18–23].
1.2 Aqueous-Phase Cross-Coupling Using Hydrophilic Catalysts
One of the important motivations for the use of water as a reaction medium in catalysis is that it provides a way to simplify the separation of homogeneous transition metal catalysts from the organic product stream. By using a hydrophilic catalyst in an aqueous/organic biphasic solvent system, it is possible to constrain the hydrophilic catalyst in the aqueous phase. The hydrophobic product can then be separated by simple decantation. This approach was first demonstrated effectively in the Rhône–Poulenc process for the hydroformylation of propene using a Rh/TTPTS (trisodium tri(3-sulfonatophenyl)phosphine) catalyst system [24]. This novel approach to heterogeneous catalysis received limited attention initially, but over the past two decades there has been an extensive effort devoted to the synthesis and catalytic application of water-soluble ligands and catalysts [22].
1.2.1 Hydrophilic Triarylphosphines and Diarylalkylphospines
Hydrophilic triarylphosphines were the first class of ligands to be applied to aqueous-phase cross-coupling reactions. Sulfonated triphenylphosphines (i.e., m-TPPTS, Figure 1.1) have been the most widely used ligand. Sulfonated arylphosphines are attractive ligands because they can be readily prepared by sulfonating the parent phosphine in fuming sulfuric acid. Other ionic triphenylphosphine derivatives have been prepared with carboxylate, phosphonate, and guanidinium functional groups. These ligands typically require more involved syntheses, which has resulted in their use being limited.
Figure 1.1 Triphenylphosphine derivatives with ionic substituents.
1.1
Genêt and coworkers first applied the more water-soluble m-TPPTS for Pd-catalyzed cross-coupling reactions. The Pd(OAc)2/m-TPPTS system (2.5 mol%) gave good yields of coupled products in Heck, Sonogashira, Suzuki, and Trost–Tsuji reactions of aryl and alkenyl iodides in a 1 : 1 water/acetonitrile solvent system [26, 27]. Aryl bromides could be coupled at 80 °C with the Pd(OAc)2/m-TPPTS system [28]. The aqueous catalyst solution could be reused for four cycles in the Suzuki coupling of an aryl bromide with good yields, although increasing reaction times were needed with each cycle. The Pd/m-TPPTS catalyst systems are generally not effective for coupling of aryl chlorides, however. A catalyst formed in situ from NiCl2(dppe) and 5 equiv of m-TPPTS in the presence of zinc catalyzes the Suzuki coupling of aryl chlorides in water/dioxane, however [29]. A high catalyst loading (10 mol% Ni) was required and the reaction was limited to activated aryl chlorides. The Ni/m-TPPTS system was applied to the synthesis of 2-cyano-4′-methylbiphenyl, an important precursor to the sartan class of angiotensin II receptor antagonists (Equation 1.2).
1.2
A drawback to the synthesis of m-TPPTS is the harsh conditions required for the sulfonation reaction because the protonated phosphonium group acts as a deactivating group. Hiemstra and coworkers reported the synthesis of 2-benzofuranylphosphines and their sulfonation to ligands 1–3 (Equation 1.3) [30]. The furanyl oxygen activates the aromatic ring toward electrophilic aromatic substitution, allowing the sulfonation reaction to be carried out in sulfuric acid rather than in fuming sulfuric acid. As a result, no oxidation of the phosphorus center was observed. In addition, the benzofuran ring could be selectively sulfonated in the presence of phenyl groups, which allows for easy access to mono- and disulfonated ligands (1 and 2). Catalysts derived from ligand 3 gave comparable or lower activity in Heck and Suzuki couplings of aryl iodides to m-TPPTS-derived catalysts. The aryl rings can be similarly activated by inclusion of methyl or methoxy substituents. Tri(2,4-dimethyl-5-sulfonatophenyl)phosphine (TXPTS) was prepared as a more sterically demanding analog of m-TPPTS. Catalysts derived from TXPTS gave superior activity compared to m-TPPTS-derived catalysts for Heck and Suzuki couplings of aryl bromides in water/acetonitrile (Equation 1.4) [31, 32].
1.3
1.4
An alternate approach to appending the sulfonate group to the phosphine is through an alkyl linkage. Diarylphosphinoalkyl sulfonates can be prepared by reaction of diarylphosphides with ω-bromoalkylsulfonates [33]. Ligand 4 in combination with Pd(OAc)2 (0.05 mol%) gave an effective catalyst for the Suzuki coupling of aryl bromides in water at 80 °C (Equation 1.5). Moderate yields were obtained in Suzuki couplings of aryl chlorides at 150 °C with microwave heating using this system.
1.5
While sulfonated triarylphosphines have been most widely studied owing to their ease of synthesis, a range of other anionic, cationic, or neutral hydrophilic substituents have also been used to generate water-soluble ligands. Phosphonate-substituted ligands are more water-soluble than their sulfonate-substituted counterparts [34]. The catalyst derived from p-TPPMP (disodium 4-(diphenylphosphino)phenylphosphonate (Figure 1.1) and Pd(OAc)2 gave higher yields than the catalyst derived from m-TPPDS(disodium phenyldi(3sulfonatophenyl)phosphine for Heck couplings of aryl iodides in water under microwave irradiation [35]. The carboxylate-substituted m-TPPTC(trisodium tri(3-carboxyphenyl)phosphine ligand provides higher activity in Heck couplings of aryl iodides than p-TPPTC ((trisodium tri(4-carboxyphenyl)phosphine) or m-TPPTG (tri(3-guanidinophenyl)phosphine trichloride) [36]. The m-TPPTC-derived catalyst is slightly more active than m-TPPTS. The m-TPPTC/Pd catalyst is also effective in the Sonogashira coupling of aryl iodides [37]. The catalyst system could be recycled four times, although increased reaction times were required to achieve high yields. The improved activity of catalysts derived from m-TPPTC can be attributed in part to the increased electron-donating ability of m-TPPTC compared to that of m-TPPTS.
Cationic ammonium or guanidinium moieties have also been applied to water-soluble triarylphosphine ligands. Guanidinium-substituted phosphines (m-TPPDG (di(3-guanidinophenyl)phenylphosphine dichloride), m-TPPTG, Figure 1.1) were shown to give effective catalysts for the Sonogashira coupling of anionic substrates 5 and 6 in water under biocompatible conditions to give amino acid 7 (Equation 1.6) [38, 39]. The m-TPPDG ligand gave higher activity than m-TPPTG or m-TPPTS. The higher activity of the m-TPPDG-derived catalyst compared to m-TPPTS was proposed to be due to favorable charge attraction between the cationic ligands and the anionic substrates. To demonstrate the biocompatibility of the coupling conditions, the reaction was performed in the presence of RNAase enzyme. The enzyme remained intact and did not lose catalytic activity.
1.6
Neutral water-soluble substituents such as poly(ethylene glycol) (PEG) or polyols are an attractive alternative to ionic substituents. Ligands with nonionic hydrophilic groups typically retain solubility in polar organic solvents, which can simplify their synthesis and purification. In addition, PEG and polyols often demonstrate thermoreversible solvation. Beller and coworkers reported the first example of a carbohydrate-modified triphenylphosphine analog (8–10, Figure 1.2) [40]. The carbohydrates were attached to diphenyl(4-hydroxyphenyl)phosphine by a glycosidic linkage to the anomeric carbons of glucose (8), galactose (9), and glucosamine (10). Both galactose-phosphine 9 and glucosamine-phosphine 10 gave higher activity catalysts than m-TPPTS for the Suzuki and Heck coupling of aryl bromides. A drawback of Beller's ligands is the hydrolytically sensitive glycosidic linkage between the phosphine and the carbohydrate. Miyaura prepared a carbohydrate-modified phosphine (11) with an amide linkage by ring opening of D-glucono-1,5-lactone with an amine-functionalized triarylphosphine [41]. Palladium complexes derived from 11 gave superior yields to catalysts derived from m-TPPTS in the Suzuki coupling of aryl bromides. An alternative approach to an amide-linked carbohydrate-modified phosphine involved condensation of glucosamine to o- or p-TPPMC to give ligands 12 and 13 [42, 43]. The para-substituted ligand 12 gave a more active catalyst for the Suzuki coupling of aryl iodides than 13. Up to 97 000 turnovers were achieved in the Suzuki coupling of highly activated 4-iodonitrobenzene.
Figure 1.2 Carbohydrate-modified phosphines.
1.2.2 Sterically Demanding, Hydrophilic Trialkyl and Dialkylbiarylphosphines
A wide range of hydrophilic triarylphosphines have been applied to palladium-catalyzed cross-coupling, but catalysts derived from these ligands are generally limited to aryl iodides and in some cases aryl bromides. Nonactivated aryl bromide substrates typically require high temperatures (80–150 °C). This level of reactivity mirrors that of triphenylphosphine in organic-phase coupling reactions. Beginning in the mid-1990s, research showed that sterically demanding and strongly electron-donating ligands provided optimal activity for Pd-catalyzed cross-couplings. Widely applicable ligand classes include trialkylphosphines with sterically demanding substituents, such as tert-butyl or adamantyl, and 2-dialkylphosphinobiaryl phosphines. These ligands generally provide catalysts that promote cross-coupling of aryl bromides at room temperature and aryl chlorides under mild conditions ( < 100 °C). On the basis of these developments, there have been efforts to prepare water-soluble phosphines with similar steric and electronic properties to these privileged ligand classes.
Our group has focused on the synthesis of water-soluble, sterically demanding trialkylphosphine ligands (Figure 1.3). Ammonium-substituted ligands, t-Bu-Amphos and t-Bu-Pip-phos, were shown to provide highly active catalysts for Suzuki coupling of aryl bromides at ambient temperature in water/acetonitrile [44]. Up to 10 000 turnovers could be achieved at room temperature over 24 h and over 700 000 turnovers at 80 °C for the coupling of 4-bromotoluene and phenylboronic acid. Analysis of crude organic products recovered from these reactions showed <1 ppm of residual Pd. The aqueous catalyst solution could be reused for two additional reaction cycles before loss of activity begins to occur. Using a hydrophilic palladacycle precatalyst allowed more than 10 reaction cycles on a single catalyst charge [45]. The Pd/t-Bu-Amphos system has been applied to the arylation of 7-iodocyclopenta[d]-[1,2]oxazine (14) to provide 7-arylcyclopenta[d][1,2]oxazines (15, Equation 1.7) [46]. The Pd/t-Bu-Amphos catalyst is also effective for the Sonogashira and Heck coupling of aryl bromides at higher temperatures [47]. The t-Bu-Amphos ligand did not provide effective catalysts for coupling of aryl chlorides, however.
1.7
Calculated steric parameters showed a good correlation between ligand steric demand and activity for Suzuki coupling of aryl bromides [48]. The t-Bu-Amphos ligand was the largest of those studied and had the highest activity catalyst. In couplings of aryl chlorides, the more electron-donating t-Bu-Pip-phos gave a more effective catalyst than t-Bu-Amphos. The cationic ammonium substituent decreased the electron-donating ability of the phosphine compared to that of the neutral phosphines, such as tri-(tert-butyl)phosphine, presumably through an inductive or field effect. To provide more electron-rich ligands, the DTBPPS(3-(di-tert-butylphosphonium)propane sulfonate) and DAPPS(3-(di-1-adamantylphosphonium)propane sulfonate) ligands with anionic water-solubilizing groups were prepared (Figure 1.3) [49]. Catalysts derived from DTBPPS promoted Sonogashira coupling of aryl bromides at lower temperature compared to the Pd/t-Bu-Amphos catalyst and were also effective in aryl chloride coupling. On the basis of the calculated ionization potential (IP) values for the Pd–L complexes derived from these ligands, the sulfonate substituent significantly increases the electron-donating ability of DTBPPS compared to t-Bu-Amphos.
Figure 1.3 Ammonium- and sulfonate-modified trialkylphosphines.
The Plenio group has developed a family of highly effective ligands based on 9-(dicyclohexylphosphino)fluorene (CataCXium F sulf®, 16). Ligand 16 provides effective catalysts in the Suzuki coupling of aryl bromides and chlorides [50]. Nonactivated aryl chlorides can be coupled at ambient temperature, although longer reaction times (one day) are required. The catalyst derived from ligand 16 is also highly effective in the Suzuki coupling of heteroaryl substrates (Equation 1.8), which are often much more challenging than simple aryl halides [51–53]. A challenge with heterocycles, particularly pyridine and pyrrole derivatives, is the competitive binding of the heteroatom to the palladium catalyst. Plenio proposes that water binds with these coordination sites through hydrogen bonding, which allows for higher activity in water than can be achieved in organic solvents [53]. Ligand 16 also provides an effective catalyst for Sonogashira coupling of aryl bromides and activated heteroaryl chlorides [50, 54].
1.8
The 2-biphenylphosphines developed by Buchwald are another privileged ligand class for cross-coupling of aryl bromide and chlorides [55]. Miyaura and coworkers synthesized a gluconic acid-modified 2-(dicyclohexylphosphino)biphenyl ligand (17, Figure 1.4) that provided catalysts with improved activity for the Suzuki coupling of aryl bromides than triphenylphosphine-based ligands, such as m-TPPTS or 11 [56]. Modest activity for Suzuki coupling of 4-chlorobenzoic acid was observed. The Sinou group reported a similar ligand with a glucosamine moiety (18) as the water-solubilizing group [57]. Good yields were obtained in Suzuki coupling of activated aryl chlorides, but unactivated aryl chlorides did not undergo conversion to biaryl products. The low activity of these ligands can be attributed in part to the fact that they are based on the simple 2-biphenylphosphine structure without ortho-substituents on the lower ring. Electron-donating substituents on the lower ring, such as in S-phos (2-(dicyclohexylphosphino)-2′, 6′-dimethoxylbiphenyl), provide more active catalysts [58]. The high electron density of the dimethoxy-substituted ring allows for easy sulfonation of S-phos to give 19 [59]. Ligand 19 also provides an effective catalyst for the Suzuki coupling of aryl chlorides at room temperature using 2 mol% palladium. At 100 °C, catalyst loadings as low as 0.1 mol% could be used. Ligand 18 also provides an effective catalyst for Sonogashira couplings of aryl bromides. Notably, the challenging propiolic acid substrate could be arylated with high yield (Equation 1.9).
1.9
Di-(tert-butyl)phosphinous acid is a water-soluble ligand under basic conditions. Complex 20 is an effective precatalyst for the aqueous-phase Stille [60] and Sonogashira coupling (Equation 1.10) [61] of aryl halides, whereas complex 21 is a more effective catalyst for the Hiyama coupling (Equation 1.11) [62, 63] than 20. High temperatures (130–150 °C) were required to achieve these couplings, however. Microwave heating was used in many cases to accelerate the reactions. Aryl bromides and chlorides could be coupled using this catalyst system. Recycling of the catalyst was demonstrated in the Stille coupling of 3-bromopyridine and phenyltrimethylstannane [60]. Over the course of four reaction cycles, the yield of product decreased from 96 to 84%.
1.10
1.11
Figure 1.4 Water-soluble 2-biphenyldicyclohexylphosphine ligands.
1.2.3 NHC Ligands
The imidazol-2-ylidine and imidazolin-2-ylidine family of stable carbenes [64], commonly referred to as N-heterocyclic carbenes (NHCs), are another class of highly effective ligands for cross-coupling reactions [65]. NHC ligands are strong electron donors and with proper substituents can be highly sterically demanding. Only recently has their use in aqueous media received attention. The carbene carbon of an NHC is strongly basic (pKa about 20 [66]), which precludes their use as free ligands in aqueous media. Metal–NHC complexes typically have strong M–L bonds, however. Metal complexes of NHCs are often water stable. Therefore, preformed metal–NHC complexes or complexes generated in situ from water-stable imidazolium preligands can be used in aqueous media.
The Plenio group reported the synthesis of a family of sulfonated 1,3-diarylimidazolium (22 and 23) and imidazolinium salts (24) that are structurally similar to the commonly used IMes and IPr ligands (Figure 1.5) [67]. The zwitterionic imidazolium salts formed active catalysts for the Suzuki coupling of aryl chlorides in the presence of Na2PdCl4. These ligands were also applied in the Sonogashira coupling of aryl bromides and activated heteroaryl chlorides in an aqueous solvent mixture [68]. Zwitterionic alkylsulfonate-functionalized imidazolium salt 25 can be easily prepared by the reaction of 1-methylimidazole with 1,3-propane sultone [69, 70]. Palladium complexes derived from monodentate and tridentate alkylsulfonate-functionalized NHCs provide effective catalysts for the Suzuki coupling of aryl bromides and activated aryl chlorides at 110 °C. The smaller steric demand of these ligands likely accounts for the lower activity of catalysts derived from them compared to the ligands reported by Plenio.
Figure 1.5 Zwitterionic imidazolium and imidazolinium ligand precursors.
A palladium complex derived from carboxylate-functionalized bis(NHC) ligand 26 was applied to the aqueous-phase Suzuki coupling of aryl bromides (Figure 1.6) [71]. The catalyst is soluble in basic water, but can be recovered intact by lowering the pH to 4. The recovered solid catalyst can be used for four cycles with only a small loss in activity. Somewhat improved performance was achieved by reusing the catalyst-containing aqueous solution. TEM analysis of the aqueous solution showed that palladium nanoparticles formed under the reaction conditions. The authors suggest that the ligand stabilizes the nanoparticles and prevents their aggregation into larger catalytically inactive particles. Pincer NHC complexes based on isonicotinic acid (27 and 28) have been synthesized and applied to Suzuki [72, 73] and Heck couplings [74]. Low catalyst loadings (8 ppb to 50 ppm) could be used, although high temperatures ( > 100 °C) were required, even for Suzuki coupling of aryl bromides. Both catalyst systems could be effectively recycled by removing the organic product and adding new substrates to the catalyst-containing aqueous phase. The active catalyst derived from imidazolium-based pincer complex 27 appears to be palladium nanoparticles [72]. In contrast, mercury and poly(vinylpyrrolidine) did not inhibit reactions catalyzed by benzimidazolium complex 28, which suggests that it acts as a molecular catalyst [73].
Figure 1.6 Hydrophilic palladium NHC complexes.
Hydrophilic NHC ligands with nonionic substituents have also been applied to Pd-catalyzed cross-coupling. Glucose-modified palladium NHC complex 29 gave an active catalyst for the Suzuki coupling of aryl bromides and chlorides at 100 °C in water (Equation 1.12) [75]. The catalyst system could be effectively used for four reaction cycles without significant loss of activity. Metallocrown NHC complex 30 was applied to the Suzuki coupling of aryl bromides in water at 100 °C at low catalyst loading (0.001–0.005 mol%, Equation 1.13) [76].
1.12
1.13
NHC ligands supported on water-soluble polymers have also been explored in palladium-catalyzed cross-coupling reactions. An imidazolium-functionalized amphiphilic poly(2-oxazoline) block copolymer (31, Figure 1.7) was used to support the palladium catalyst in the hydrophobic block [77]. The amphiphilic polymer was designed to promote a micellar phase to enhance interaction between the catalyst and the hydrophobic substrate. The water-soluble polymeric catalyst was applied to the Suzuki and Heck coupling of aryl iodides and bromides in water. A hyperbranched polyglycerol-supported NHC–Pd complex (32) was applied to the Suzuki coupling of aryl bromides in water at 80 °C [78]. In the coupling of 2-tolylboronic acid, the yields were similar to those obtained with a PEG-modified bis(NHC) ligand. In contrast, significantly higher activity was seen with the hyperbranched polymer-supported ligand for the Suzuki coupling of 4-pyridylboronic acid.
Figure 1.7 Hydrophilic, polymer-supported palladium NHC complexes.
1.2.4 Nitrogen Ligands
Nitrogen ligands have received significantly less attention in Pd-catalyzed cross-coupling compared to phosphine ligands. Amines tend to coordinate weakly to palladium resulting in low stability complexes. Bipyridine ligands provide stable complexes, but are much less electron donating than phosphines. Given the lower cost and toxicity of nitrogen-based ligands, there has been renewed interest in using these types of ligands, however.
4,4′-Bis(trimethylammoniummethyl)-2,2′-bipyridine (33, Equation 1.14) has been shown to be an effective ligand for a variety of cross-coupling reactions. This ligand provides active catalysts for the Suzuki coupling of aryl bromides at low catalyst loading (0.001–0.1 mol% Pd) [79]. The catalyst solution could be recycled five times to give the product in high yield, although the reaction time had to be increased from 30 min to 6 h from the first to fifth cycle. Activated aryl chlorides could be coupled at a higher temperature (140 °C) and catalyst loading (0.1–1 mol%). Similar results were obtained in the Hiyama coupling using this ligand [80]. The catalyst derived from ligand 33 could be used for the Heck coupling of aryl iodides, but unactivated aryl bromides showed no activity [81]. Good recyclability was obtained using 0.01 mol% Pd/33 in the Heck coupling of 4-iodoacetophenone.
1.14
Palladium complex 34 derived from an ammonium-substituted 2-(2-imidazolyl)pyridine ligand was applied to the aqueous-phase Suzuki coupling of aryl bromides at 120 °C (Equation 1.15) [82]. Activated aryl chlorides could also be coupled with this catalyst system when tetrabutylammonium bromide (TBAB) was used. TEM analysis showed that palladium nanoparticles were formed during the reaction. The ligand is considered to stabilize the palladium nanoparticles. The palladium complex of 8-hydroxyquinoline-5-sulfonic acid is moderately active for the Suzuki coupling of aryl bromides in water [83]. Only electron-deficient aryl bromides gave good yields.
1.15
Simple monodentate pyridine ligands have also been shown to be effective ligands for cross-coupling reactions. Alkylsulfonate-modified pyridine ligand 35 in combination with Pd(OAc)2 catalyzed the Heck coupling of aryl iodides and ethyl acrylate at room temperature in good yield (Equation 1.16) [84]. A 17 : 1 ligand/Pd ratio was used. Use of water as the solvent gave higher yields than use of polar aprotic solvents, such as a DMF or NMP, or mixed water/DMF solvent systems. 2-Amino-4,6-dihydroxypyrimidine is an inexpensive ligand for the aqueous-phase Suzuki coupling [85]. The palladium complex of this ligand was applied to the Suzuki coupling of iodide-functionalized amino acids and peptides under physiological conditions (37 °C, buffered solution) to give arylated products in good yield. Di-2-pyridylmethane ligand 36 supported on PEG has been applied to the Suzuki coupling of aryl bromides and chlorides (Equation 1.17) [86, 87]. Good yields were achieved with aryl chlorides using 0.1 mol% Pd/36.
1.16
1.17
Sulfonated diimine complex 37 was applied to the Suzuki coupling of aryl bromides in water (Figure 1.8) [88]. Only activated aryl chlorides could be coupled with this system, however. Using 0.1 mol% catalyst 37, the catalyst could be recycled for one use before the yield dropped significantly. Similar results were obtained using sulfonated β-diketimine ligand 38 [89]. Palladium–salen complex 39 was an effective catalyst for the Sonogashira coupling of aryl iodides in water in the presence of sodium lauryl sulfate (SLS) [90]. A Cu-catalyzed Sonogashira coupling in water was performed using sulfonated Cu–salen complex 40 (10 mol%) [91]. The reaction required TBAB as a phase-transfer catalyst (PTC) and was limited to aryl iodides. The catalyst was applied to the cascade coupling of 2-iodoaniline with phenylacetylene derivatives to give 2-arylindoles in excellent yield in water (Equation 1.18).
1.18
Ethylenediamine tetracetic acid (EDTA) is a commonly used water-soluble ligand for metals. Good yields were obtained using Pd(EDTA)Cl2 as a precatalyst for the Suzuki coupling of aryl iodides and bromides [92]. N,N,N′,N′-Tetra(2-hydroxyethyl)ethylene diamine has also been used as a ligand for palladium-catalyzed Suzuki coupling of aryl bromides in water [93]. Low catalyst loadings (0.001–0.1 mol%) were used, although higher catalyst loadings were required with nonactivated aryl bromides.
Figure 1.8 Water-soluble imine ligands and complexes.
1.2.5 Palladacyclic Complexes
Palladacyclic complexes formed by C–H activation near a coordination site in the ligand often provide stable precursors to effective catalyst systems [94, 95]. The palladacycles can be used alone or in some cases with additional supporting ligands. There has been much debate about the nature of the active species derived from these precatalysts, but in most cases it has been shown that the palladacycle is either converted to a Pd(0) active species or decomposes to palladium nanoparticles.
Oxime-derived palladacycles have been shown to be effective precatalysts for a variety of reactions [96]. Oxime-derived palladacycle 41 was the first catalyst system to effectively promote Suzuki couplings of aryl chlorides in water (Equation 1.19) [97, 98]. The PTC TBAB was required, particularly with less reactive aryl chlorides. Palladacycle 41 has also been used in the Suzuki coupling of aryl chlorides and aryl or alkenyl trifluoroborates [99, 100]. Complex 41 is also an effective precatalyst for the Hiyama coupling of aryl halides and vinylsiloxanes [101]. The palladacycle catalyst gives slightly higher yields and improved recyclability compared to Pd(OAc)2. Palladium leaching averaged 21 ppm over three reaction cycles for palladacycle 41, while it averaged 25 ppm for Pd(OAc)2. The similar result for the palladacycle and Pd(OAc)2 suggests that the palladacycle decomposes to palladium nanoparticles, which are the catalytically active species. Complex 41 also catalyzes the Heck coupling of aryl iodides [102, 103].
1.19
Imine palladacycle 42 provides an active catalyst for the Suzuki coupling of aryl bromides in the presence of t-Bu-Amphos (Equation 1.20) [45]. Good yields could be obtained at catalyst loadings as low as 0.01 mol% Pd. The catalyst derived from 42/t-Bu-Amphos gave a quantitative yield of 4-methylbiphenyl for 11 reaction cycles using the same loading of catalyst and ligand without increasing the reaction time (1 h/cycle). The palladacycle derived from sulfonated 2-arylnaphthoxazole 43 is an effective catalyst for the Suzuki coupling of aryl bromides at 100 °C in water (Equation 1.21) [104].
1.20
1.21
1.3 Cross-Coupling in Aqueous Media Using Hydrophobic Ligands
The initial motivation to use water in metal-catalyzed cross-coupling reactions was to allow for catalyst recovery and recycling while decreasing the environmental impact of the reaction. A number of authors have shown that water can be used as the reaction medium even when using hydrophobic catalysts and substrates. In some cases, reactions carried out in this manner give superior results to traditional homogeneous organic-phase reactions. In recent years, “on-water” reactions of this sort have received significant attention [11, 12]. Reactions of hydrophobic substrates and catalysts can be promoted by using surfactants or PTCs.
1.3.1 Surfactant-Free Reactions
An early example of the use of a palladium complex for the on-water Suzuki coupling was reported by Hor et al. [105]. Using a palladium diimine complex, Suzuki coupling of aryl bromides were performed at 80 °C using 1 mol% catalyst. The water- and ether-insoluble catalyst could be recovered as a solid after extraction of the organic products with ether. The aqueous suspension of catalyst could be used for six cycles with a slight decrease in yield in the last two cycles. Eppinger reported hydrophobic phosphinite palladacycle catalysts (44 and 45, Scheme 1.2) that promoted the Suzuki coupling of aryl bromides at 30 °C with low catalyst loading (0.02 mol%) [106, 107]. When 45 is used as the precatalyst, the water-insoluble product can be filtered off leaving a solution that retains full catalytic activity. Thus, the catalytic species remains in the aqueous phase despite the fact that precatalyst 45 is water insoluble. The authors proposed that the active species is formed by reduction of the Pd(II) palladacycle without dissociation of the anionic ligand to give 46, which may be water soluble.
Scheme 1.2 Conversion of phosphinite palladacycles to the active catalyst.
The Suzuki coupling of aryl bromides in water was studied with a range of ligand-free and ligand-supported palladium catalysts [108]. Ligand-free catalysts, such as Pd/C or Pd(OAc)2 gave low conversion. Of the phosphine-supported catalysts, Pd(DPPF)Cl2 (1,1′-bis(diphenylphosphino)ferrocene) provided the highest yields of coupled products. Good yields were obtained with a range of aryl bromides at 80 °C using 0.1 mol% Pd(DPPF)Cl2. The palladium complex of an amino-NHC ligand (47, Equation 1.22) was active for the Suzuki coupling of aryl bromides at room temperature in water [109]. Typical catalyst loadings were 1 mol%, but an 89% yield was obtained using 0.2 mol% of the complex in the coupling of 4-bromoanisole and 4-tolylboronic acid. P2N2 ligand 48 in combination with palladium was a highly effective catalyst for Suzuki coupling of aryl bromides [110]. Over 700 000 turnovers were obtained in the coupling of 4-bromoacetophenone and phenylboronic acid at 100 °C. An 82% yield of product was obtained with 0.4 mol% of the Pd(OAc)2/48 system in the coupling of 4-chlorobenzonitrile and phenylboronic acid (Equation 1.23).
1.22
1.23
Sonogashira coupling catalyzed by palladium/triphenylphosphine complexes in water has been reported by a number of authors. Coupling of aryl iodides and bromides catalyzed by Pd(PPh3)4 (0.5 mol%) and CuI (1 mol%) with diisopropylethylamine occurred in good yield [111, 112]. The reaction occurred in two phases. Addition of DMF significantly reduced the reaction rate and resulted in increased side product formation. This system has been successfully applied to Sonogashira coupling of halopyridines [113]. Good yields were obtained with iodo- and bromopyridines, but no conversion occurred with 2-chloropyridine. By increasing the reaction temperature to 120 °C, the Sonogashira coupling could be accomplished with Pd(PPh3)2Cl2 (2 mol%) [114]. Phosphinite-derived palladacycle 45 catalyzes the copper-free Sonogashira coupling of aryl iodides at 40 °C in water [115]. Aryl bromides gave low yields, however. The palladium-free Sonogashira reaction using CuI/PPh3 as the catalyst can be accomplished in water in a sealed tube at 140 °C, but only aryl iodides can be used as substrates [116].
2-Aminophenyl diphenylphosphinite 49 in combination with Pd(OAc)2 is a recyclable catalyst for the Sonogashira coupling of aryl iodides, bromides, and chlorides in water at 80–95 °C (Equation 1.24) [117]. The insoluble catalyst could be recovered by centrifugation and reused five additional times with no significant change in yield while keeping the reaction time constant (1 h). High melting substrates required the use of TBAB as a phase-transfer catalyst. Using TBAB also allowed the reactions of aryl iodides to occur at room temperature. The Pd/49 catalyst system is also effective for the Heck coupling of aryl iodides and bromides [118]. Good yields with aryl chlorides were achieved at 130 °C in a sealed tube. Again, the insoluble catalyst could be filtered off and used for five additional cycles with no decrease in activity.
1.24
A limitation of the use of aqueous media is the reactivity of many main group organometallic species with water. Thus, cross-coupling reactions based on Grignard reagents (Kumada) or organozinc reagents (Negishi) are generally not possible. Zinc-mediated reactions are possible in water under Barbier-type conditions, however [8]. The Lipshutz group has developed a method for the on-water coupling of aryl and vinyl halides with benzyl chlorides using catalyst 50 and stoichiometric zinc (Equation 1.25) [119–121]. The zinc and palladium reagents react chemoselectively with the benzyl and aryl/vinyl halide substrates, respectively, and then cleanly form the cross-coupled product. This methodology was extended to the arylation of protected iodoalanine derivative 51 to prepare phenylalanine derivatives (e.g., 52, Equation 1.26) [122]. The TMEDA-supported alkylzinc intermediate derived from 51 was observed by ESI-MS and infrared multiphoton dissociation spectroscopy, which was supported by DFT calculations.
1.25
1.26
1.3.2 Surfactant-Promoted Reactions
Because of the low solubility of typical organic substrates in water, reaction rates are often suppressed when an organic cosolvent is not used. One approach to overcoming this limitation is through the use of surfactants or phase-transfer catalysts to enhance the solubility of water-insoluble reactants in the aqueous phase. A wide variety of surfactant and phase-transfer catalysts have been employed, including tetraalkylammonium salts, anionic surfactants, and nonionic surfactants. Surfactants and PTCs have been shown to promote cross-coupling reactions using water-soluble catalysts, hydrophobic catalysts, and heterogeneous catalysts.
1.3.2.1 Cationic Surfactants
The role of tetraalkylammonium salts in accelerating palladium-catalyzed cross- coupling reactions carried out in water was first demonstrated by Jeffery [123]. Low yields were obtained in the Heck coupling of phenyl iodide and methyl acrylate catalyzed by Pd(PPh3)4 in water at 50 °C. When 1 equiv of tetrabutylammonium chloride (TBAC) was added, the yield increased from 5 to 98% under otherwise identical conditions. Nearly identical yields were obtained with TBAB and hydrogensulfate salts. In contrast, LiCl and KCl did not improve reaction yields significantly. Jeffery concluded that the tetrabutylammonium ion promoted the reaction by acting as a PTC. TBAB is the most commonly used PTC for promoting cross-coupling reactions in aqueous media.
The Suzuki coupling of aryl bromides catalyzed by Pd(PPh3)2Cl2 was carried out in water using TBAB as a promoter under microwave heating [124]. High yields were obtained with reactions times of 10 min. Hydrophobic β-diketiminate palladium complex 53 gave good yields in the Hiyama coupling of aryl chlorides and aryltriethoxysilanes in water/TBAB [125]. Higher catalyst loading, higher temperature, and a longer reaction time were required in the absence of TBAB. This system was applied to the diarylation of o-dichloroarenes to give ortho-terphenyls in excellent yields. Tetraarylation of 1,2,4,5-tetrachlorobenzene was accomplished in good yield with 53 (Equation 1.27).
1.27
In the Sonogashira coupling of aryl iodides and bromides with a dipyridylmethane ligand, the use of TBAB gave higher reaction rates, slightly higher yields, and decreased formation of alkyne homodimerization products compared to reactions run in water alone [126]. Copper-catalyzed Sonogashira-type reactions are also promoted by TBAB [127, 128]. The copper catalysts were limited to aryl iodides and required high reaction temperatures. Microwave heating allowed the reactions to be completed with short reaction times. Using TBAB as the promoter gave higher yields than when the anionic surfactant sodium dodecyl sulfate (SDS) was used.
1.3.2.2 Anionic Surfactants
Anionic surfactants such as SDS or SLS are inexpensive commodity chemicals that can be used to generate microemulsions from water organic biphasic media. The high interfacial surface area of the microemulsion promotes reactions taking place at the water/organic interface. In the synthesis of liquid crystalline compounds by Pd(PPh3)4-catalyzed Suzuki coupling, SDS was shown to significantly improve product yields (Equation 1.28) [129]. Water/toluene/n-BuOH (1 : 1 : 0.14) was used as the solvent system. Butanol was added as a cosurfactant in the reaction mixture. The anionic surfactant was chosen because of the basic conditions required by the Suzuki coupling. The Sonogashira coupling of aryl iodides using a Ni(PPh3)2Cl2 (1 mol%)/CuI (2 mol%) catalyst system gave good yields when SLS was used as the surfactant [130]. Optimal yields were obtained using 7 mol% surfactant (0.014 M), whereas higher and lower concentrations gave lower product yields.
1.28
A range of surfactants were tested in the asymmetric Heck coupling of 4-chlorophenyltriflate and 2,3-dihydrofuran using a palladium/(R)-BINAP catalyst (Equation 1.29) [131]. With no surfactant, a 33% yield was obtained and 60% ee. Cationic surfactants, such as cetyltrimethylammonium bromide (CTAB) gave little product. Modest yields and enantioselectivities were obtained with anionic surfactants, such as SDS or SLS. Using the zwitterionic surfactant N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (54) the product was formed in 73% yield and 67% ee.
1.29
1.3.2.3 Nonionic Surfactants
PEG is a cheap, nontoxic surfactant that is commonly used to enhance solubility of hydrophobic compounds in water. When heterogeneous catalysts are used in aqueous media, they often cannot be recycled because they cannot be easily separated from the organic product. The Pd(DPPF)Cl2-catalyzed Suzuki coupling of aryl bromides could be carried out in water with good yield, but the catalyst could not be recycled [108]. Using a 20% PEG 2000 aqueous solution, the catalyst could be retained in the aqueous/PEG phase, while the biaryl product was extracted with pentane. The aqueous catalyst solution was used for three reaction cycles with the yield decreasing from 91% in the first cycle to 80% in the third. PEG-400 was used in the Pd/DABCO-catalyzed Suzuki, Stille, Sonogashira, and Heck coupling of aryl bromides and iodides [132]. In the Suzuki coupling of 4-bromoanisole, a quantitative yield was obtained with PEG-400 compared to 87% without a surfactant. Other surfactants such as TBAB and 18-crown-6 did not significantly improve the yield compared to the reaction without surfactant. The use of PEG gave higher yields in the copper-catalyzed Sonogashira coupling of aryl iodides than were obtained in water alone or water in combination with water-miscible organic cosolvents, such as DMF or ethanol [133].
The Lipshutz group has pioneered the use of the nonionic polyoxyethanyl β-tocopheryl sebacate (PTS, 55, Figure 1.9) surfactant. The PTS amphiphile is commercially available and forms nanoscale micelles in water that can accommodate hydrophobic compounds within the micelle interior. The Lipshutz group has applied the PTS surfactant to a wide range of palladium-catalyzed cross-coupling reactions, including those that normally do not proceed in aqueous solvents. The catalysts used in these reactions are based on hydrophobic phosphines that have been successfully applied in organic-phase reactions. The hydrophobic catalyst is believed to partition into the hydrophobic core of the micelle. Hydrophobic substrates can also partition into the micelle allowing the reactions to occur at very high local concentration.
Figure 1.9 Polyoxyethanyl α-tocopheryl sebacate (PTS).
The PTS/water solvent system allows Suzuki coupling of aryl and heteroaryl halides catalyzed by Pd(DtBPPF)Cl2 (56) to be carried out under mild conditions even with highly hydrophobic substrates (Equation 1.30) [134, 135]. Sonogashira coupling of aryl bromides is efficiently catalyzed in water with 3% PTS by PdCl2(CH3CN)2/X-Phos [136]. The Negishi coupling catalyzed by 50 is a particularly interesting example of Pd-catalyzed C–C bond formation, given the water-sensitivity of organozinc reagents (Equation 1.31) [137–139]. The aryl zinc species is formed in situ by the reaction of an alkyl iodide with zinc in the presence of TMEDA [138]. The highly hydrophobic nature of the alkyl iodides, used along with the stabilizing effect of the TMEDA on the organozinc species, allows it sufficient time to partition into the micelle and be coupled with the aryl halide before reacting with water.
1.30
1.31
Examples of the powerful Buchwald–Hartwig C–N bond-forming reaction in aqueous solvents are rare [140, 141]. Using the PTS/water solvent system, [Pd(allyl)Cl]2 in combination with the cBRIDP ligand 57 effectively catalyzes the coupling of aryl bromides with aniline derivatives (Equation 1.32) [142]. Miyaura borylation of aryl bromides catalyzed by Pd(P(t-Bu)3)2 is promoted by TPGS-750-M (58), which is a derivative of PTS in which the sebacate diester is replaced with a succinate diester (Equation 1.33) [143].
1.32
1.33
1.4 Heterogeneous Catalysts in Aqueous Media
1.4.1 Supported Palladium–Ligand Complexes
Biphasic catalysis using a water-soluble catalyst allows the catalyst to be easily separated from the organic product. A disadvantage of this methodology is that it is often difficult to separate the catalyst from the inorganic salt by-products formed in these reactions. Although these salts often do not hinder catalyst activity initially, they eventually begin to precipitate from the aqueous catalyst solution, which can hinder catalyst recovery. To address this issue, there has been significant interest in attaching metal–ligand complexes to insoluble supports and using these in aqueous-phase catalysis. In this way, the insoluble catalyst can be recovered and reused.
1.4.1.1 Polymer-Supported Palladium Complexes
1.34
Good yields for the Suzuki coupling of aryl bromides were obtained with a PS-supported palladium salen complex 60 (Figure 1.10) [146]. Unlike reactions catalyzed by supported phosphines [144], a small amount of toluene (30 : 1 H2O/toluene) was required for optimal yields. The product yield decreased from 98 to 74% over five uses of the same catalyst in the coupling of 4-bromoanisole and phenylboronic acid at 90 °C. A similar PS-supported palladium salen complex (61) gave good yields in the Sonogashira coupling of aryl iodides and activated aryl bromides [147]. The catalyst was used for five reaction cycles in the coupling of phenyl iodide and phenyl acetylene with yields ranging from 99 to 85%. Analysis of the supported catalyst after the fifth cycle showed less than 0.3% palladium loss. Polystyrene-supported palladacycle catalysts based on Schiff base (62) [148] and a diazo ligand (63) [149] were applied to the Suzuki and Sonogashira coupling of aryl iodides and bromides in aqueous DMF. Similar results were obtained with a Schiff-base palladacycle attached to poly(vinylcarbazole) in Suzuki and Sonogashira couplings [150].
Figure 1.10 Cross-linked polystyrene-supported palladium complexes.
Cross-linked polystyrene is a convenient support due to the range of commercially available functionalized resins such as Merrifield resin. Its application in aqueous-phase reactions is limited by the poor swelling characteristics of polystyrene in water, though. Grafted PEG–PS resin is more water compatible because of the ability of the PEG region to be swollen by water. The Uozumi group prepared PS–PEG-supported triphenylphosphine 64. After complexation with [Pd(allyl)Cl]2, the resin (65, Equation 1.35) could be applied for the Suzuki [151, 152], Sonogashira [153, 154], and Heck couplings [155] in water. The PS–PEG-supported catalysts were more active than PS-supported catalysts allowing the reactions to be carried out at lower temperature. A bulky trialkylphosphine supported on the PS–PEG resin (66) provided an active catalyst for the Buchwald–Hartwig amination of aryl halides (Equation 1.36) [156–158]. This catalyst system represents one of the few examples of aqueous-phase Buchwald–Hartwig reactions. A PS–PEG-supported NHC ligand coordinated to [Pd(allyl)Cl]2 gave good activity in the Suzuki coupling of aryl iodides and bromides at 50 °C in water [159]. The catalyst was used for five reaction cycles with a slow decrease in yield from 91 to 82%.
1.35
1.36
A novel network polymer containing coordination sites was prepared by the free radical polymerization of 2,4,6-triallyloxy-1,3,5-triazine (67, Scheme 1.3) [160]. The resulting polymer (68) was coordinated to Pd(OAc)2 to give a material (69) that was active for the Heck coupling of aryl iodides and bromides in 50% aqueous ethanol at 100–140 °C. The catalyst could also be used for the Sonogashira and Heck coupling of aryl iodides at 85 °C. The catalyst could be reused, although a gradual decrease in product yield was observed in each cycle. The catalyst appears to remain bound to the polymeric support. Little catalyst activity was observed after removal of the polymeric catalyst by hot filtration. In addition, 3-mercaptopropyl-functionalized silica, which would be expected to inhibit a soluble catalyst species, did not inhibit the catalyst activity.
Scheme 1.3 Synthesis of a cross-linked polymeric support for palladium.
1.4.1.2 Palladium Complexes Supported on Inorganic Materials
The use of inorganic materials as supports for metal catalysts has a long history in heterogeneous catalysis. Cross-linked polymer supports have the advantage of highly flexible attachment chemistry. Their mechanical stability, particularly when swollen with solvent, is often limited, though. Inorganic materials, such as silica or alumina, are often mechanically stronger. While the range of attachment chemistry is limited with inorganic materials, a wide variety of organic ligands can be attached to metal oxides through the siloxane linker group. In addition, composite inorganic/polymer materials can provide more flexible attachment chemistry.
Polymer- and inorganic-supported oxime palladacycles were prepared and tested as catalysts for the Suzuki coupling of 4-chloroacetophenone [161]. Catalysts supported on silica and MCM-41 inorganic supports (70) gave > 90% yields after 2 h at 100 °C in water (Equation 1.37). The same catalyst supported on cross-linked polystyrene or poly(ethylene glycol bis(methacrylate)) gave yields below 40% under the same conditions. Leaching studies indicated that the palladium remained coordinated to the solid support and that the reaction was truly heterogeneous. Palladium loss was <1% per cycle. Magnetic nanoparticles are attractive catalyst supports because they can be separated from the reaction mixture using magnets. Core–shell γ-Fe2O3/polymer-supported dendritic diphosphine palladium complex 71 was prepared and applied to the Sonogashira reaction (Figure 1.11) [162]. Good yields were obtained with aryl bromides using water as the solvent with Triton X-405 as surfactant. The catalyst was highly recyclable with yields slowly decreasing from quantitative to 80% over 10 reaction cycles. Using methanol as a solvent gave higher yields, but the catalyst lost activity after five reaction cycles.
1.37
It is not necessary to physically attach the catalyst to the solid support. Instead, the catalyst can be dissolved in hydrophobic or hydrophilic phases attached to inorganic supports [163]. Glass beads derivatized with a hydrophobic surface adsorb Pd(PPh3)4 to give a supported catalyst [164]. The resulting beads were effective for the Suzuki coupling of aryl iodides and bromides in water. Because the catalyst was not covalently attached to the support, palladium leaching was higher (2–4%/cycle) than that seen in covalently attached systems. A palladium–NHC complex dissolved in a magnetite (Fe3O4)-supported ionic liquid phase catalyzed the Suzuki coupling of aryl bromides in water [165]. The magnetic particles could be magnetically recovered and recycled. Nearly identical yields were obtained over five cycles. The water-insoluble catalyst remained in the hydrophobic IL phase. Palladium leaching into the aqueous phase was 10 ppm in the first reaction cycle (9% of total palladium lost), but then dropped to 1–2 ppm over the next four cycles.
Figure 1.11 Magnetic particle-supported palladium complex.
In supported aqueous-phase catalysis (SAPC), a thin water layer is supported on a hydrophilic inorganic support, such as silica or porous glass beads. Water-soluble catalysts, such as Pd/m-TPPTS, can be dissolved in the supported aqueous phase. The resulting catalyst can then be used for cross-coupling reactions in hydrophobic solvents [166–169]. The SAPC systems typically require careful optimization of water and catalyst loading. Too much water will allow the catalyst solution to disperse into the organic reaction solvent. Too little water will limit the mobility of the catalyst resulting in low activity.
1.4.2 Nanoparticle-Catalyzed Coupling
Palladium nanoparticles are readily formed under typical cross-coupling conditions, particularly in reactions performed at high temperatures. It is often unclear whether a particular Pd/ligand complex catalyzes a reaction as molecular species or through the formation of nanoparticles [170–172]. Examples of Pd/ligand catalyst systems in which nanoparticles are believed to be the true active species were discussed in previous sections. In some cases, the ligand may play a role in stabilizing the nanoparticles from agglomeration into larger catalytically inactive particles. In this section, palladium catalysts without strong supporting ligands, where nanoparticle formation is expected, and preformed palladium nanoparticle catalysts are discussed.
1.4.2.1 Unsupported Palladium Nanoparticle Catalysts
The use of phosphine or other strong ligands increases the cost of the catalyst system and can potentially complicate the product isolation. Early studies by Novak showed that triphenylphosphine can inhibit catalytic activity in the Suzuki coupling of highly activated aryl iodides in water/acetone [173]. Palladium acetate is an effective catalyst for the Suzuki coupling of water-soluble aryl iodides and bromides in water without supporting ligands or surfactants [174]. In the absence of ligands, the palladium nanoparticles aggregate into larger particles that precipitate from the solution as palladium black. To avoid precipitation, the substrate must react rapidly with the nanoparticles. Thus, these systems are often limited to highly reactive and water-soluble aryl iodides. Adding the base last to the reaction mixture resulted in improved catalyst performance with less reactive aryl iodides [175]. By adding the base last, nanoparticle formation occurs in the presence of the aryl iodide substrate and the catalytically active nanoparticle can enter the catalytic cycle before agglomeration occurs.
