Microwaves in Organic and Medicinal Chemistry E-Book

C. Oliver Kappe

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 968

Veröffentlichungsjahr: 2013

Beschreibung

Tailored to the needs of medicinal and natural products chemists, the second edition of this unique handbook brings the contents up to speed,
almost doubling the amount of chemical information with an additional volume.
As in the predecessor, a short introductory section covers the theoretical background and evaluates currently available instrumentation and
equipment. The main part of the book then goes on to systematically survey the complete range of published microwave-assisted synthesis
methods from their beginnings in the 1990s to mid-2011, drawing on data from more than 5,000 reports and publications. Throughout, the
focus is on those reactions, reagents and reaction conditions that work, and that are the most relevant for medicinal and natural products
chemistry. A much expanded section is devoted to combinatorial, highthroughput and flow chemistry methods.

Leseprobe

Contents

Cover

Series Page

Title Page

Copyright

Preface

Personal Foreword to the First Edition

Personal Foreword to the Second Edition

Chapter 1: Introduction: Microwave Synthesis in Perspective

1.1 Microwave Synthesis and Medicinal Chemistry

1.2 Microwave-Assisted Organic Synthesis (MAOS): A Brief History

1.3 Scope and Organization of the Book

References

Chapter 2: Microwave Theory

2.1 Microwave Radiation

2.2 Microwave Dielectric Heating

2.3 Dielectric Properties

2.4 Microwave versus Conventional Thermal Heating

2.5 Microwave Effects

References

Chapter 3: Equipment Review

3.1 Introduction

3.2 Domestic Microwave Ovens

3.3 Dedicated Microwave Reactors for Organic Synthesis

3.4 Single-Mode Instruments

3.5 Multimode Instruments

References

Chapter 4: Microwave Processing Techniques

4.1 Solvent-Free Reactions

4.2 Phase-Transfer Catalysis

4.3 Open- versus Closed-Vessel Conditions

4.4 Pre-pressurized Reaction Vessels

4.5 Nonclassical Solvents

4.6 Passive Heating Elements

4.7 Processing Techniques in Drug Discovery and High-Throughput Synthesis

4.8 Scale-Up in Batch and Continuous Flow

References

Chapter 5: Literature Survey Part A: Transition Metal-Catalyzed Reactions

5.1 General Comments

5.2 Carbon–Carbon Bond Formations

5.3 Carbon–Heteroatom Bond Formations

5.4 Other Transition Metal-Mediated Processes

References

Chapter 6: Literature Survey Part B: Miscellaneous Organic Transformations

6.1 Rearrangement Reactions

6.2 Cycloaddition Reactions

6.3 Oxidations

6.4 Reductions and Hydrogenations

6.5 Mitsunobu Reactions

6.6 Glycosylation Reactions and Related Carbohydrate-Based Transformations

6.7 Organocatalytic Transformations

6.8 Organometallic Transformations (Mg, Zn, and Ti)

6.9 Multicomponent Reactions

6.10 Alkylation Reactions

6.11 Nucleophilic Aromatic Substitutions

6.12 Ring-Opening Reactions

6.13 Addition and Elimination Reactions

6.14 Substitution Reactions

6.15 Enamine and Imine Formations

6.16 Reductive Aminations

6.17 Ester and Amide Formation

6.18 Decarboxylation Reactions

6.19 Free Radical Reactions

6.20 Protection/Deprotection Chemistry

6.21 Preparation of Isotopically Labeled Compounds

6.22 Miscellaneous Transformations

References

Chapter 7: Literature Survey Part C: Heterocycle Synthesis

7.1 Three-Membered Heterocycles with One Heteroatom

7.2 Four-Membered Heterocycles with One Heteroatom

7.3 Five-Membered Heterocycles with One Heteroatom

7.4 Five-Membered Heterocycles with Two Heteroatoms

7.5 Five-Membered Heterocycles with Three Heteroatoms

7.6 Five-Membered Heterocycles with Four Heteroatoms

7.7 Six-Membered Heterocycles with One Heteroatom

7.8 Six-Membered Heterocycles with Two Heteroatoms

7.9 Six-Membered Heterocycles with Three Heteroatoms

7.10 Larger Heterocyclic and Polycyclic Ring Systems

References

Chapter 8: Literature Survey Part D: Combinatorial Chemistry and High-Throughput Organic Synthesis

8.1 Solid-Phase Organic Synthesis

8.2 Soluble Polymer-Supported Synthesis

8.3 Fluorous-Phase Organic Synthesis

8.4 Grafted Ionic Liquid-Phase-Supported Synthesis

8.5 Polymer-Supported Reagents

8.6 Polymer-Supported Catalysts

8.7 Polymer-Supported Scavengers

References

Index

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. FolkersEditorial BoardH. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Smith, Dennis A. / Allerton, Charlotte /Kalgutkar, Amit S. / van de Waterbeemd,Han / Walker, Don K.

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Sotriffer, Christoph (Ed.)Virtual ScreeningPrinciples, Challenges, and PracticalGuidelines2011ISBN: 978-3-527-32636-5Vol. 48

Rautio, Jarkko (Ed.)Prodrugs and Targeted DeliveryTowards Better ADME Properties2011ISBN: 978-3-527-32603-7Vol. 47

Smit, Martine J. / Lira, Sergio A. / Leurs,Rob (Eds.)Chemokine Receptors as DrugTargets2011ISBN: 978-3-527-32118-6Vol. 46

Ghosh, Arun K. (Ed.)Aspartic Acid Proteases asTherapeutic Targets2010ISBN: 978-3-527-31811-7Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)Transporters as Drug CarriersStructure, Function, Substrates2009ISBN: 978-3-527-31661-8Vol. 44

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Sippl, Wolfgang / Jung, Manfred (Eds.)Epigenetic Targets in DrugDiscovery2009ISBN: 978-3-527-32355-5Vol. 42

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Preface

The application of microwaves marks a real revolution in synthetic organic ?chemistry. Although it was more or less a curiosity, only a few decades ago, the rapid development within this field made it necessary to come up with a second, completely revised edition of the standard monograph, Microwaves in Organic and Medicinal Chemistry, by Oliver Kappe and Alexander Stadler, published in this book series in 2005. Indeed, the current edition is not just an updated version, but a completely new monograph as one can see from the increase in size, from originally 409 pages to almost 700 pages! An enormous amount of recent literature has been considered and included, making these two volumes now the new “gold standard” of microwave chemistry.

Especially in medicinal chemistry, yield and elegance of the synthesis of a new compound are no issue – only a minor amount of pure material is needed to screen for biological properties. Only later and only for a negligibly small number of potential candidates, better synthetic strategies have to be developed. Thus, microwave-supported synthesis is the first choice to quickly (and simply) create a multitude of test compounds.

We, the editors of the book series Methods and Principles in Medicinal Chemistry, are very grateful to Oliver Kappe, Alexander Stadler, and Doris Dallinger for having undertaken this enormous effort. We are also grateful to Frank Weinreich for his ongoing engagement in our book series and to Heike Noethe, both at Wiley-VCH Verlag GmbH, for her editorial support.

January 2012

Düsseldorf

Raimund Mannhold

Weisenheim am Sand

Hugo Kubinyi

Zurich

Gerd Folkers

Personal Foreword to the First Edition

We are currently witnessing an explosive growth in the general field of “microwave chemistry.” The increase of interest in this technology stems from the realization that microwave-assisted synthesis, apart from many other enabling technologies, actually provides significant practical and economic advantages. Although microwave chemistry is currently used in both academic and industrial contexts, the impact on the pharmaceutical industry especially has developed microwave-assisted organic synthesis (MAOS) from a laboratory curiosity in the 1980s and 1990s to a fully accepted technology today. The field has grown such that nearly every pharmaceutical company and more and more academic laboratories now actively utilize this technology for their research.

One of the main barriers facing a synthetic chemist contemplating to use microwave synthesis today is – apart from access to suitable equipment – obtaining education and information on the fundamental principles and possible applications of this new technology. Thus, the aim of this book is to give the reader a well-structured, up-to-date, and exhaustive overview of known synthetic procedures involving the use of microwave technology and to illuminate the “black box” stigma that microwave chemistry still has.

Our main motivation for writing Microwaves in Organic and Medicinal Chemistry derived from our experience in teaching microwave chemistry in the form of short courses and workshops to researchers from the pharmaceutical industry. In fact, the structure of this book closely follows a course developed for the American Chemical Society and can be seen as a compendium for this course. It is hoped that some of the chapters of this book are sufficiently convincing as to encourage scientists not only to use microwave synthesis in their research but also to offer training for their students or coworkers.

We would like to thank Hugo Kubinyi for his encouragement and motivation to write this book. Thanks are also due to Mats Larhed, Nicholas E. Leadbeater, Erik Van der Eycken, and scientists from Anton Paar GmbH, Biotage AB, CEM Corp., and Milestone srl, who have been kind enough to read various sections of this book and to provide valuable suggestions. First and foremost, we would like to thank Doris Dallinger, Bimbisar Desai, Toma Glasnov, Jenny Kremsner, and other members of the Kappe research group for spending their time searching the “microwave literature” and for tolerating this distraction. We are particularly indebted to Doris Dallinger for carefully proofreading the complete text and to Jenny Wheedby for providing the cover art. We are very grateful to Dr. Frank Weinreich and other editors at Wiley-VCH Verlag GmbH for their assistance in bringing out this book.

This book is dedicated to Rajender S. Varma, a pioneer in the field of microwave synthesis, who inspired us to enter this exciting research area in the 1990s.

Graz, Austria

C. Oliver Kappe

December 2004

Alexander Stadler

Personal Foreword to the Second Edition

In more than 6 years since the manuscript submission for the first edition of Microwaves in Organic and Medicinal Chemistry, many things have changed. In contrast to 2004, microwave chemistry now is truly an established technology, especially in the pharmaceutical industry. Most medicinal chemists are now so accustomed to this nonclassical form of heating that taking their microwave reactors away from them would probably cause significant chaos in the laboratory. To a somewhat smaller extent, dedicated microwave instruments are however slowly replacing oil baths and heating mantles in many academic labs. Importantly, the speculation and confusion about “microwave effects” that persisted for many years have now subsided and most scientists today accept the fact that microwave chemistry is a great way to heat reaction mixtures in sealed tubes with very accurate control of the reaction parameters and to do synthesis in general.

Based on these facts, we now present the second, extensively updated, edition of Microwaves in Organic and Medicinal Chemistry. This edition covers the literature till early 2011, which has led to a significant increase in the number of references and examples in most chapters. We have tried not to greatly increase the page numbers of the introductory Chapters 1–4, but rather to selectively update the fundamental and more technical information on the concept of microwave chemistry contained therein (removing some outdated content). Having the practicing organic and medicinal chemist in mind, most of the changes and additions have occurred in the chapters (now Chapters 5–8) describing the examples of microwave chemistry. Close to 1000 additional references have been included in these chapters. We hope that this revised version will become an indispensable reference work for all chemists interested in microwave chemistry.

Graz, Austria

C. Oliver Kappe

July 2011

Alexander Stadler

Doris Dallinger

Chapter 1

Introduction: Microwave Synthesis in Perspective

1.1 Microwave Synthesis and Medicinal Chemistry

Improving research and development (R&D) productivity is one of the biggest tasks facing the pharmaceutical industry. In a few years, the pharmaceutical industry will see many patents of drugs expire. In order to remain competitive, pharma companies need to pursue strategies that will offset the sales decline and see robust growth and improved shareholder value. The impact of genomics and proteomics is creating an explosion in the number of drug targets. Today's drug therapies are solely based on approximately 500 biological targets; in a few years' time, it is expected that the number of targets will well reach 10 000. In order to identify more potential drug candidates for all these targets, pharmaceutical companies have made major investments in high-throughput technologies for genomic and proteomic research, automated/parallel chemistry, and biological screening. However, lead compound optimization and medicinal chemistry remain one of the bottlenecks in the drug discovery process. Developing chemical compounds with the desired biological properties is time-consuming and expensive. Consequently, increasing interest is being directed toward technologies that allow more rapid synthesis and screening of chemical substances to identify compounds with functional qualities.

Medicinal chemistry has benefited tremendously from the technological advances in the field of combinatorial chemistry and high-throughput synthesis. This discipline has been an innovative machine for the development of methods and technologies that accelerate the design, synthesis, purification, and analysis of compound libraries. These new tools have had a significant impact on both lead identification and lead optimization in the pharmaceutical industry. Large compound libraries can now be designed and synthesized to provide valuable leads for new therapeutic targets. Once a chemist develops a suitable high-speed synthesis of a lead, it becomes possible to synthesize and purify hundreds of molecules in parallel to discover new leads and/or derive structure–activity relationships (SAR) in unprecedented timeframes.

The bottleneck of conventional parallel/combinatorial synthesis is typically optimization of reaction conditions to afford the desired products in high yields and with suitable purities. Since many reaction sequences require at least one or more heating steps for extended time periods, these optimizations are often difficult and time-consuming. Microwave-assisted heating under controlled conditions has been shown to be an invaluable technology for medicinal chemistry and drug discovery applications since it often dramatically reduces reaction times, typically from days or hours to minutes or even seconds. Many reaction parameters can be evaluated in a few hours to optimize the desired chemistry. Compound libraries can then be rapidly synthesized in either a parallel or (automated) sequential format using this new, enabling technology. In addition, microwave synthesis allows the discovery of novel reaction pathways that serve to expand “chemical space” in general and “biologically relevant, medicinal chemistry space” in particular.

Specifically, microwave synthesis has the potential to impact upon medicinal chemistry efforts in at least three major phases of the drug discovery process: lead generation, hit-to-lead efforts, and lead optimization. Medicinal chemistry addresses what are fundamentally biological and clinical problems. Focusing first on the preparation of suitable molecular tools for mechanistic validation, efforts ultimately turn to the optimization of biochemical, pharmacokinetic, pharmacological, clinical, and competitive properties of drug candidates. A common theme throughout this drug discovery and development process is speed. Speed equals competitive advantage, more efficient use of expensive and limited resources, faster exploration of structure–activity relationship, enhanced delineation of intellectual property, more timely delivery of critically needed medicines, and ultimately determines positioning in the marketplace. To the pharmaceutical industry and the medicinal chemist, time truly does equal money, and microwave chemistry has become a central tool in this fast-paced, time-sensitive field.

Chemistry, like all sciences, consists of never-ending iterations of hypotheses and experiments, with results guiding the progress and development of projects. The short reaction times provided by microwave synthesis make it ideal for rapid reaction scouting and optimization, allowing very rapid progress through the “hypotheses–experiment–results” iterations, resulting in more decision points per time unit. In order to fully benefit from microwave synthesis, one has to “be prepared to fail in order to succeed.” While failure could cost a few minutes, success would gain many hours or even days. The speed at which multiple variations of reaction conditions can be performed allows a morning discussion of “What should we try?” to become an after lunch discussion of “What were the results?” (the “let's talk after lunch” mantra) [1]. Not surprisingly, therefore, most pharmaceutical, agrochemical, and biotechnology companies are already heavily using microwave synthesis as frontline methodology in their chemistry programs, both for library synthesis and for lead optimization, as they realize the ability of this enabling technology to speed chemical reactions and therefore the drug discovery process.

1.2 Microwave-Assisted Organic Synthesis (MAOS): A Brief History

While fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, the oil bath, or the hot plate as a means of applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community [1, 2].

Microwave energy, originally applied for heating foodstuff by Percy Spencer in the 1940s, has found a variety of technical applications in the chemical and related industries since the 1950s, in particular in food processing, drying, and polymer industries. Other applications range from analytical chemistry (microwave digestion, ashing, and extraction) [3] to biochemistry (protein hydrolysis and sterilization) [3], pathology (histoprocessing and tissue fixation) [4], to medical treatments (diathermy) [5]. Somewhat surprisingly, microwave heating has only been implemented in organic synthesis since the mid-1980s. The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published 25 years ago by the groups of Gedye et al. (Scheme 1.1) [6] and Giguere et al. [7] in 1986. In those early days, experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements. The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions. In the 1990s, several groups started to experiment with solvent-free microwave chemistry (so-called dry media reactions), which eliminated the danger of explosions [8]. Here, the reagents were preadsorbed onto either a more or less microwave-transparent (i.e., silica, alumina, or clay) or strongly absorbing (i.e., graphite) inorganic support that additionally may have been doped with a catalyst or reagent. Particularly in the early days of MAOS, the solvent-free approach was very popular since it allowed the safe use of domestic microwave ovens and standard open-vessel technology. While a large number of interesting transformations using “dry media” reactions have been published in the literature [8], technical difficulties relating to nonuniform heating, mixing, and the precise determination of the reaction temperature remained unsolved, in particular when scale-up issues needed to be addressed.

Scheme 1.1 Hydrolysis of benzamide. The first published example (1986) of microwave-assisted organic synthesis.

Alternatively, microwave-assisted synthesis has been carried out using standard organic solvents under open-vessel conditions. If solvents are heated by microwave irradiation at atmospheric pressure in an open vessel, the boiling point of the solvent typically limits the reaction temperature that can be achieved. Nonetheless, in order to achieve high reaction rates, high-boiling microwave-absorbing solvents have been frequently used in an open-vessel microwave synthesis [9]. However, the use of these solvents presented serious challenges in relation to product isolation and recycling of the solvent. Because of the recent availability of modern microwave reactors with online monitoring of both temperature and pressure, MAOS in dedicated sealed vessels using standard solvents – a technique pioneered by Christopher R. Strauss in the mid-1990s [10] – has been celebrating a comeback in recent years. This is clearly evident surveying the recently published (since 2001) literature in the area of controlled microwave-assisted organic synthesis (Figure 1.1). In addition to the primary and patent literature, many review articles, several books, special issues of journals, feature articles, online databases, information on the World Wide Web, and educational publications provide extensive coverage of the subject (see Section 5.1 for a comprehensive survey). Among the approximately 1000 original publications that appeared in 2010 describing microwave-assisted reactions under controlled conditions, a careful analysis demonstrates that in about 90% of all cases, sealed-vessel processing (autoclave technology) in dedicated single-mode microwave instruments has been employed. A 2007 survey has however found that as many as 30% of all published MAOS papers still employ kitchen microwave ovens [11], a practice banned by most of the respected scientific journals today. For example, the American Chemical Society (ACS) organic chemistry journals will typically not consider manuscripts describing the use of kitchen microwave ovens or the absence of a reaction temperature as specified in the relevant author guidelines [12].

Figure 1.1 Publications on microwave-assisted organic synthesis (1986–2010). Gray graphs: Number of articles involving MAOS for seven selected synthetic organic chemistry journals (Journal of Organic Chemistry, Organic Letters, Tetrahedron, Tetrahedron Letters, Synthetic Communications, Synthesis, and Synlett; SciFinder scholar search, keyword: “microwave”). The black graphs represent the number of publications (2001–2008) reporting MAOS experiments in dedicated reactors with adequate process control (about 50 journals, full text search: microwave). Data for 2009 and 2010 are not available, but are estimated to be in the 1000–1200 publications per year range.

Since the early days of microwave synthesis, the observed rate accelerations and sometimes altered product distributions compared to oil bath experiments have led to speculation on the existence of so-called “specific” or “nonthermal” microwave effects [13]. Historically, such effects were claimed when the outcome of a synthesis performed under microwave conditions was different from that of the conventionally heated counterpart at the same apparent temperature. Reviewing the present literature [14, 15], it appears that today most scientists agree that in the majority of cases the observed rate enhancement is a purely thermal/kinetic effect, that is, a consequence of the high reaction temperatures that can rapidly be attained when irradiating polar materials in a microwave field, although effects that are caused by the unique nature of the microwave dielectric heating mechanism (specific microwave effects) also need to be considered. While for the medicinal chemist in industry, this discussion may seem futile, the debate on “microwave effects” is undoubtedly going to continue for a few years in the academic world. Regardless of the nature of the observed rate enhancements (for further details on microwave effects, see Section 2.5), microwave synthesis has now truly matured and has moved from a laboratory curiosity in the late 1980s to an established technique in organic synthesis, heavily used in both academia and industry.

The initially slow uptake of the technology in the late 1980s and 1990s has been attributed to its lack of controllability and reproducibility, coupled with a general lack of understanding of the basics of microwave dielectric heating. The risks associated with the flammability of organic solvents in a microwave field and the lack of available dedicated microwave reactors allowing adequate temperature and pressure control were major concerns. Important instrument innovations (see Chapter 2) now allow a careful control of time, temperature, and pressure profiles, paving the way for reproducible protocol development, scale-up, and transfer from laboratory to laboratory and scientist to scientist. Today, microwave chemistry is as reliable as the vast arsenal of synthetic methods that preceded it. Since 2001, therefore, the number of publications related to MAOS has increased dramatically (Figure 1.1) to such a level that it might be assumed that in a few years, many more chemists than today will probably use microwave energy to heat chemical reactions on a laboratory scale [1, 2]. However, it should be emphasized that the potential for growth is still very large as a recent survey has found that less than 10% of all publications in synthetic organic chemistry currently make use of microwave technology [15].

Recent innovations in microwave reactor technology now allow controlled parallel and automated sequential processing under sealed-vessel conditions and the use of continuous or stop-flow reactors for scale-up purposes. In addition, dedicated vessels for solid-phase synthesis, for performing transformations using pre-pressurized conditions and for a variety of other special applications, have been developed. Today, there are four major instrument vendors that produce microwave instrumentation dedicated toward organic synthesis. All those instruments offer temperature and pressure sensors, built-in magnetic stirring, power control, software operation, and sophisticated safety controls. The number of users of dedicated microwave reactors is therefore growing at a rapid rate, and it appears only to be a question of time until most laboratories will be equipped with suitable microwave instrumentation.

In the past, microwave chemistry was often used only when all other options to perform a particular reaction failed or when exceedingly long reaction times or high temperatures were required to complete a reaction. This practice is now slowly changing and due to the growing availability of microwave reactors in many laboratories, routine synthetic transformations are also now being carried out by microwave heating. One of the major drawbacks of this relatively new technology still is equipment cost. While prices for dedicated microwave reactors for organic synthesis have come down considerably since their first introduction in the late 1990s, the current price range for microwave reactors is still many times higher than that of conventional heating equipment. As with any new technology, the current situation is bound to change over the next several years and less expensive equipment should become available. By then, microwave reactors will have truly become the “Bunsen burners of the twenty first century” and will be a standard equipment in every chemical laboratory.

1.3 Scope and Organization of the Book

Today, a large body of work on microwave-assisted synthesis exists in the published and patent literature. Many review articles, several books, and information on the World Wide Web already provide extensive coverage of the subject (see Section 5.1). The goal of the present book is to present carefully scrutinized, useful, and practical information for advanced practitioners of microwave-assisted organic synthesis. Special emphasis is placed on concepts and chemical transformations that are of importance to medicinal chemists, and that have been reported in the most recent literature (2002–2010). The extensive literature survey is limited to reactions that have been performed using controlled microwave heating conditions, that is, where dedicated microwave reactors for synthetic applications with adequate temperature and pressure measurements have been employed. After a discussion of microwave dielectric heating theory and microwave effects (Chapter 2), a review of the existing equipment for performing MAOS will be presented (Chapter 3). This is followed by a chapter outlining the different processing techniques in a microwave-heated experiment (Chapter 4). Finally, a literature survey with more than 1500 references will be presented in Chapters 5–8.

Beginners in the field of microwave-assisted organic synthesis are referred to a recent book containing a chapter with useful practical tips (“How To Get Started”) and an additional section with carefully selected and documented microwave experiments that may be used by scientists in academia to design a course on microwave-assisted organic synthesis [16].

References

1. Leadbeater, N. (2004) Chemistry World, 1, 38–41.

2. (a) Adam, D. (2003) Nature,421, 571–572; (b) Marx, V. (2004) Chemical and Engineering News,82 (50), 14–19; (c) Yarnell, A. (2007) Chemical and Engineering News,85 (21), 32–33.

3. Kingston, H.M. and Haswell, S.J. (eds) (1997) Microwave-Enhanced Chemistry: Fundamentals, Sample Preparation and Applications, American Chemical Society, Washington.

4. Giberson, R.T. and Demaree, R.S. (eds) (2001) Microwave Techniques and Protocols, Humana Press, Totowa, NJ.

5. Prentice, W.E., (2002) Therapeutic Modalities for Physical Therapists, McGraw-Hill, New York.

6. Gedye, R., Smith, F., Westaway, K., Ali, H., Baldisera, L., Laberge, L., and Rousell, J. (1986) Tetrahedron Letters, 27, 279–282.

7. Giguere, R.J., Bray, T.L., Duncan, S.M., and Majetich, G. (1986) Tetrahedron Letters, 27, 4945–4958.

8. (a) Loupy, A., Petit, A., Hamelin, J., Texier-Boullet, F., Jacquault, P., and Mathé, D. (1998) Synthesis, 1213–1234; (b) Varma, R.S. (1999) Green Chemistry, 43–55.

9. (a) Bose, A.K., Banik, B.K., Lavlinskaia, N., Jayaraman, M., and Manhas, M.S. (1997) Chemtech,27, 18–24; (b) Bose, A.K., Manhas, M.S., Ganguly, S.N., Sharma, A.H., and Banik, B.K. (2002) Synthesis, 1578–1591.

10. (a) Strauss, C.R. and Trainor, R.W. (1995) Australian Journal of Chemistry,48, 1665–1692; (b) Strauss, C.R. (1999) Australian Journal of Chemistry,52, 83–96.

11. Moseley, J.D., Lenden, P., Thomson, A.D., and Gilday, J.P. (2007) Tetrahedron Letters, 48, 6084–6087 (Ref. 13).

12. (2011) The Journal of Organic Chemistry, 76 (1), Author Guidelines.

13. (a) Perreux, L. and Loupy, A. (2001) Tetrahedron,57, 9199–9223; (b) Perreux, L. and Loupy, A. (2006) Chapter 4, in Microwaves in Organic Synthesis, 2nd edn (ed. A. Loupy), Wiley-VCH Verlag GmbH, Weinheim, pp. 134–218; (c) de la Hoz, A., Díaz-Ortiz, A., and Moreno, A. (2005) Chemical Society Reviews,34, 164–178; (d) de la Hoz, A., Diaz-Ortiz, A., and Moreno, A. (2006) Chapter 5, in Microwaves in Organic Synthesis, 2nd edn (ed. A. Loupy), Wiley-VCH Verlag GmbH, Weinheim, pp. 219–277.

14. (a) Caddick, S. and Fitzmaurice, R. (2009) Tetrahedron,65, 3325–3355; (b) Kappe, C.O. and Dallinger, D. (2009) Molecular Diversity,13, 71–193.

15. Leadbeater, N.E. (ed.) (2011) Microwave Heating as a Tool for Sustainable Chemistry, CRC Press, Boca Raton.

16. Kappe, C.O., Dallinger, D., and Murphree, S.S. (2009) Practical Microwave Synthesis for Organic Chemists, Wiley-VCH Verlag GmbH, Weinheim.

Chapter 2

Microwave Theory

The physical principles behind and the factors determining the successful application of microwaves in organic synthesis are not widely familiar to chemists. Nevertheless, it is essential for the synthetic chemist involved in microwave-assisted organic synthesis to have at least a basic knowledge of the underlying principles of microwave–matter interactions and of the nature of microwave effects. The basic understanding of macroscopic microwave interactions with matter was formulated by von Hippel in the mid-1950s [1]. In this chapter, a brief summary of the current understanding of microwaves and their interactions with matter is given. For more in-depth discussion on this quite complex field, the reader is referred to recent review articles [2–5].

2.1 Microwave Radiation

Microwave irradiation is an electromagnetic irradiation in the frequency range of 0.3–300 GHz, corresponding to wavelengths of 1 mm–1 m. The microwave region of the electromagnetic spectrum (Figure 2.1) therefore lies between infrared (IR) and radio frequencies. The major use of microwaves is either for transmission of information (telecommunication) or for transmission of energy. Wavelengths between 1 mm and 25 cm are extensively used for RADAR transmissions and the remaining wavelength range is used for telecommunications. All domestic “kitchen” microwave ovens and all dedicated microwave reactors for chemical synthesis that are commercially available today operate at a frequency of 2.45 GHz (corresponding to a wavelength of 12.25 cm) in order to avoid interference with telecommunication, wireless networks, and cellular phone frequencies. There are other frequency allocations for microwave heating applications (ISM (industrial, scientific, and medical) frequencies (see Table 2.1) [6], but these are generally not employed in dedicated reactors for synthetic chemistry. Indeed, published examples of organic synthesis carried out with microwave heating at frequencies other than 2.45 GHz are extremely rare [7].

Figure 2.1 The electromagnetic spectrum.

Table 2.1 ISM microwave frequencies.

Frequency (MHz)Wavelength (cm)433.92 ± 0.2%69.14915 ± 1332.752450 ± 5012.245800 ± 755.1724 125 ± 1251.36Data from Ref. [6].

From comparison of the data presented in Table 2.2 [8], it is obvious that the energy of the microwave photon at a frequency of 2.45 GHz (about 10−5 eV) is too low to cleave molecular bonds and is also lower than Brownian motion. It is therefore clear that microwaves cannot “induce” chemical reactions by direct absorption of electromagnetic energy, as opposed to ultraviolet and visible radiation (photochemistry).

Table 2.2 Comparison of radiation types and bond energies.

2.2 Microwave Dielectric Heating

Microwave chemistry is based on the efficient heating of materials by “microwave dielectric heating” effects [4, 5]. Microwave dielectric heating depends on the ability of a specific material (e.g., a solvent or reagent) to absorb microwave energy and convert it into heat. Microwaves are electromagnetic waves that consist of an electric and a magnetic field component (Figure 2.2). For most practical purposes related to microwave synthesis, it is the electric component of the electromagnetic field that is of importance for wave–material interactions, although in some instances magnetic field interactions (e.g., with metals or metal oxides) can also be of relevance [9, 10].

Figure 2.2 Electric and magnetic field components in microwaves.

The electric component of an electromagnetic field causes heating by two main mechanisms: dipolar polarization and ionic conduction. The interaction of the electric field component with the matrix is called the dipolar polarization mechanism (Figure 2.3a) [4, 5]. For a substance to be able to generate heat when irradiated with microwaves, it must possess a dipole moment. When exposed to microwave frequencies, the dipoles of the sample align with the applied electric field. As the field oscillates, the dipole field attempts to realign itself with the alternating electric field and, in the process, energy is lost in the form of heat through molecular friction and dielectric loss. The amount of heat generated by this process is directly related to the ability of the matrix to align itself with the frequency of the applied field. If the dipole does not have enough time to realign (high-frequency irradiation) or it reorients too quickly (low-frequency irradiation) with the applied field, no heating occurs. The allocated frequency of 2.45 GHz, used in all commercial systems, lies between these two extremes and gives the molecular dipole time to align in the field but not to follow the alternating field precisely. Therefore, as the dipole reorients to align itself with the electric field, the field is already changing and generates a phase difference between the orientation of the field and that of the dipole. This phase difference causes energy to be lost from the dipole by molecular friction and collisions, giving rise to dielectric heating. In summary, field energy is transferred to the medium and electrical energy is converted into kinetic or thermal energy and ultimately into heat. It should be emphasized that the interaction between microwave radiation and the polar solvent, which occurs when the frequency of the radiation approximately matches the frequency of the rotational relaxation process, is not a quantum mechanical resonance phenomenon. Transitions between quantized rotational bands are not involved and the energy transfer is not a property of a specific molecule but the result of a collective phenomenon involving the bulk [4, 5]. The heat is generated by frictional forces occurring between the polar molecules whose rotational velocity has been increased by the coupling with the microwave irradiation. It should also be noted that gases cannot be heated under microwave irradiation, since the distance between the rotating molecules is too far. Similarly, ice is also (nearly) microwave transparent, since the water dipoles are constrained in a crystal lattice and cannot move as freely as in the liquid state.

Figure 2.3 (a) Dipolar polarization mechanism. Dipolar molecules try to align with an oscillating electric field. (b) Ionic conduction mechanism. Ions in solution will move in the electric field.

The second major heating mechanism is the ionic conduction mechanism (Figure 2.3b) [4, 5]. During ionic conduction, as the dissolved charged particles in a sample (usually ions) oscillate back and forth under the influence of the microwave field, they collide with their neighboring molecules or atoms. These collisions cause agitation or motion, creating heat. Thus, if two samples containing equal amounts of distilled water and tap water, respectively, are heated by microwave irradiation at a fixed radiation power, more rapid heating will occur for the tap water sample due to its ionic content. Such ionic conduction effects are particularly important when considering the heating behavior of ionic liquids in a microwave field (see Section 4.5.2). The conductivity principle is a much stronger effect than the dipolar rotation mechanism with regard to the heat-generating capacity.

A related heating mechanism exists for strongly conducting or semiconducting materials such as metals, where microwave irradiation can induce a flow of electrons on the surface. This flow of electrons can heat the material through resistance (ohmic) heating mechanisms [11]. In the context of organic synthesis, this becomes important for heating strongly microwave-absorbing materials, such as thin metal films (Pd and Au), graphite supports (see Section 4.1), or so-called passive heating elements made of silicon carbide (see Section 4.6).

2.3 Dielectric Properties

The heating characteristics of a particular material (e.g., a solvent) under microwave irradiation conditions depend on the dielectric properties of the material. The ability of a specific substance to convert electromagnetic energy into heat at a given frequency and temperature is determined by the so-called loss tangent, tan δ. The loss factor is expressed as the quotient, tan δ = ε″/ε′, where ε″ is the dielectric loss, indicative of the efficiency with which electromagnetic radiation is converted into heat, and ε′ is the dielectric constant describing the polarizability of molecules in the electric field. A reaction medium with a high tan δ is required for efficient absorption and, consequently, for rapid heating. Materials with a high dielectric constant, such as water (ε′ at 25 °C = 80.4), may not necessarily have a high tan δ value. In fact, ethanol has a significantly lower dielectric constant (ε′ at 25 °C = 24.3), but heats much more rapidly than water in a microwave field due to its higher loss tangent (tan δ: ethanol = 0.941, water = 0.123). The loss tangents for some common organic solvents are summarized in Table 2.3 [12]. In general, solvents can be classified as high (tan δ > 0.5), medium (tan δ 0.1–0.5), and low microwave-absorbing (tan δ < 0.1) solvents. Other common solvents without a permanent dipole moment, such as carbon tetrachloride, benzene and dioxane, are more or less microwave transparent. It has to be emphasized that a low tan δ value does not preclude a particular solvent from being used in a microwave-heated reaction. Since either the substrates or some of the reagents/catalysts are likely to be polar, the overall dielectric properties of the reaction medium will, in most cases, allow sufficient heating by microwaves. Furthermore, polar additives (such as alcohols or ionic liquids) or passive heating elements can be added to otherwise low-absorbing reaction mixtures in order to increase the absorbance level of the medium (see Sections 4.5.2 and 4.6).

Table 2.3 Loss tangents (tan δ) of different solvents (2.45 GHz, 20 °C).

The loss tangent values are both frequency and temperature dependent. Figure 2.4 shows the dielectric properties of distilled water as a function of frequency at 25 °C [1, 4, 5]. It is apparent that appreciable values of the dielectric loss ε″ exist over a wide frequency range. The dielectric loss ε″ goes through a maximum as the dielectric constant ε′ falls. The heating, as measured by ε″, reaches its maximum around 18 GHz, while all domestic microwave ovens and dedicated reactors for chemical synthesis operate at a much lower frequency of 2.45 GHz. The practical reason for the lower frequency is the necessity to heat food efficiently throughout its interior. If the frequency is optimal for a maximum heating rate, the microwaves are absorbed in the outer regions of the food and penetrate only a short distance (skin effect) [4].

Figure 2.4 Dielectric properties of water as a function of frequency at 25 °C [13].

According to definition, the penetration depth is the point where 37% (1/e) of the initially irradiated microwave power is still present [6]. The penetration depth is inversely proportional to tan δ and, therefore, critically depends on factors such as temperature and irradiation frequency. Materials with relatively high tan δ values are thus characterized by low values of penetration depth and, therefore, microwave irradiation may be totally absorbed within the outer layers of these materials. For a solvent such as water (tan δ = 0.123 at 25 °C and 2.45 GHz), the penetration depth at room temperature is only on the order of a few centimeters (Table 2.4). Beyond this penetration depth, volumetric heating due to absorption of microwave energy becomes negligible. This means that during microwave experiments on a larger scale, only the outer layers of the reaction mixture may be directly heated by microwave irradiation via dielectric heating mechanisms. The inner part of the reaction mixture will, to a large extent, be heated by conventional heat convection and/or conduction mechanisms. Issues relating to the penetration depth are therefore critically important when considering the scale-up of MAOS (see Section 4.8).

Table 2.4 Penetration depth of some common materials.

MaterialTemperature (°C)Penetration depth (cm)Water251.4Water955.7Ice−121100Polyvinylchloride20210Glass2535Teflon259200Quartz glass2516 000Data from Ref. [11].

The dielectric loss and loss tangent of pure water and most other organic solvents decrease with increasing temperature (Figure 2.5). The absorption of microwave radiation in water therefore decreases at higher temperatures. While it is relatively easy to heat water from room temperature to 100 °C by 2.45 GHz microwave irradiation, it is significantly more difficult to heat water further to 200 °C and beyond in a sealed vessel. In fact, supercritical water (T > 374 °C) is transparent to microwave irradiation (see Section 4.5.1).

Figure 2.5 Dielectric properties of water as a function of temperature and frequency [13].

Most organic materials and solvents behave like that of water, in the sense that the dielectric loss ε″ will decrease with increasing temperature [2–5]. From the practical point of view, this may be somewhat inconvenient, since microwave heating at higher temperatures may often be compromised. On the other hand, from the standpoint of safety, it should be stressed that the opposite situation may lead to a scenario where a material will become a stronger microwave absorber with increasing temperature. This is the case for some inorganic/polymeric materials [4], and will lead to the danger of a thermal runaway during microwave heating. Another notable exception of more practical relevance to synthetic chemistry is ionic liquid, which is heated via the ionic conduction mechanism rather than by dipolar polarization. As the temperature increases, the dielectric loss ε″ sometimes increases dramatically [14].

In summary, the interaction of microwave irradiation with matter is characterized by three different processes: absorption, transmission, and reflection (Figure 2.6). Highly dielectric materials, like polar organic solvents, lead to a strong absorption of microwaves and consequently to a rapid heating of the medium (tan δ 0.05–1) (Table 2.3). Nonpolar microwave-transparent materials exhibit only small interactions with penetrating microwaves (tan δ < 0.01) (Table 2.5) and can thus be used as construction materials (insulators) for reactors because of their high penetration depth values (Table 2.4). If microwave radiation is reflected by the material surface, there is no, or only small, coupling of energy into the system. The temperature increases in the material only marginally. This holds true especially for metals with high conductivity, although in some cases resistance heating for these materials can occur [10].

Figure 2.6 Interaction of microwaves with different materials. (a) Electrical conductors. (b) Absorbing materials (tan δ 0.05–1). (c) Insulators (tan δ < 0.01).

Table 2.5 Loss tangents (tan δ) of low-absorbing materials (2.45 GHz, 25 °C).

2.4 Microwave versus Conventional Thermal Heating

Traditionally, organic synthesis is carried out by conductive heating with an external heat source (e.g., an oil bath or heating mantle). This is a comparatively slow and inefficient method for transferring energy into the system since it depends on convection currents and on the thermal conductivity of the various materials that must be penetrated, and generally results in the temperature of the reaction vessel being higher than that of the reaction mixture (Figure 2.7). This is particularly true if reactions are performed under reflux conditions, whereby the temperature of the bath fluid is typically kept at 10–30 °C above the boiling point of the reaction mixture in order to ensure an efficient reflux. In addition, a temperature gradient can develop within the sample and local overheating can lead to product, substrate, or reagent decomposition.

Figure 2.7 Comparison of conventional (a) and microwave heating (b).

In contrast, microwave irradiation produces efficient internal heating (in core volumetric heating) by direct coupling of microwave energy with the molecules (solvents, reagents, and catalysts) that are present in the reaction mixture. Microwave irradiation, therefore, raises the temperature of the whole volume simultaneously (bulk heating), whereas in the conventionally heated vessel, the reaction mixture in contact with the vessel wall is heated first (Figure 2.7a). Since the reaction vessels employed in modern microwave reactors are typically made of (nearly) microwave-transparent materials such as borosilicate glass, quartz, or Teflon (Table 2.5), the radiation passes through the walls of the vessel and an inverted temperature gradient compared to conventional thermal heating results. If the microwave cavity is well designed, the temperature increase will be uniform throughout the sample (see Section 2.5.1). The very efficient internal heat transfer results in minimized wall effects (no hot vessel surface) that may in principle lead to the observation of so-called specific microwave effects (see Section 2.5.3), for example, in the context of diminished catalyst deactivation. It should be emphasized that microwave dielectric heating and thermal heating by convection are totally different processes, and that any comparison between the two is inherently difficult.

2.5 Microwave Effects

Despite the relatively large body of published work on microwave-assisted chemistry (Figure 1.1) and the basic understanding of high-frequency electromagnetic irradiation and microwave–matter interactions, the exact reasons why and how microwaves enhance chemical processes are still a matter of debate. Since the early days of microwave synthesis, the observed rate accelerations and sometimes altered product distributions compared to conventionally heated experiments have led to speculations on the existence of so-called specific or nonthermal microwave effects [15, 16]. Such effects have been claimed when the outcome of a synthesis performed under microwave conditions was different from the conventionally heated counterpart at the same measured reaction temperature. Today it is generally agreed that in most standard cases, the observed enhancements in microwave-heated reactions are in fact the result of purely thermal/kinetic effects; in other words, they are a consequence of the high reaction temperatures that can rapidly be attained when irradiating polar materials/reaction mixtures under closed-vessel conditions in a microwave field (see Section 2.5.2). Similarly, the possible existence of so-called specific microwave effects that cannot be duplicated by conventional heating and result from the uniqueness of the microwave dielectric heating phenomenon is largely undisputed [15, 16]. In this category fall, for example (i) the superheating effect of solvents at atmospheric pressure, (ii) the selective heating of, for example, strongly microwave-absorbing heterogeneous catalysts or reagents in a less polar reaction medium, and (iii) the elimination of wall effects caused by inverted temperature gradients (see Section 2.5.3).

In contrast, the subject of “nonthermal microwave effects” (also referred to as athermal effects) is highly controversial and has led to heated debates in the scientific community [17]. Essentially, nonthermal effects have been postulated to result from a proposed direct interaction of the electric field with specific molecules in the reaction medium that is not related to a macroscopic temperature effect (see Section 2.5.4) [15, 16]. It has been argued, for example, that the presence of an electric field leads to orientation effects of dipolar molecules or intermediates and hence changes the preexponential factor A or the activation energy (entropy term) in the Arrhenius equation for certain types of reactions. Furthermore, a similar effect has been proposed for polar reaction mechanisms, where the polarity is increased going from the ground state to the transition state, resulting in an enhancement of reactivity by lowering of the activation energy. Significant nonthermal microwave effects have been suggested for a wide variety of synthetic transformations [15, 16].

It should be obvious from a scientific standpoint that the question of nonthermal microwave effects needs to be addressed in a serious manner, given the rapid increase in the use of microwave technology in chemical sciences, in particular organic synthesis. There is an urgent need to provide a scientific rationalization for the observed effects and to investigate the general influence of the electric field (and therefore of the microwave power) on chemical transformations. This is even more important if one considers engineering and safety aspects once this technology moves from the small-scale laboratory work to pilot or production-scale instrumentation. Although the detailed discussion on microwave effects lies outside the scope of this book, this chapter provides a short summary of the basic concepts of relevance to the microwave chemistry practitioner.

Historically, microwave effects were claimed when the outcome of a synthesis performed under microwave conditions was different from the conventionally heated counterpart at the same apparent temperature. An extreme example is highlighted in Scheme 2.1. Here, Soufiaoui and coworkers [18] have synthesized a series of 1,5-aryldiazepin-2-ones in high yield in only 10 min by the condensation of ortho-aryldiamines with β-ketoesters in xylene under microwave irradiation in an open vessel at reflux temperature, utilizing a conventional domestic microwave oven. Surprisingly, they observed that no reaction occurred when the same reactions were heated conventionally for 10 min at the same temperature. In their publication, the authors specifically point to the involvement of “specific effects” (which are not necessarily thermal) in rationalizing the observed product yields. These results could be taken as clear evidence for a specific microwave effect. Interestingly, Gedye and Wei have later reinvestigated the exact same reaction under thermal and microwave conditions and found that there is virtually no difference in the rate of the microwave and the conventionally heated reactions, leading to similar product yields [7, 19]. The literature is full of examples like the one highlighted above, with conflicting reports on the involvement or noninvolvement of “specific” or “nonthermal” microwave effects for a wide variety of different types of chemical reactions [15–17]. Microwave effects are the subject of considerable current debate and controversy and it is evident that extensive research efforts are necessary in order to truly understand these and related phenomena.

Scheme 2.1 Molecular magic with microwaves.

Essentially, one can envision three different possibilities for rationalizing rate enhancements observed in a microwave-assisted chemical reaction [20]:

Thermal effects (kinetics)Specific microwave effectsNonthermal (athermal) microwave effects.

Clearly, a combination of two or all three contributions may be responsible for the observed phenomena, which makes the investigation of microwave effects an extremely complex subject. Before discussing the above-mentioned effects in detail, it is important to have an understanding of how the reaction temperature in a microwave-heated reaction can be adequately determined. In order to obtain reproducible and reliable results from a microwave-assisted reaction, it is absolutely essential to have an accurate way of directly measuring the temperature of the reaction mixture online during the irradiation process. This is even more important if a comparison with conventionally heated experiments is performed.

2.5.1 Temperature Monitoring in Microwave Chemistry

Dedicated microwave reactors for organic synthesis are in most cases operated in “temperature control” mode, which means that the desired reaction temperature is selected by the user (see Chapter 3). By coupling the feedback from a suitable temperature probe to the modulation of magnetron output power, the reaction mixture is heated and kept at the preselected value (see, for example, Figures 2.12 and 2.13). This process requires a reliable way of rapidly monitoring the reaction temperature online during the microwave irradiation process. The correct temperature measurement in microwave-assisted reactions, however, often presents a problem since classical temperature sensors such as thermometers or metal-based thermocouples will fail as they will couple with the electromagnetic field [6]. In the most popular single-mode microwave reactors (Biotage Initiator, CEM Discover, see Section 3.4), the reaction temperature is generally determined by a calibrated external infrared sensor, integrated into the cavity, that detects the surface temperature of the reaction vessel from a predefined distance. It is assumed that the measured temperature on the outside of the reaction vessel will correspond more or less to the temperature of the reaction mixture contained inside. Unfortunately, this is not always the case and extreme care must be taken relying on these data [6, 21–26]. The reactor wall is typically the coldest spot of the reaction system due to the inverted heat flux in comparison to conventional heating as the energy conversion using microwave irradiation takes place directly in the reaction mixture (Figure 2.7) [6].

A more accurate way is to determine the temperature of the reaction mixture directly by an internal probe such as a fiber-optic sensor [21–26], as implemented in the Anton Paar Monowave 300 reactor, that allows both external temperature measurement by an IR sensor and internal temperature monitoring by a ruby-based immersing fiber-optic probe (see Section 3.4) [26]. Fiber-optic probes are more accurate than IR sensors, but are also more expensive. Another disadvantage, compared to other temperature measurement systems, is the generally more narrow operating range of 0–300 °C. In addition, for some types of probes, permanent aging phenomena can already be observed above 250 °C after a few hours [6]. These probes are also very sensitive toward mechanical stress and one reason for the lower temperature resistance is the unavoidable use of polymers during their fabrication, for example, for gluing the sensor crystal to the optical fiber. Until recently, the routine use of fiber-optic probes in microwave-assisted synthesis was therefore often not practical. Fiber-optic probes are also available to monitor internal reaction temperatures in the CEM Discover system and are used in some of the multimode reactors discussed in Chapter 3. In certain instances, it can also be of interest to investigate the temperature of a microwave-heated reaction mixture or vessel surface with the aid of a thermovision camera [27–29].

For routine synthetic applications in single-mode microwave reactors, the use of standard IR probes is often acceptable, mainly because of the convenience, the robust nature, and the low cost of these types of probes. However, the user should be aware of the limitations of these devices and should recognize situations where the use of these external probes is not appropriate. In general, external IR sensors will only represent the internal reaction temperature properly if efficient agitation of the homogeneous reaction mixture is ensured. Inefficient agitation can lead to temperature gradients within the reaction mixture due to field inhomogeneities in the high-density single-mode microwave cavities [25, 26, 30]. Extreme care must therefore be taken with heterogeneous reactions, such as solvent-free, dry media, or highly viscous systems (see Section 4.1).

In addition, it has to be emphasized that in the three most popular single-mode microwave reactors, the temperature is measured at different positions of the otherwise more or less identical microwave vessels (Figure 2.8). Taking into account inherent field inhomogeneities that likely exist in all these cavities [25], this fact in itself can lead to discrepancies when comparing the results obtained from running the exact same chemical reaction in these systems [30]. It has to be noted that in the Biotage microwave systems, a certain minimum filling volume must be used in order to ensure a proper temperature reading. These differences are aggravated when biphasic mixtures are concerned, where one of the phases is strongly microwave absorbing and the other phase is only weakly absorbing. A case in point are, for example, unstirred biphasic mixtures of ionic liquids and nonpolar organic solvents where a strong differential heating (see Section 2.5.3) of the ionic liquid phase will occur [23]. Depending on the microwave system used, either the temperature of the very hot ionic liquid phase (IR from the bottom) or the temperature of the cooler organic layer (IR from the side) will be recorded.

Figure 2.8 Position of infrared temperature sensors in single-mode microwave cavities from Anton Paar, Biotage, and CEM (10 mL reaction vessel).

Importantly, external IR sensors should never be used in conjunction with simultaneous external cooling of the reaction vessel. Using this patented technique, the reaction vessel is cooled from the outside by compressed air while being irradiated by microwaves [31]. This allows a higher level of microwave power to be directly administered to the reaction mixture, but will prevent overheating by continuously removing latent heat [32]. It has been demonstrated by several research groups that by using this technique the internal reaction temperatures will be significantly higher than recorded by the IR sensor on the outside [6, 21, 22, 24, 25]. When using simultaneous external cooling, an internal fiber-optic probe device must therefore be employed. Even without using external cooling, one should be aware of the fact that the IR sensor will need some time until it reflects the actual internal reaction temperature. This is because it will take a certain time for the reaction vessel, made of glass, to be warmed “from the inside” by microwave dielectric heating of its polar contents. Although this delay is typically only on the order of a few seconds, it may suffice to lead to an undetected small overshooting of the internal reaction temperature, in particular in case of strongly microwave-absorbing reaction mixtures that are rapidly heated by microwave irradiation [25, 26, 33].

In case of low-absorbing or nearly microwave-transparent reaction mixtures, the opposite phenomenon may occur. Since the glass used for making the comparatively low-cost microwave process vials used in single-mode reactors is not completely microwave transparent (for loss tangents of different types of glasses, see Table 2.5), significant heating of the reaction vessel, rather than of the reaction mixtures, will occur under these circumstances (Figure 2.9). In contrast, no detectable heating of the microwave-transparent reaction mixture is seen when a custom-made reaction vessel made of high-purity quartz is employed (Figure 2.9). Heating of the microwave-transparent solvent, when using the standard glass vessel, is the result of indirect heating by conduction and convection phenomena via the hot surface of the self-absorbing glass. Since an IR sensor directly monitors the surface temperature of the glass (rather than of its contents), the observed effects are more pronounced using this type of monitoring method [23]. It is important to note, however, that in case of medium or strongly microwave-absorbing reaction mixtures, the heating of the glass reaction vessel can be considered negligible and is therefore of little practical concern in microwave synthesis [23].

Figure 2.9 Heating profiles for microwave-transparent CCl4 in Pyrex and quartz reaction vessels at constant 150 W magnetron output power (CEM Discover, IR sensor). Reproduced with permission from Ref. [23].

From a practical point of view, it should be highlighted that IR sensors need to be re-calibrated from time to time against internal probes, and that the path between the actual sensor and the reaction vessel must be unobstructed in order to ensure a proper temperature measurement. This is particularly important when the IR sensor is housed at the bottom of the microwave cavity where debris can more easily accumulate (Figure 2.8).

Based on the information provided above, it is evident that more accurate temperature measurements in conjunction with microwave-assisted reactions can be obtained using internal fiber-optic probes. In contrast to thermocouples, fiber-optic sensors are immune to electromagnetic interference and high voltage, do not require shielding, and do not spark or transmit current. Although different types of sensing technologies exist, most microwave reactor manufacturers that provide fiber-optic temperature sensors rely on probes that use semiconductor bandgap technology (CEM, Milestone) or ruby-based probes (Anton Paar). These devices typically have an accuracy of ±1.5 °C.

Although internal fiber-optic temperature probes are more accurate than external IR sensors, their use is also not without complications. This is, in part, because the mechanically sensitive sensor crystal needs to be protected, requiring the use of appropriate protective immersion wells for the fiber-optic probes. In some fiber-optic probes, the actual sensor crystal (GaAs) is in addition protected by a polymer coating. This increases the lifetime of the probe, but slows down the response time. Delay times of up to 13 s have been measured for some commercially available fiber-optic probes/immersion wells [25]. In other, “faster,” probes, the GaAs crystal is unprotected and can in fact be seen at the tip of the probe, but at the same time it is more prone to destruction. In some commercial systems, a very fast probe is used in combination with an inert immersion well that slows down the response time significantly. Care must therefore be taken in selecting a fiber-optic probe with a short response time for a particular measurement problem [25, 33].

Recent evidence suggests that in fact the use of one single fiber-optic probe may not suffice to represent the temperature profile of a microwave-heated reaction mixture [25]. If efficient stirring/agitation cannot be ensured, temperature gradients may develop as a consequence of inherent field inhomogeneities inside a single-mode microwave cavity (Figure 2.10). In contrast to an oil bath experiment, even completely homogeneous solutions, therefore, need to be stirred when using single-mode microwave reactors. The formation of temperature gradients will therefore be a particular problem in case of, for example, solvent-free or dry media reactions (see Section 4.1) and for very viscous or biphasic reaction systems where standard magnetic stirring is not effective, as in the synthesis of polymers.

Figure 2.10