Palladium-Catalyzed Coupling Reactions E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 854

Veröffentlichungsjahr: 2013

Beschreibung

This handbook and ready reference brings together all significant issues of practical importance in selected topics discussing recent
significant achievements for interested readers in one single volume. While covering homogeneous and heterogeneous catalysis, the text is unique in focusing on such important aspects as using different reaction media, microwave techniques or catalyst recycling. It also provides a comprehensive treatment of key issues of modern-day coupling reactions having emerged and matured in recent years and emphasizes those topics that show potential for future development, such as continuous flow systems, water as a reaction medium, and catalyst immobilization, among others.

With its inclusion of large-scale applications in the pharmaceutical industry, this will equally be of great interest to industrial chemists.

From the contents
* Palladium-Catalyzed Cross-Coupling Reactions - A General Introduction
* High-turnover Heterogeneous Palladium Catalysts in Coupling Reactions: the Case of Pd Loaded on Dealuminated Y Zeolites
Palladium-Catalyzed Coupling Reactions with Magnetically Separable Nanocatalysts
* The Use of Ordered Porous Solids as Support Materials in Palladium-Catalyzed Cross-Coupling Reactions
* Coupling Reactions Induced by Polymer-Supported Catalysts
* Coupling Reactions in Ionic Liquids
* Cross-Coupling Reactions in Aqueous Media
* Microwave-Assisted Synthesis in C-C and C-Heteroatom Coupling Reactions
* Catalyst Recycling in Palladium-Catalyzed Carbon-Carbon Coupling Reactions
* Nature of the True Catalytic Species in Carbon-Carbon Coupling Reactions with
* Heterogeneous Palladium Precatalysts
* Coupling Reactions in Continuous Flow Systems
* Large-Scale Applications of Palladium-Catalyzed Couplings in the Pharmaceutical Industry

Leseprobe

Contents

Cover

Related Titles

Title Page

Copyright

Foreword

Preface

List of Contributors

Chapter 1: Palladium-Catalyzed Cross-Coupling Reactions – A General Introduction

1.1 Introduction

1.2 Carbon–Carbon Cross-Coupling Reactions Catalyzed by Palladium

1.3 The Catalysts

1.4 Mechanistic Aspects

1.5 Future Challenges

Abbreviations

References

Chapter 2: High-Turnover Heterogeneous Palladium Catalysts in Coupling Reactions: the Case of Pd Loaded on Dealuminated Y Zeolites

2.1 Introduction

2.2 Various Methodologies to Afford High Turnover Numbers Over Supported Pd Catalysts

2.3 Structure and Characteristics of Ultrastable Y Zeolites

2.4 Suzuki–Miyaura Reactions Catalyzed by Pd/USY

2.5 Catalytic Performance of Pd/USY in Mizoroki–Heck Reactions

2.6 Conclusion and Perspective

Abbreviations

References

Chapter 3: Palladium-Catalyzed Coupling Reactions with Magnetically Separable Nanocatalysts

3.1 Introduction

3.2 General Considerations Concerning Magnetic Particles as Catalyst Supports

3.3 Palladium Nanoparticles on Magnetic Supports

3.4 Molecular Palladium Complexes on Magnetic Supports

3.5 Outlook

Abbreviations

References

Chapter 4: The Use of Ordered Porous Solids as Support Materials in Palladium-Catalyzed Cross-Coupling Reactions

4.1 Introduction

4.2 Catalyst Synthesis and Characterization

4.3 Carbon–Carbon Couplings

4.4 Miscellaneous Coupling Reactions

4.5 The Question of Solution-Phase Catalysis

4.6 Summary and Future Prospects

Abbreviations

References

Chapter 5: Coupling Reactions Induced by Polymer-Supported Catalysts

5.1 Introduction

5.2 Polysaccharides

5.3 Poly(ethylene glycol)

5.4 Polystyrene

5.5 Poly(norbornene)

5.6 Polyacrylamide

5.7 Polyaniline

5.8 Poly(N-vinyl-2-pyrrolidone)

5.9 Polypyrrole

5.10 Poly(4-vinylpyridine)

5.11 Ionic Polymers

5.12 Organometallic Polymers

5.13 Functionalized Porous Organic Polymers

5.14 Miscellaneous Polymers

5.15 Summary and Outlook

Abbreviations

References

Chapter 6: Coupling Reactions in Ionic Liquids

6.1 Introduction

6.2 Metal Complexes

6.3 Metal Salts and Metal on Solid Support

6.4 Metal Nanoparticles

6.5 Summary and Outlook

Abbreviations

References

Chapter 7: Cross-Coupling Reactions in Aqueous Media

7.1 Introduction

7.2 Cross-Coupling of Organic Halides to Form C–C Bonds in Aqueous Media

7.3 Carbon–Heteroatom Coupling Reactions

7.4 C–H Activation in Aqueous Media

7.5 Conclusion and Future Prospects

Abbreviations

References

Chapter 8: Microwave-Assisted Synthesis in C–C and Carbon–Heteroatom Coupling Reactions

8.1 Introduction

8.2 C–C Bond Formation

8.3 C–X Bond Formation

8.4 Conclusions

Abbreviations

References

Chapter 9: Catalyst Recycling in Palladium-Catalyzed Carbon–Carbon Coupling Reactions

9.1 Introduction

9.2 General Issues of Catalyst Recycling

9.3 Catalyst Systems Providing High, Consistent Yields in Recycling

9.4 Catalysts Affording the Highest Cumulative TON Values in Recycling Studies

9.5 Summary Evaluation

9.6 Future Outlook

Abbreviations

References

Chapter 10: Nature of the True Catalytic Species in Carbon–Carbon Coupling Reactions with Heterogeneous Palladium Precatalysts

10.1 Introduction

10.2 Heck Reactions

10.3 Suzuki Reactions

10.4 Sonogashira Reactions

10.5 Concluding Remarks

Abbreviations

References

Chapter 11: Coupling Reactions in Continuous-Flow Systems

11.1 Introduction

11.2 Coupling Reactions in Flow

11.3 Palladium Catalysts for Flow Systems

11.4 Continuous-Flow Technologies for Cross-Coupling

11.5 Summary and Outlook

Abbreviations

References

Chapter 12: Palladium-Catalyzed Cross-Coupling Reactions – Industrial Applications

12.1 Introduction

12.2 Suzuki–Miyaura Reactions

12.3 Heck–Mizoroki Reactions

12.4 Sonogashira–Hagihara Reactions

12.5 Carbonylations

12.6 Cyanations

12.7 Negishi Coupling

12.8 Novel Pd-Catalyzed C–C Cross-Coupling Reaction

12.9 Buchwald–Hartwig Aminations

12.10 Pd-Catalyzed C–S Bond Formation

12.11 Summary and Outlook

Acknowledgments

Abbreviations

References

Index

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Foreword

The field defined by the title of this monograph, “Palladium-Catalyzed Coupling Reactions,” has had a transformative effect upon organic synthesis, enabling bond constructions that could only have been dreamed about four decades ago. This has given rise to an immense and exponentially growing literature that encompasses far-reaching fundamental and applied topics. As of this writing, there is clearly “no end in sight” or approaching state of maturity.

The ongoing stream of developments can be ascribed to a number of factors, but one can begin with mechanism, where there are intricate subtleties regarding the homogeneous or heterogeneous nature of many transformations, as well as possibilities for cycles differing in the palladium redox states involved. Another driver would be applications, for example, the ability to effect new transformations or sequences of transformations, or render transformations that afford chiral products enantioselective or more highly enantioselective, or create catalysts with either improved functional group tolerance, or the ability to activate normally inert groups.

This line of thought leads into optimization issues. The desirability of longer lived catalysts capable of millions of turnovers is widely appreciated. One fundamental aspect of the quest for longer lived catalysts is to understand the processes by which they decompose or deactivate. When catalysts attain high turnover levels, recycling becomes especially attractive, and there are a plethora of strategies that can be applied, each with its own special strengths.

It is clearly a challenge to capture the essence of such a fast-moving field in a monograph. However, the Editor, Prof. Árpád Molnár, is superbly credentialed. He has many original research articles dealing with catalyst development to his credit, as well as authoritative reviews on the subjects of recyclable palladium catalysts and sustainable Heck chemistry. He has furthermore assembled an outstanding team of authors with many leading luminaries of the field. It is clear from the end product that this group has been up to the task, going beyond a mere collection of reports and giving readers new ways of thinking about palladium-catalyzed cross-coupling.

The leadoff chapter by Köhler, Wussow, and Wirth provides a textbook level introduction to various types of palladium-catalyzed cross-coupling reactions, representative types of molecular species that come into play, and equilibria involving monopalladium species, palladium cluster complexes, palladium nanoparticles, and bulk palladium. This is followed by Okumura's treatment of high-turnover zeolite-supported heterogeneous palladium catalysts, which illustrates the value of EXAFS and XANES techniques for catalyst characterization.

Recycling then becomes the focus in a chapter by Salih and Thiel, who describe the rapidly growing types of palladium catalysts that have been grafted to magnetic materials. The Editor, Molnár, then takes a turn, systematically reviewing the various classes of ordered porous solids that have been used as support materials for cross-coupling catalysts. Karimi, Abedi, and Zamani highlight a complementary theme, coupling reactions mediated by polymer-supported catalysts, in the following chapter.

The reaction medium then becomes the message. A chapter by Keßler, Scholten, Galbrecht, and Prechtl describes cross-coupling reactions in ionic liquids. Shaughnessy then plumbs the depths of coupling reactions in water. In both cases, volatile organic solvents are avoided. Catalysts with appropriate phase labels are generally required, but these provide “handles” for recovery. In the following chapter, Wang and Wang detail the intricacies of microwave-assisted coupling processes, in which greatly reduced reaction times can be achieved.

In an essential chapter, Molnár begins by describing key general issues in catalyst recovery, and then vividly conveys the state of the art, concluding with tabular summaries of numerous recycling studies. Subsequently, Huang and Wong analyze the nature of the true catalytic species in recipes employing heterogeneous palladium precatalysts. Much evidence supports a role for soluble “leached” moieties. Process then becomes the focus. Reynolds and Frost review coupling reactions that have been carried out using continuous-flow systems. The volume concludes with a survey of industrial applications of cross-coupling reactions by Dumrath, Lübbe, and Beller.

In summary, this monograph informs, educates, and inspires. Both experienced practitioners and newcomers to this field will benefit from the insight and vision of a fantastic assembly of authors. Their superbly interwoven chapters are poised to influence every reader's future, and foster the next generation of seminal developments in palladium-catalyzed cross-coupling reactions.

College Station, Texas

John A. Gladysz

November 2012

Preface

It all began in 1968 when Robert Heck published seven successive papers in the Journal of the American Chemical Society. In one of the articles [1], he reported the formation of styrene and trans-stilbene in the reaction of phenylmercuric acetate and ethene in the presence of stoichiometric amount of Li2[PdCl4]. He even put forward a correct mechanistic proposal and accounted for the stereochemistry of the reaction [2]. Further studies showed that palladium acetate can also act as catalyst and is capable of inducing the coupling of iodobenzene and styrene in the presence of stoichiometric amount of a base. Metallic palladium was subsequently shown to be active using the hindered tributylamine [3]. At about the same time, Mizoroki described the same coupling process performed under somewhat different conditions but could not pursue it further because of his untimely death [4, 5].

Soon the field broadened and a range of related palladium-catalyzed carbon–carbon bond forming reactions were described in the 1970s followed by reports from the Suzuki and Negishi groups in the 1980s [6]. The chemical community, apparently, did not recognize the significance of these early observations. However, since the 1990s Pd-catalyzed coupling reactions have undergone a phenomenal development to encompass an amazingly rich and varied chemistry. Nowadays, these are indispensable and powerful methodologies for constructing diverse organic compounds including drugs, natural products, and new materials. The reactions may involve the use of phosphane and carbene ligands as well as palladacycles as catalyst precursors. General features are high activity and selectivity, tolerance of a wide range of functional groups, and mild conditions in most cases. In addition to C–C cross-couplings, efficient carbon–heteroatom couplings and, recently, functionalization with direct C–H bond cleavage have emerged as viable possibilities. In this still burgeoning field of organic synthesis, Pd stands out as the most prolific metal catalyst. The ultimate recognition of the seminal contribution by three pioneers of the field came in 2010 by awarding the Nobel Prize in Chemistry to Professors Heck, Suzuki, and Negishi.

This book is not about the chemistry of individual cross-coupling reactions. Rather, it is a collection of selected topics each discussing recent important achievements. Most subject areas covered in individual chapters have emerged and matured in recent years and appear to represent key issues for further successful development. Consequently, discussions will mainly center on recent progress over the past decade. Each chapter concludes with a short discussion about potential for future advancements.

It has been a genuine enjoyment to be involved as Editor in this book project. It is my pleasure to warmly thank all the authors for their efforts in producing such an informed collection of contributions and sharing with the reader the latest news of their respective specialties. Twenty-three contributors from nine countries make this book an international achievement. Palladium chemistry, without doubt, has been a flourishing prime area of organic chemistry. It still is and we all believe that will certainly be. It is our sincere hope that our book will be of interest and use to those interested in this rich and fascinating field.

Finally, I am indebted to Dr. Elke Maase who initiated this book project in early 2011 for her encouragement to undertake this adventure and to Bernadette Gmeiner being a supportive project editor helping along the project.

Szeged

Árpád Molnár

September 2012

References

1. Heck, R.F. (1968) J. Am. Chem. Soc., 90, 5518–5526.

2. Heck, R.F. (1969) J. Am. Chem. Soc., 91, 6707–6714.

3. Heck, R.F. and Nolley, J.P., Jr. (1972) J. Org. Chem., 37, 2320–2322.

4. Mizoroki, T., Mori, K., and Ozaki, A. (1971) Bull. Chem. Soc. Jpn., 44, 581.

5. Mizoroki, T., Mori, K., and Ozaki, A. (1973) Bull. Chem. Soc. Jpn., 46, 1505–1508.

6. de Meijere, A. and Diederich, F. (eds) (2008) Metal-Catalyzed Cross-Coupling Reactions, 2nd edn, Wiley-VCH Verlag GmbH, Weinheim.

List of Contributors

Sedigheh Abedi

Institute for Advanced Studies in Basic Sciences (IASBS)

Department of Chemistry

Gava Zang

PO Box 45195-1159

Zanjan 45137-66731

Iran

Matthias Beller

Leibniz-Institut für Katalyse e.V. an der Universität Rostock

Albert-Einstein-Str. 29a

18059 Rostock

Germany

Andreas Dumrath

Leibniz-Institut für Katalyse e.V. an der Universität Rostock

Albert-Einstein-Str. 29a

18059 Rostock

Germany

Christopher G. Frost

University of Bath

Department of Chemistry and Centre for Sustainable Chemical Technologies

Claverton Down

Bath BA2 7AY

UK

Frank Galbrecht

Universität zu Köln

Institut für Anorganische Chemie

Greinstraße 6

50939 Köln

Germany

Lin Huang

Agency for Science, Technology and Research

Institute of Chemical and Engineering Sciences

1 Pesek Road, Jurong Island

Singapore 627833

Singapore

Babak Karimi

Institute for Advanced Studies in Basic Sciences (IASBS)

Department of Chemistry

Gava Zang

PO Box 45195-1159

Zanjan 45137-66731

Iran

Michael T. Keßler

Universität zu Köln

Institut für Anorganische Chemie

Greinstraße 6

50939 Köln

Germany

Klaus Köhler

Technische Universität München

Catalysis Research Center

Department of Chemistry

Lichtenbergstraße 4

85747 Garching

Germany

Christa Lübbe

Leibniz-Institut für Katalyse e.V. an der Universität Rostock

Albert-Einstein-Str. 29a

18059 Rostock

Germany

Árpád Molnár

University of Szeged

Department of Organic Chemistry

Dóm tér 8

6720 Szeged

Hungary

Kazu Okumura

Tottori University

Department of Chemistry and Biotechnology

Graduate School of Engineering

4-101, Koyama-cho Minami

Tottori 680-8552

Japan

Martin H.G. Prechtl

Universität zu Köln

Institut für Anorganische Chemie

Greinstraße 6

50939 Köln

Germany

William R. Reynolds

University of Bath

Department of Chemistry and Centre for Sustainable Chemical Technologies

Claverton Down

Bath BA2 7AY

UK

Kifah S.M. Salih

TU Kaiserslautern

Fachbereich Chemie

Erwin Schrödinger Straße 54

67705 Kaiserslautern

Germany

Jackson D. Scholten

Universidade Federal do Rio Grande do Sul

Instituto da Química

Avenida Bento Gonçalves 9500

CEP 91501-970

Porto Alegre RS

Brazil

Kevin H. Shaughnessy

The University of Alabama

Department of Chemistry

Box 870336

Tuscaloosa, AL 35487-0336

USA

Werner R. Thiel

TU Kaiserslautern

Fachbereich Chemie

Erwin Schrödinger Straße 54

67663 Kaiserslautern

Germany

Jin-Xian Wang

Northwest Normal University

Department of Chemistry

Institute of Chemistry

An Ning Road (E.) 967

Lanzhou 730070

China

Ke-Hu Wang

Northwest Normal University

Department of Chemistry

Institute of Chemistry

An Ning Road (E.) 967

Lanzhou 730070

China

Andreas Sebastian Wirth

Technische Universität München

Catalysis Research Center

Department of Chemistry

Lichtenbergstraße 4

85747 Garching

Germany

Pui Kwan Wong

Agency for Science, Technology and Research

Institute of Chemical and Engineering Sciences

1 Pesek Road, Jurong Island

Singapore 627833

Singapore

Katharina Wussow

Technische Universität München

Catalysis Research Center

Department of Chemistry

Lichtenbergstraße 4

85747 Garching

Germany

Asghar Zamani

Institute for Advanced Studies in Basic Sciences (IASBS)

Department of Chemistry

Gava Zang

PO Box 45195-1159

Zanjan 45137-66731

Iran

1

Palladium-Catalyzed Cross-Coupling Reactions – A General Introduction

Klaus Köhler, Katharina Wussow, and Andreas Sebastian Wirth

1.1 Introduction

1.1.1 Historical Reflection

Fifty years ago, when palladium began to make its way into organic chemistry, carbon–carbon bond formation in organic synthesis was mainly achieved by stoichiometric reactions of, for example, reactive nucleophiles with electrophiles. The introduction of palladium to this chemistry by Richard Heck, who developed coupling reactions of aryl compounds in the presence of either stoichiometric or catalytic amounts of palladium(II) in the late 1960s, designates a breakthrough toward the fascinating area of palladium-catalyzed carbon–carbon bond forming reactions. A number of new C–C coupling reactions mediated by palladium have been published in the following years. Today, palladium-catalyzed coupling reactions provide extraordinarily useful and widely applied tools for organic synthesis. Famous representatives are the Heck, Negishi, and Suzuki reactions [1] whose importance and excellence in organic chemistry were acknowledged by awarding the Nobel Prize in Chemistry in 2010 [2]. The pioneering work in the 1960s and 1970s of the three Nobel Prize winners has led to cross-coupling reactions nowadays becoming extremely valuable and reliable transformations in complex natural product syntheses, and even more importantly for numerous pharmaceutical and agrochemical applications, as well as for the production of new materials. In addition, there are several other named palladium-catalyzed cross-coupling reactions to be mentioned and presented in this introductory chapter. The most important ones are the Sonogashira reaction, the Stille coupling, and the Tsuji–Trost reaction, while less common ones such as the Hiyama coupling, the Kumada reaction, and carbon–nitrogen coupling reactions according to Buchwald and Hartwig are established as well.

Since their discovery, palladium-catalyzed cross-coupling reactions have come a long way and there are several reasons for their continuing popularity and success. Carbon–carbon bond formation was mainly performed using Grignard reagents and organoalkali metal compounds before the introduction of Pd into this area. While these reactions are applicable for sterically undemanding alkyl halides, conversion of unsaturated substrates such as alkenyl, alkynyl, and aryl electrophiles is dissatisfactory [3]. On the contrary, Pd-catalyzed reactions favor sp2-hybridized reactants. Exemplary taking into account that organometallic complexes with alkyl groups tend to perform β-hydride elimination, saturated educts are not suitable for transition metal-mediated cross-couplings. Such an intermediate state would clearly reduce the selectivity to the coupling products.

1.1.2 Characteristics, Recent Developments, and Progress

The application of Pd is characterized by additional striking features and synthetic advantages. Mild reaction conditions minimize the formation of unwanted side products and, consequently, high selectivities can be achieved. Furthermore, the Pd catalysis shows tolerance toward a large number of functional groups on both coupling partners. Hence, it is possible to construct complex organic building blocks efficiently in fewer steps than by traditional stoichiometric reactions. In addition, the development of ligands and cocatalysts allows fine-tuning of reactivity. High stability of organopalladium compounds to water and air (except some phosphane complexes) enables easy processing and lower costs. It is not surprising that these reactions are widely employed for various applications. General disadvantages of the Pd-mediated reactions are rooted in high noble metal prices and toxicity of the metal residue that can become problematic in pharmaceutical products. Thanks to excellent activities of palladium catalysts, these problems can be minimized, because only very small amounts are required for high conversions and yields. Not surprisingly, the development of alternative Pd catalysts (separation, reuse) is a flourishing field. In fact, in addition to palladium complexes in homogeneous solution, a series of new, highly active, and effective heterogeneous (supported) palladium catalysts has been developed in recent years. They can be repeatedly used and thus contribute to efficient and economic application of coupling reactions (see also Ref. [4]). Clearly, numerous cross-coupling reactions are sufficiently efficient to be run in industry on a ton scale. Thus, this palladium-catalyzed approach has very often made the transfer from gram-scale synthesis in academic laboratories to ton-scale production in the pharmaceutical, agrochemical, and fine chemical industries in the past two decades.

In conclusion, during the past decade very important advances have taken place in the development of highly active catalysts to carry out the coupling of unreactive and sterically hindered substrates. This progress is likewise due to development from the point of view of (i) organic synthesis, (ii) improved mechanistic understanding, and (iii) “engineering” aspects (separation and catalyst reuse). Thus, (i) tailor-made, for example, bulky electron-rich, ligands that have been developed have contributed greatly to the diversity and utility of cross-coupling chemistry. Various protocols have been developed that are of practical use to the organic chemist. The majority of functional groups can be tolerated, which certainly simplifies the construction of complex heterocyclic structures. The success of the described systems provides a good basis for a more rational approach to the design and development of new catalytic systems for cross-coupling reactions. (ii) Important structure–activity relationships have been established that open possibilities for even more active and universal catalytic systems that are becoming an increasingly more powerful tool in synthetic organic chemistry. (iii) Separation and reuse of the palladium catalyst have been demonstrated numerous times in the past few years in particular using supported Pd catalysts. No expensive ligands, for example, phosphanes, are required and the “ligand-free” systems are not sensitive to air and moisture. At least for reactive substrates, coupling products can be obtained in high yields after short reaction times. In several cases, reactions can be carried out in water or even solventless. These catalyst systems are valuable alternatives to homogeneous complexes, but also new ways to separate dissolved palladium from reaction mixtures have been proven to be successful: use of ionic liquids or solvent mixtures composed of an ionic liquid and an organic solvent or water offers additional advantages.

1.1.3 Literature Reviews and Organization of the Chapter

Because of the extensive developments in particular of the past 10 years, the task to comprehensively review carbon–carbon cross-coupling reactions is a hopeless adventure, even for a single reaction type only. Also, a book like this cannot provide it; rather, a multivolume series would be required. According to the academic interest and practical importance of the coupling reactions under consideration, books [5] and a remarkable number of review articles are available. Some reviews address the topic in general [6]. Other reviews focus on specific subjects such as the use of cross-coupling reactions in total synthesis [7] or coupling reactions performed in ionic liquids [8] (see Chapter 6). A series of reviews focus on particularly heterogeneous systems [4, 9], for example, the use of silica-supported [10] and polymer-supported catalysts [11], Pd/C [12], or palladium nanoparticles (NPs) [13] in coupling reactions. There are a number of reviews dealing with the nature of the active species [14] and particular high-turnover palladium catalysts [15] (see Chapter 7). Coupling catalysis in pure water has been extensively reviewed too [16]. Particular approaches to convert unreactive substrates such as aryl chlorides [17], Pd-catalyzed C–C coupling for the synthesis of polymers [18], and theoretical approaches to understand carbon–carbon cross-coupling reactions [19] are other more specific subjects addressed in review articles. Not surprisingly, a number of review articles deal with the synthetic importance of C–C couplings [20], the use of selected groups of ligands and Pd complexes [21], and industrial applications in the production of fine chemicals [22]. The majority of the results treat the three most important coupling reactions, that is, the Heck, Suzuki–Miyaura, and Sonogashira couplings. Other reaction types such as the Stille reaction, a few examples of coupling reactions studied less frequently (Kumada, Hiyama, and Negishi reactions), allylations including the Tsuji–Trost reaction, and relevant homocoupling processes are also covered. The main emphasis, naturally, is on palladium with a few additional examples for the use of other metals (Cu, Ni, Co, and Rh).

Due to the intention of this book and taking into account the enormous amount of literature, the aim of this introductory chapter is (i) to classify and define the reactions under consideration, (ii) to give an overview of the chemistry behind (i.e., substrates, reaction parameters, and catalysts), and (iii) to introduce the reader to generally accepted and new knowledge on the mechanisms in homogeneous as well as heterogeneous C–C cross-coupling catalysis by palladium. The latter will be summarized mainly for Heck and Suzuki coupling reactions due to the extensive literature and clearly visible progress in mechanistic understanding during the past few years. Thus, this opening chapter rather focuses on common features and unifying concepts in the coupling reactions and the nature of Pd. In addition, it derives challenges for future work, the main subject of this book.

After these historical and general introducing remarks, the next section tries to give an overview of, that is, to classify and describe, the most relevant characteristics of carbon–carbon cross-coupling reactions. Then we summarize and discuss typical organic substrates, reaction parameters, and catalysts including general, unifying mechanistic features of the reactions and catalytic cycles being generally accepted by the scientific community. This background is, evidently, a necessary prerequisite for a critical review and understanding of the literature. For example, one important mistake made in Heck and Suzuki couplings in the literature is the uncritical comparison of various substrates, neglecting that there are differences of orders of magnitudes between reaction rates of reactive and deactivated substrates and that the former ones can be converted under mild conditions by ultratraces of palladium (see also Chapter 2). Wrong conclusions can easily result. The chapter will be concluded by a summarizing discussion of new developments and approaches concerning currently discussed mechanistic aspects, for example, the nature of the active palladium species and future developments and challenges mainly based on the literature about Heck and Suzuki reactions.

1.2 Carbon–Carbon Cross-Coupling Reactions Catalyzed by Palladium

1.2.1 Classification and Overview

The overall scope of Pd-catalyzed cross-coupling reactions may be presented in various ways. In a recent review, the modern and conventional reactions have been divided into 72 classes of cross-coupling reactions [20a]. We attempt here to summarize the most relevant reaction and substrate types using palladium as catalyst. A common and critical feature of these catalytic processes is the formation of aryl- or alkylpalladium(II) intermediates that can be subsequently functionalized to form carbon–carbon and carbon–heteroatom bonds. The versatility of these C–C (and carbon–heteroatom) bond forming processes stems from the reactivity of the corresponding aryl- and alkylpalladium(II) species.

Beside the three recently awarded reaction types, many other cross-couplings with palladium as catalytically active metal exist. Scheme 1.1 gives an overview of the typically applied Pd-catalyzed cross-coupling reactions. Whereas the similarity of these reactions, apart from the catalyst, is the halide (or pseudohalide), the second reactant diverges [23]. Not included are some halide-free versions, for example, the oxidative Heck coupling [24]. By avoiding saline side products, this synthetic approach seems promising. Nevertheless, the necessary C–H activation still bears unsolved difficulties for yields and selectivities. Therefore, it is – at the state of the art – more of academic interest, than a reaction for a wide application.

Scheme 1.1 Overview of well-established Pd-catalyzed cross-coupling reactions (R = organic group; X = halogen atom or pseudohalide such as triflate (F3CSO2O, Tf); “Pd” = Pd catalyst; Nu = nucleophile such as enolate or amine).

Like all classical Pd-catalyzed carbon–carbon cross-couplings, the Heck and Heck–Matsuda reactions (Scheme 1.2) start with the oxidative addition of the aryl halide at the catalyst. However, with an olefinic compound as second substrate, the Heck reaction [1a] obviously differs in its mechanism. Traditionally, the coupling has been performed under homogeneous conditions with phosphane ligands, which require exclusion of oxygen. A slight modification tolerating the presence of oxygen was established by Matsuda and Kikukawa [25]. By replacing the halide by an arenediazonium salt, no air-sensitive phosphane ligands are necessary. Furthermore, no hydrogen halide acid is generated and the reaction proceeds without addition of base.

Scheme 1.2 General equation of the Heck reaction (X = I, Br, Cl) and Heck–Matsuda coupling (X = N2+Y−).

Another variation of the Heck reaction, introduced by Blaser, is the application of acid chlorides instead of halide substrates. Next to the saline products, a stoichiometric amount of carbon monoxide is released. Due to the need of suitable chlorine educts and the generation of toxic gaseous by-products, this method is not widely used [26].

Negishi, Suzuki, Hiyama, Kumada, and Stille reactions (Scheme 1.3) require another organometallic compound as coupling partner for the product of the oxidative addition at palladium. These reactions can be summarized mechanistically and interpreted by oxidative addition, transmetalation, and reductive elimination (see also Section 1.4).

Scheme 1.3 General equation of a Pd-catalyzed reaction with electrophilic organometallic compounds.

In the Negishi coupling (R1–MR2n = R1–ZnX) [1b] as well as the Kumada (also known as Kumada–Corriu) reaction (R1–MR2n = R1–MgX) [27], the replacement of palladium as catalyst by nickel has successfully been performed. Nickel is preferred due to lower investment costs, but it provides toxic metal complexes that have to be separated from the product. In both reaction types, the electrophilic organometallic reactant can be prepared in situ with the metal (Zn or Mg) and an organic halide. This fact is more important for the organozinc compounds, since Grignard reagents (organomagnesium halides) are also commercially available in large variations. However, the sensitivity of these reagents to water is an operational drawback.

Most widely used is the Suzuki (also known as Suzuki–Miyaura) cross-coupling (R1–MR2n = R1–B(OH)2) [1c] because of very mild experimental conditions and high stabilities of the substrate boronic acids to water, air, and elevated temperatures. However, the reaction scope is limited because of low availability of organoboranes in large scale and higher costs.

In order to polarize the Si–C bond of the organosilane used in the Hiyama reaction (R1–MR2n = R1–Si(OR3)3; R1–SiR3(3−n)Fn) [28], activation via fluoride is accomplished. Hence, synthetic routes based on fluoride-labile protecting groups such as silyl ethers are unfavorable. The Hiyama–Denmark coupling is a modification that avoids the toxic fluoride. With an organic group substituted by a hydroxyl function, the reaction proceeds after deprotonation by a base [29].

Similar poisonous issues arise at the Stille coupling (R1–MR2n = R1–SnR23) [30] because of the toxicity of the organotin compounds used as electrophilic substrate. Nevertheless, this cross-coupling possesses synthetic value because of neutral reaction conditions, very few limitations on the organic substituent at Sn, and excellent functional group compatibility.

The Sonogashira reaction [31] is a copper(I) cocatalyzed cross-coupling of aryl halides with terminal alkynes (Scheme 1.4). The electrophilic reactant is generated in situ by a second catalytic cycle. Herein, a base abstracts the acetylenic proton and a copper(I) acetylide complex is formed, which transfers the sp-hybridized group via transmetalation to the palladium [32].

Scheme 1.4 General equation of the Sonogashira reaction.

Initially applied as a catalytic way of reducing carboxylic acids to aldehydes, the Fukuyama coupling (R2–MR3n = R2–ZnX) [33] and the Liebeskind–Srogl reaction (R2–MR3n = R2–B(OH)2) [34] manage to couple a thioester with an organometallic compound to produce a ketone (Scheme 1.5). Since carbonyl groups are widely required in organic synthesis, these cross-couplings provide very mild reaction conditions, high selectivity, and excellent tolerance of functional groups, especially aldehydes, esters, and ketones.

Scheme 1.5 General equation of a Pd-catalyzed reaction with thioesters.

First reported by Tsuji in 1965 for allylpalladium chloride dimer, nearly two decades later Trost extended the allylic alkylation to an asymmetric application by introduction of phosphane ligands (Scheme 1.6) [35]. The oxidative addition generates a η3-π-allylpalladium complex followed by the attack of a nucleophile, typically activated methylenes, enolates, amines, or phenol derivatives [36]. Consequently, the Tsuji–Trost reaction is not restricted to carbon–carbon cross-coupling exclusively, but is rather more important for forming bonds between allylic carbon and heteroatoms. Bromides or acetates are commonly used as leaving group in allylic position. In order to generate the nucleophile, the addition of a base is required. Important benefit for pharmaceutical synthesis is that an enantioselective coupling can be achieved by the application of chiral ligands.

Scheme 1.6 General equation of the Tsuji–Trost reaction.

In Buchwald–Hartwig aminations, aryl halides are reacted with primary or secondary amines (Scheme 1.7) [37]. Thus, these reactions represent an exception of the listed Pd-catalyzed cross-couplings. While all the mentioned reactions form exclusively (except Tsuji–Trost) carbon–carbon bonds, a carbon–nitrogen bond is formed in Buchwald–Hartwig aminations. After the oxidative addition of the halide to palladium, the amine coordinates to the aryl halide complex where it is deprotonated by the base. Due to kinetic reasons, the β-hydride elimination can be neglected and the coupling product is released via reductive elimination [38]. Analogous carbon–oxygen atom bond formations have been reported, too [39].

Scheme 1.7 General equation of the Buchwald–Hartwig amination.

1.2.2 Common Mechanistic Features of Cross-Coupling Reactions and Reactivity of the Substrates

The working hypothesis on the mechanism can be split into three basic microsteps, all of which are assumed to be kinetically accessible: (i) oxidative addition, (ii) transmetalation, and (iii) reductive elimination (Scheme 1.8). For Heck reactions using reagents without a carbon–metal bond (R–M), syn-addition and β-hydride elimination take place instead of transmetalation (Scheme 1.9). The formation of MX or HX, respectively, renders the reaction thermodynamically favorable. Specifics on the mechanism will be explained in more detail in Section 1.4.

Scheme 1.8 Standard mechanism for palladium-catalyzed C–C cross-coupling reactions.

Scheme 1.9 Standard mechanism for the palladium-catalyzed Heck reaction; order of reactivity of reagents R1: allyl/propargyl > benzyl/acyl > alkenyl/alkynyl > allyl.

For fine-tuning of the reactivity and selectivity pattern, in synthetic chemistry one has the following parameters to vary [20a].

1.2.2.1 Choice of the Carbon Electrophile

The reactivity decreases in the order I > Br > Cl > F > OTf. In laboratory-scale synthetic approaches, the choice will usually be aryl iodides due to the high yields under mild conditions. On the contrary, in industrial production where cost efficiency plays an important role, substrates containing chlorides as leaving group are the most favored. Iodides and bromides are less popular regarding reaction economy, but the broad availability of bromides can also be relevant.

1.2.2.2 Choice of the Carbon Nucleophile – What Makes the Difference?

The higher the electronegativity of the metal, the less reactive is the carbon nucleophile. This is depicted in the higher reactivity of organoalkali compounds and Grignard compounds in comparison to organozinc or organoboron compounds. Even a Heck reaction might be possible in which case no organometallic substrate is needed. Organoboron compounds are by far the most common organometallic educts in C–C cross-coupling reactions to yield the Suzuki product in the reaction with aryl halides. Their popularity is only shared by metal-free Heck substrates among which acrylic acids or styrenes are very typical coupling compounds. As illustrated earlier in this chapter, each of the organometallic C nucleophiles has a special reactivity pattern. This variety is of high significance in synthetic organic chemistry, for example, in total synthesis and in the conversion of small amounts of precious products acquired in multistep synthesis. Working under inert gas conditions at very low temperatures with toxic and expensive compounds such as organotin reagents under Stille conditions is routine. For commercial applications including upscaling, facile reaction protocols are favored. This need is especially fulfilled by Heck and Suzuki substrates. Organoboron compounds are expensive but stable and do not need inert conditions. Indeed, Suzuki reactions can be conveniently conducted in water at room temperature. Heck reactions usually require more severe conditions: for conversion of aryl chlorides usually temperatures at least above 140 °C are needed. This is the price for the simple metal-free substrate. Drawbacks of the Heck reaction include that only relatively unhindered alkenes can serve as substrates. In addition, stereocontrol is not as successful as with alkenyl metals as substrates and turnover numbers (TONs) are usually lower than those of the more reactive RM substrates. Brought to the point by Negishi [20a], metals take the important role of regio- and stereospecifiers, kinetic activators, and thermodynamic promoters.

1.3 The Catalysts

1.3.1 The Particular Features of Palladium

Palladium represents one of the most interesting transition metals applied in organic synthesis [5a]. Due to the unique combination of various properties relevant for catalytic cycles, Pd compounds are the catalysts of choice for a variety of rather different reactions such as hydrogenation, oxidation, and carbon–carbon coupling reactions. Regarding cross-coupling reactions, palladium as catalyst competes with nonprecious metals such as copper [40], nickel [27, 41], and, more recently, iron [42]. Although these and some other d-block transition metals have been shown to be useful elements in C–C cross-coupling, it is Pd that proves to be the clearly most useful catalyst. Though nickel, copper, and iron are more cost effective, several advantages of palladium-catalyzed bond formations are decisive. In particular, palladium catalysts show clearly higher activity than their metal alternatives in most cases, enabling the conversion of less reactive substrates at relatively low temperatures and providing high catalyst TONs.

In fact, the outstanding role and the particular properties of palladium in catalysis compared to other transition metals can be understood only in the context of the whole catalytic cycle. Of course, palladium shares some crucially important features with other transition metals, such as the ability to readily interact with nonpolar π-bonds, such as those in alkenes, alkynes, and arenes. This interaction leads to facile, selective, and often reversible oxidative addition, transmetalation, and reductive elimination shown in Scheme 1.8. But what makes Pd special in catalysis and in particular as unique for the transition metal-catalyzed cross-coupling? Several arguments must be mentioned. In contrast to the high reactivity of organic halides, most of the traditionally important heteroatom-containing functional groups, such as various carbonyl derivatives, are much less reactive toward Pd and their presence is readily tolerated. From a more general point of view, the specific features of the metal type of reactions are the facile coordination of the metal to the π-electrons of a double bond, the easy reversibility of uptake and release of two electrons at a time, and the facile reductive elimination (low activation energy barriers between the intermediates). The metal needs to participate in redox processes in both directions under one set of reaction parameters and in one vessel. In comparison with the other members of the Ni group all of which fulfill the required frontier orbital conditions (i.e., the carbenoid-like structure), only Pd preferentially undergoes two-electron redox reactions, being stable as Pd0 and PdII (and PdIV). Oxidative addition and reductive elimination are two-electron redox reactions. For Ni or Cu, one-electron processes are typical possibly leading to highly reactive carbon radical intermediates and thus increasing the number of possible products resulting in lower selectivity. Also, the higher reactivity of nickel compounds decreases its tolerance against functional groups. Platinum, on the other hand, readily undertakes oxidative addition. Yet, the reductive elimination is kinetically hindered, so the reaction rate would be very slow and hence is not in the focus of interest in catalysis. Scheme 1.10 depicts the molecular orbital interactions for the substrate–catalyst interactions.

Scheme 1.10 Dewar–Chatt–Duncanson synergistic synergetic bonding schemes. (Modified from Ref. [20a].)

Recent comparisons of the TONs of various classes of Ni- and Pd-catalyzed cross-coupling reactions between two unsaturated carbon groups [43] have indicated that the Ni-catalyzed reactions generally display lower TONs by a factor of 102 and lower stereo- and regioselectivity. For Pd-catalyzed cross-coupling reactions, often TONs of millions are reported. In some cases, TONs of 109 have been observed. For example, the reaction of phenylzinc bromide with p-iodotoluene and that of (E)-1-decenylzinc bromide with iodobenzene exhibited TONs of 9.7 × 109 and 8 × 107, respectively, producing the desired products in high yields [20a]. Even for the more critical Heck reactions of bromobenzene (TON: 4 × 107; TOF (turnover frequency): 1.2 × 107) [44], traces of palladium in simplest forms [Pd(OAc)2] gave highest conversions and selectivity in useful times and under acceptable conditions. At such levels, cost and Pd-related toxicity issues become significantly less serious.

In short, although much effort is put into replacing palladium by nonprecious catalysts such as Ni [45], Cu [46], or Fe [47], palladium remains the metal of choice in the majority of cases. The (often much) higher activity allows conversion of less reactive substrates under milder reaction conditions (especially lower temperature) providing higher TONs and TOFs. Of similar importance is the tolerance of functional groups when palladium is employed: protection group chemistry is generally not required [22c].

Having rationalized with the help of the conventional working hypothesis for the C–C cross-coupling mechanism why palladium is the best fitting metal for catalysis, the next step will be to elucidate how far the characteristics of a catalytic system can be influenced by the form in which the metal is introduced into the reaction (choice of ligands, supported or homogeneous systems).

1.3.2 Classes of Palladium Catalysts Applied to Cross-Coupling Reactions

The following discussion on the classification and the design of new catalytic systems will be limited to Heck and Suzuki reactions as prominent examples. For both reactions, reviews on recent advances in catalyst design exist, for example, by Bellina [48], Beletskaya [49], and Bedford [17a]. Publications on these two types of cross-coupling reactions have been dominating literature on cross-coupling chemistry over the past few years. It is instructive to present a few data here. Namely, literature search via the browser SciFinder gave the following results: “Heck reaction” – 4703 hits, “Suzuki reaction” – 1121 hits, “Negishi reaction” – 78 hits, and “Stille reaction” – 422 hits (time frame was limited to the period 2000–2012).

The form in which the metal is introduced into the reaction does have a great influence on the catalytic performance. First, there is the question of dealing with homogeneous or heterogeneous catalysts. Initially, homogeneous catalyst systems showed much higher activity; yet recyclability and applicability in continuous processing are crucial arguments for choosing heterogeneous ones [9a].

For both reactions, all forms of Pd precatalysts can be used for converting reactive substrates such as iodides and activated bromides. Yet, deactivated bromides and chlorides with stronger carbon–halogen bonds or bulky substrates need refined catalytic strategies for successful conversion. Chlorides are especially appealing as they are more abundant and cheaper substrates than, for example, iodides. In addition, from the point of view of waste production (i.e., the saline side product that is produced for each molecule of product), lower molecular weight of the side product is favored.

Two main challenges of research in this field during the past few years turned out to be (a) finding highly active catalyst systems for aryl chloride conversion and (b) economical optimization of systems for high recyclability and suppression of product contamination. Two recently published reviews deal with the first topic on a level of molecular catalyst design [17].

1.3.2.1 Ligands and Palladium Complexes – Homogeneous Systems

Scheme 1.11 gives an overview of the most common classes of palladium complexes (ligands) in C–C cross-coupling reactions. According to the working hypothesis of a Pd0/II mechanism, optimization of ligands in homogeneous catalyst systems aims at stabilization of Pd0 in solution and simultaneously preventing the formation of palladium black. Palladium black is supposed to be catalytically inactive and its formation is considered to be a sign for catalyst deactivation [14a]. Ligands are known to determine the solubility of the metal complexes. Thermal stability of the complexes also plays a crucial role. In general, precursor complexes will thermally decompose to liberate highly active palladium species, yet there are cases in which release of palladium is reversible [50]. Finally, ideal electronic and steric characteristics result in fast reaction rates. In C–C coupling reactions, these are donor ligands that increase the electron density at palladium with bulky moieties that decrease the bond strength between complex and substrate (facile reductive elimination) [51].

Scheme 1.11 Most common classes of palladium precursor systems developed and applied in C–C cross-coupling reactions during the past decade.

Typical ligand classes are phosphanes, N-heterocyclic carbenes (NHCs), palladacycles, and pincer structures. Some of the most relevant shall be discussed briefly in the following.

Phosphorous-Containing Ligands

The phosphane ligands can be regarded as classical. The structures have been developed from triphenylphosphanes to the equally simple yet highly efficient bulky, monodentate PtBu3 or PCy3 ligands and then to the combination in the form of dialkylbiaryl phosphanes reviewed by Fu [52] and Martin [21c]. Examples are compounds 1–3. These ligands are mostly air sensitive and catalyst deactivation might occur at elevated temperatures by decomposition or oxidation of the P moiety. Phosphane oxides are less prone to oxidation and stable against moisture [53]. Effort has been put into finding the best P to Pd ratio in the individual reactions and in situ NMR studies were helpful to gain information on the nature of the prevailing Pd species.

N-Heterocyclic Carbenes

Similar or even better σ-donor characteristics as in phosphanes are observed in N-heterocyclic carbene ligands that have the advantage of being much less toxic and generally show higher thermal stability than phosphanes [54]. For example, Nolan and coworkers reviewed the developments [55]. The combination of a palladacycle with an NHC ligand has enabled the reaction of a substituted aryl chloride in a Suzuki-type reaction with an aryl boronic acid to yield the biaryl product at room temperature within 1 h (Scheme 1.12).

Scheme 1.12 Suzuki-type reaction with an NHC Pd complex as highly active catalyst [55].

Palladacycles

The first breakthrough in the development of thermally stable catalyst systems has been the introduction of palladacycles such as 5 into cross-coupling reactions by Herrmann and Beller in 1995 [56]. Only traces of palladium black were formed after 25 h at standard Heck temperatures of about 130 °C and conversion of aryl chlorides turned out to be feasible [57]. Catalyst concentrations could be reduced to amounts as low as 5 × 10−3 mol% for the first time and high activity was observed (up to a TOF of 200 000) [56b]. A general review on the potential of palladacycles was published by Dupont et al. in 2005 [58].

Pincer Complexes

Pincer complexes consist of a tridentate ligand bound to the metal center by at least one carbon–metal σ-bond and two further donor atoms covalently bonded in ortho position via a linker to the carbon atom. These further donor atoms usually are P, N, S, or O and the systems are called PCP, NCN, SCS, and OCO pincers, respectively. As catalyst systems, palladium pincer complexes show relatively high thermal stability and are less prone to dissociation mainly because of the strong C–Pd σ-bond. Milstein was the first who reported on the application of palladium PCP pincer complexes such as 6 and 7 as catalysts in the conversion of aryl iodides and bromides in Heck-type reactions. It was observed that complexes are stable at 180 °C for 300 h and proved air and moisture insensitive [59]. Fine-tuning of the reactivity pattern and stereoselectivity is achieved by modifications of the heteroatom substituents. A thorough review on the application of pincer complexes in catalysis is published by Singleton [60]. There was a long debate on the oxidation states of palladium during catalysis of the Heck type: the high stability of the complexes led to the assumption that a PdII/PdIV cycle might be active. Yet, thorough studies on leaching via a modified three-phase test gave evidence that catalysis only takes place with leached Pd species, making it very likely that the traditional Pd0/PdII cycle is operative [61].

Macrocyclic Palladium Complexes

Palladium coordinated by macrocyclic ligands of extremely high stability even at high temperatures cannot be catalytically active in cross-coupling reactions unless Pd is (temporarily) released from the complex. In fact, such release of palladium from a Robson-type complex 8 seems to be responsible for its extraordinarily high activity in the conversion of challenging substrates such as deactivated electron-rich aryl chlorides (4-chloroanisole) being converted completely and selectively within a few hours at 160 °C with catalyst concentrations of less than 0.1 mol% in Heck- and Suzuki-type reactions. Obviously, the macrocyclic complex reversibly releases effectual amounts of palladium into solution, allowing high reaction rates at these high temperatures and thereby avoiding formation of Pd black, and recaptures Pd at the end of the reaction. Other macrocyclic palladium complexes, especially phthalocyanine derivatives, turned out to be ineffective as Pd release was not reversible. As a result, at elevated temperatures all palladium was released at once to form palladium black [50]. These observations underline the necessity of further discussion on the nature of the active Pd species and the bonding of ligands during the catalytic cycle (see below).

Ligand-Free Systems – “Naked Palladium”

Due to economical and chemical reasons, catalytic systems in homogeneous catalysis for cross-coupling reactions that work without additional ligands such as phosphanes are, in principle, attractive: ligand-free systems are less expensive and toxicity would be reduced. Since the early experiments of Heck and Mizoroki, formation of metallic palladium particles, that is, palladium black, has been observed and soon been identified as consequence of and sign for catalyst deactivation [14b, 62]. Yet, simple, ligand-free palladium systems are much more prone to deactivation by metal precipitation under typical reaction conditions than metal–organic complexes sheltered by the effect of ligands stabilizing Pd0. One important breakthrough was the introduction of quaternary ammonium salts by Jeffery [63], the most broadly applied being tetrabutylammonium bromide (TBAB). Applied as additives in Heck reactions with ligand-free PdII salts such as PdCl2 or Pd(OAc)2 as precursor, they enable Heck reactions under mild reaction conditions even in aqueous medium. As discussed by Beletskaya [64], ammonium halides do not only serve as phase-transfer agent but the anions also stabilize the catalytically active form of Pd during the reaction. In fact, palladium is of course never really “ligand free,” but always coordinated by substrate molecules and/or halides.

The second method to reduce palladium black formation is by decreasing the palladium content in solution up to “homeopathic doses.” These homeopathic doses initially sometimes led to the conclusion that Pd-free reactions are possible until refined analytical methods were applied to detect Pd traces in the range of ppb levels [65]. Indeed, Reetz [66] and de Vries [14b] intensively investigated systems with rather low Pd loadings and developed conditions under which deactivated aryl bromides are smoothly converted in Heck-type reactions with Pd concentrations in the range of 0.01–0.1 mol%. Lower concentrations of catalyst would turn the reaction too slow, whereas higher concentrations also decrease the reaction rate and Pd black visibly forms. What is revealed by these studies is that ligand-free palladium precursors have the potential to turn into highly active catalysts under reaction conditions. Yet, there is only a narrow concentration range in which this is effective.

1.3.2.2 Immobilized or Supported Palladium Complexes and Particles – Heterogeneous Systems

Major motivation and advantage of heterogeneous systems is the ability to immobilize the catalyst preventing product contamination and allowing separation, recycling, and reuse of the catalyst. Thus, it not surprising that the number of heterogeneous catalytic systems reported in the literature drastically and continuously increased during the past 10 years. In fact – in the majority of studies reported – these catalysts can easily be removed from the reaction mixture by filtration or centrifugation and reused following appropriate workup processes. Supports most widely used are various silica materials [10a] and polymers [11], but practically all imaginable other support materials have also been proposed and applied. Namely, the whole variety of oxidic supports including mesoporous ones [67], hybrid organic–inorganic materials, carbon [12], and layered double hydroxides have been applied. A substantial percentage of the studies deal with palladium nanoparticles as catalysts for C–C coupling reactions [68]. Amorphous silica and ordered mesoporous siliceous materials with anchored ligands of practically all types mentioned before (see Section 1.3.2.1) have been applied to immobilize Pd and to perform the coupling reactions (see also Chapter 4). Condensation of trialkoxysilanes bearing the appropriate functional groups or ligand structures with surface hydroxyl groups is the typical preparation procedure used [67, 69]. The solids have often been reduced before use to form Pd0 nanoparticles.

Polymers were often functionalized with phosphane donors to bind palladium [70]. Such polymers with immobilized palladium potentially have the advantages of homogeneous catalysts and can fulfill the engineering requirements of easy separation and recycling. They have been successfully applied in a variety of coupling reactions [71] (see Chapter 5). Palladium complexes and Pd nanoparticles involved in dendritic structures have been reported, too [72]. More special applications include the use of Pd complexes and (supported) nanoparticles in biphasic systems of immiscible solvents and in ionic liquids [8b, 73]. In the case of ionic liquids, recycling can be achieved by recharging the ionic liquid phase containing the catalyst with new educts and base after product extraction, washing, and drying [8b, 74].

1.3.2.3 Palladium Colloids and (Nonsupported) Nanoparticles

The role and application of palladium nanoparticles in C–C coupling reactions are of particular interest and have been studied extensively. The observation of small Pd nanoparticles (in the range of 1–2 nm) during reactions led to further studies on ammonium halide-stabilized Pd NPs (Figure 1.1) and opened the field for techniques and methods for preformation of Pd colloids or nanoparticles [14b]. In his review from 2007, Astruc discusses the scopes and limitations of Pd nanoparticles and their stabilization techniques [75]. The use of palladium nanoparticles and colloids especially in carbon–carbon coupling reactions has been reviewed, too [13, 68c].

Figure 1.1 Model of a palladium nanoparticle stabilized by quaternary ammonium salts.

1.3.2.4 Activity of Heterogeneous Catalysts

The majority of heterogeneous reaction systems in palladium-catalyzed cross-coupling reactions are characterized by clearly lower catalytic activity compared to the best molecular Pd species in homogeneous systems, at least originally. Conversion of mainly less demanding substrates such as aryl iodides and activated aryl bromides has been reported in the majority of papers. However, screening, optimization, and adjustment of the reaction conditions to heterogeneous systems as well as a better understanding of the reaction mechanism have led to a number of very simple supported palladium catalysts such as Pd/C of high activity and selectivity even converting aryl chlorides with rates comparable to highly active homogeneous Pd complexes [9a]. For simple catalysts such as Pd/C or metal oxide-supported Pd catalysts, crucial parameters have turned out to be palladium dispersion (should be high), oxidation state of palladium in the precatalyst [best PdII, that is, PdO or Pd(OH)2 particles], and Pd loading. Hydrodehalogenation is an unwanted side reaction that mainly occurs when supported Pd catalysts are employed. Research in the development of supported Pd systems is strongly related to research on the microkinetics of the reaction under investigation, thereby being a major question what happens with the palladium during conversion (see, for example, Ref. [61]).

1.4 Mechanistic Aspects

1.4.1 General Mechanism of C–C Cross-Coupling and Heck Reactions with Homogeneous Catalyst Precursors

The postulated mechanism for the catalytic cycle of homogeneous catalytic systems as shown in Scheme 1.9 (see Section 1.2.2) is well established by now. It is based on fundamental organometallic reaction steps that have been rationalized in many studies by both experimental and computational methods [19]. The first step, the oxidative addition, works well on an electron-rich catalytically active metal center that is coordinatively unsaturated [76]. In general, this step is considered to be rate determining. The active 14- or 16-electron Pd0 species is usually formed in situ from a PdII precursor. Transmetalation becomes a thermodynamically feasible process due to the differences in electronegativities between Pd and the organometallic substrates. The product is released upon reductive elimination and the activation barrier for this step is supposed to be small [76a]. In the case of Heck-type reactions, the equivalent to transmetalation is the insertion of Pd into the C–H bond in β-position to the aryl. The syn-addition is followed by σ-bond rotation and consecutive β-H syn-elimination to yield the trans-alkene (Scheme 1.13).

Scheme 1.13 Standard model explaining the trans reaction product in Heck C–C coupling reactions.

Electroanalytical studies by Amatore and Jutand [77] revealed a threefold coordinated anionic Pd0 species instead of the twofold coordinated species postulated before. Their studies are discussed in more detail in Section 1.4.3.

1.4.2 Models for Heck and Suzuki Reactions with Supported Pd Precursors

The most extensive literature concerning mechanistic understanding, heterogeneous catalysis, and engineering criteria such as separation and reuse is available for Heck and Suzuki couplings and more limited for Sonogashira reactions. The reason may be their particular practical importance as well as the ease of handling, that is, convenient reaction conditions and guaranteed conversion of reactive substrates with any form of palladium. All forms of palladium can be used as precatalysts in these reactions with less demanding substrates such as aryl iodides or activated aryl bromides. Experiments aiming at the understanding of the nature of the true catalytic species are found to be very difficult due to a number of aspects: ppb traces of Pd are often active, in particular, for less demanding substrates. On the other hand, such species can quickly deactivate to form Pd particles. Catalytic steps occurring on a solid surface are equally challenging to prove.

In most research papers, the active form of palladium is not studied or even discussed. However, there have been an increasing number of studies focusing on mechanistic aspects and the true active species in heterogeneous systems in the past decade. Based on a variety of approaches and investigations, literature reports claim soluble molecular palladium, Pd nanoparticles or colloids, and solid metal surfaces as active species.

For an entirely pure heterogeneous, surface-based reaction mechanism, models introduced either an interaction between substrate molecules and the planar metal surface (Figure 1.2a) or an interaction between the substrate molecules and coordinatively undersaturated Pd atoms at the kinks and edges of the supported metal particles (Figure 1.2b) [78].

Figure 1.2 Models for interaction between substrate and catalyst via (a) the planar surface or (b) edges. (Modified from Ref. [9a].)

At present, it is not clear if complete catalytic turnovers can occur on the surface of a palladium particle. This possibility cannot be completely ruled out, although no definitive or suggestive proof has been presented up to now.

Instead of such surface mechanisms, palladium atoms or small clusters are proved in many cases to be detached from the surface during Heck and Suzuki reactions as shown in Scheme 1.14 . Initial studies were based on Heck reactions and conducted by Arai and coworkers [79] and Köhler et al. [80] and reviewed, for example, by Biffis [81], Köhler [82], and Jones [14a]. Studies have revealed that palladium redeposition after complete conversion can be positively influenced under reducing conditions. For Suzuki reactions, the situation is not that clear. The milder reaction conditions, the lower reaction temperatures (<80 °C), in particular, are often brought forward as argument for a surface-based mechanism. Also, potential leaching mechanisms can be different from higher temperature conditions discussed above (>120 °C).

Scheme 1.14 Heck reaction including Pd leaching upon oxidative addition.

In fact, heterogeneous palladium precatalysts show very similar characteristics to soluble palladium species especially concerning the concept of de Vries of the homeopathic characteristics of palladium catalysts [83]. That is, the leaching process of the precious metal from the surface, which was considered to be very unfavorable considering economic aspects, turns out to be essential for substrate conversion with high reaction rates. Pd dissolution and redeposition processes correlate strongly with the reaction rate and are strongly influenced by reaction conditions and parameters. Solvent, temperature, substrates, base, additives, and atmosphere must be adjusted carefully for high catalytic activity (and Pd leaching). For simple supported Pd catalysts (Pd on carbon or metal oxide supports), the best catalyst performance can be achieved mainly by the following two properties: (i) Pd should be highly dispersed on the support surface and (ii) Pd should be present as PdII (oxide or hydroxide). The classical prereduction in hydrogen at elevated temperatures, in general, decreases activity significantly. This is true for Heck, Suzuki, and Sonogashira reactions.

1.4.3 Recent Results on the Reaction Mechanism and the Nature of the Active Pd Species

Investigations aiming at exploring the true catalytically active species provide important contributions toward a rational design of catalysts. Three major questions dominate research in this field: (i) where does the reaction take place? (ii) which oxidation states does palladium take? and (iii) what does the coordination sphere of palladium look like? Of course, the answers may depend on the system under investigation. For molecular catalyst precursors, only the second and the third question are of interest, except when working in a multiphase system. A selection of reports on such mechanistic aspects published recently will be briefly discussed in the following subsections.

1.4.3.1 Observation of Intermediates in Homogeneous Catalysis by Electrochemical Methods

In the field of molecular catalysis, much light on the nature of the catalytically active species was shed by the electrochemical experiments conducted by Amatore and Jutand as summarized in a review [77]. Investigations on short-lived species can be provided by transient cyclic voltammetry or chronoamperometry taking into account that redox processes of the species under investigation are part of the cycle. Measuring the reduction and oxidation current progress versus time or potential allows in situ