Microwaves in organic and medicinal chemistry second edition

Preface XI Personal Foreword to the First Edition XIII Personal Foreword to the Second Edition XV 1 Introduction: Microwave Synthesis in Perspective 1 1.1 Microwave Synthesis and Medicin

Microwaves in Organic andMedicinal Chemistry

Editorial Board

H 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.

Pharmacokinetics and

Metabolism in Drug Design

Third, Revised and Updated Edition

2012

ISBN: 978-3-527-32954-0

Vol 51

De Clercq, Erik (Ed.)

Antiviral Drug Strategies

Rautio, Jarkko (Ed.)

Prodrugs and Targeted Delivery

Towards Better ADME Properties

Ghosh, Arun K (Ed.)Aspartic Acid Proteases as Therapeutic Targets2010

ISBN: 978-3-527-31811-7 Vol 45

Ecker, Gerhard F / Chiba, Peter (Eds.)Transporters as Drug CarriersStructure, Function, Substrates

2009 ISBN: 978-3-527-31661-8 Vol 44

Faller, Bernhard / Urban, Laszlo (Eds.)Hit and Lead Profiling

Identification and Optimization of Drug-like Molecules

2009 ISBN: 978-3-527-32331-9 Vol 43

Sippl, Wolfgang / Jung, Manfred (Eds.)Epigenetic Targets in Drug Discovery

2009 ISBN: 978-3-527-32355-5 Vol 42

Stadler, and Doris Dallinger

Microwaves in Organic and

Medicinal Chemistry

Second, Completely Revised and Enlarged Edition

Molecular Drug Research Group

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Preface XI

Personal Foreword to the First Edition XIII

Personal Foreword to the Second Edition XV

1 Introduction: Microwave Synthesis in Perspective 1

1.1 Microwave Synthesis and Medicinal Chemistry 1

1.2 Microwave-Assisted Organic Synthesis (MAOS): A Brief History 31.3 Scope and Organization of the Book 6

2.5.1 Temperature Monitoring in Microwave Chemistry 20

2.5.2 Thermal Effects (Kinetics) 26

2.5.3 Specific Microwave Effects 29

2.5.4 Nonthermal (Athermal) Microwave Effects 34

References 36

3.1 Introduction 41

3.2 Domestic Microwave Ovens 42

3.3 Dedicated Microwave Reactors for Organic Synthesis 43

3.5.3.1 MARS Scale-Up System Accessories 68

3.5.3.2 MARS Parallel System Accessories 69

4.3 Open- versus Closed-Vessel Conditions 87

4.4 Pre-pressurized Reaction Vessels 91

4.5 Nonclassical Solvents 96

4.5.1 Water as Solvent 96

4.5.2 Ionic Liquids 98

4.6 Passive Heating Elements 104

4.7 Processing Techniques in Drug Discovery and High-Throughput

Synthesis 107

4.7.1 Automated Sequential versus Parallel Processing 108

4.7.2 High-Throughput Synthesis Methods 120

4.7.2.1 Solid-Phase Synthesis 121

4.7.2.2 Soluble Polymer-Supported Synthesis 124

4.7.2.3 Fluorous-Phase Organic Synthesis 125

4.7.2.4 Polymer-Supported Reagents, Catalysts, and Scavengers 1264.8 Scale-Up in Batch and Continuous Flow 131

4.8.1 Scale-Up in Batch and Parallel 132

4.8.2 Scale-Up Using Continuous Flow Techniques 135

4.8.3 Scale-Up Using Stop-Flow Techniques 137

4.8.4 Microwave Reactor Systems for Production Scale 139

References 141

5 Literature Survey Part A: Transition Metal-Catalyzed Reactions 151

5.2.7 Asymmetric Allylic Alkylations 212

5.2.8 Miscellaneous Carbon–Carbon Bond-Forming Reactions 220

5.3 Carbon–Heteroatom Bond Formations 232

5.3.1 Buchwald–Hartwig Reactions 232

5.3.2 Ullmann Condensation Reactions 240

5.3.3 Miscellaneous Carbon–Heteroatom Bond-Forming Reactions 245

5.4 Other Transition Metal-Mediated Processes 251

5.4.1 Ring-Closing Metathesis and Cross-Metathesis 251

5.4.2 Pauson–Khand Reactions 260

5.4.3 Carbon–Hydrogen Bond Activation 261

5.4.4 Copper-Catalyzed Azide–Acetylene Cycloaddition (CuAAC) 267

6.1.2 Domino/Tandem Claisen Rearrangements 299

6.1.3 Squaric Acid–Vinylketene Rearrangements 303

6.12.1 Cyclopropane and Cyclobutene Ring Openings 3816.12.2 Aziridine Ring Openings 382

6.12.3 Epoxide Ring Openings 383

6.13 Addition and Elimination Reactions 387

7.7.2 Pyridines 489

7.7.3 Pyrans 501

7.8 Six-Membered Heterocycles with Two Heteroatoms 505

7.9 Six-Membered Heterocycles with Three Heteroatoms 524

7.10 Larger Heterocyclic and Polycyclic Ring Systems 527

References 534

8 Literature Survey Part D: Combinatorial Chemistry

and High-Throughput Organic Synthesis 543

8.1 Solid-Phase Organic Synthesis 543

8.1.1 Peptide Synthesis and Related Examples 543

8.2 Soluble Polymer-Supported Synthesis 587

8.3 Fluorous-Phase Organic Synthesis 599

8.4 Grafted Ionic Liquid-Phase-Supported Synthesis 609

8.5 Polymer-Supported Reagents 613

8.6 Polymer-Supported Catalysts 626

8.6.1 Catalysts on Polymeric Support 627

8.6.2 Silica-Grafted Catalysts 634

8.6.3 Catalysts Immobilized on Glass 634

8.6.4 Catalysts Immobilized on Carbon 636

8.6.5 Miscellaneous 637

8.7 Polymer-Supported Scavengers 639

References 642

Index 649

The application of microwaves marks a real revolution in synthetic organicchemistry Although it was more or less a curiosity, only a few decades ago, therapid development within thisfield made it necessary to come up with a second,completely revised edition of the standard monograph,Microwaves in Organic andMedicinal Chemistry, by Oliver Kappe and Alexander Stadler, published in this bookseries in 2005 Indeed, the current edition is not just an updated version, but acompletely 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 beenconsidered and included, making these two volumes now the new ‘‘gold standard’’ ofmicrowave chemistry

Especially in medicinal chemistry, yield and elegance of the synthesis of a newcompound are no issue– only a minor amount of pure material is needed to screenfor biological properties Only later and only for a negligibly small number ofpotential candidates, better synthetic strategies have to be developed Thus, micro-wave-supported synthesis is thefirst choice to quickly (and simply) create a multi-tude 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 havingundertaken this enormous effort We are also grateful to Frank Weinreich for hisongoing engagement in our book series and to Heike Noethe, both at Wiley-VCHVerlag GmbH, for her editorial support

January 2012

Personal Foreword to the First Edition

We are currently witnessing an explosive growth in the generalfield of “microwavechemistry.” The increase of interest in this technology stems from the realization thatmicrowave-assisted synthesis, apart from many other enabling technologies, actuallyprovides significant practical and economic advantages Although microwavechemistry is currently used in both academic and industrial contexts, the impact

on the pharmaceutical industry especially has developed microwave-assisted organicsynthesis (MAOS) from a laboratory curiosity in the 1980s and 1990s to a fullyaccepted technology today Thefield has grown such that nearly every pharmaceuticalcompany and more and more academic laboratories now actively utilize thistechnology for their research

One of the main barriers facing a synthetic chemist contemplating to usemicrowave synthesis today is– apart from access to suitable equipment – obtainingeducation 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 structured, up-to-date, and exhaustive overview of known synthetic proceduresinvolving the use of microwave technology and to illuminate the “black box” stigmathat microwave chemistry still has

well-Our main motivation for writingMicrowaves in Organic and Medicinal Chemistryderived from our experience in teaching microwave chemistry in the form of shortcourses and workshops to researchers from the pharmaceutical industry In fact, thestructure of this book closely follows a course developed for the American ChemicalSociety and can be seen as a compendium for this course It is hoped that some of thechapters of this book are sufficiently convincing as to encourage scientists not only touse 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 towrite this book Thanks are also due to Mats Larhed, Nicholas E Leadbeater, Erik Vander Eycken, and scientists from Anton Paar GmbH, Biotage AB, CEM Corp., andMilestone srl, who have been kind enough to read various sections of this book and toprovide valuable suggestions First and foremost, we would like to thank DorisDallinger, Bimbisar Desai, Toma Glasnov, Jenny Kremsner, and other members ofthe Kappe research group for spending their time searching the “microwave

literature” and for tolerating this distraction We are particularly indebted to DorisDallinger for carefully proofreading the complete text and to Jenny Wheedby forproviding 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 thefield of microwavesynthesis, who inspired us to enter this exciting research area in the 1990s

Personal Foreword to the Second Edition

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

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

Doris Dallinger

Introduction: Microwave Synthesis in Perspective

1.1

Microwave Synthesis and Medicinal Chemistry

Improving research and development (R&D) productivity is one of the biggesttasks facing the pharmaceutical industry In a few years, the pharmaceutical industrywill see many patents of drugs expire In order to remain competitive, pharmacompanies need to pursue strategies that will offset the sales decline and seerobust growth and improved shareholder value The impact of genomics andproteomics is creating an explosion in the number of drug targets Today’s drugtherapies 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 toidentify more potential drug candidates for all these targets, pharmaceutical com-panies have made major investments in high-throughput technologies for genomicand proteomic research, automated/parallel chemistry, and biological screening.However, lead compound optimization and medicinal chemistry remain one of thebottlenecks in the drug discovery process Developing chemical compounds with thedesired biological properties is time-consuming and expensive Consequently,increasing interest is being directed toward technologies that allow more rapidsynthesis and screening of chemical substances to identify compounds with func-tional qualities

Medicinal chemistry has benefited tremendously from the technologicaladvances in the field of combinatorial chemistry and high-throughput synthesis.This discipline has been an innovative machine for the development of methods andtechnologies that accelerate the design, synthesis, purification, and analysis ofcompound libraries These new tools have had a significant impact on both leadidentification and lead optimization in the pharmaceutical industry Large compoundlibraries can now be designed and synthesized to provide valuable leads for newtherapeutic 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

Microwaves in Organic and Medicinal Chemistry, Second Edition.

C Oliver Kappe, Alexander Stadler, and Doris Dallinger.

Ó 2012 Wiley-VCH Verlag GmbH & Co KGaA Published 2012 by Wiley-VCH Verlag GmbH & Co KGaA.

to discover new leads and/or derive structure–activity relationships (SAR) inunprecedented timeframes.

The bottleneck of conventional parallel/combinatorial synthesis is typicallyoptimization of reaction conditions to afford the desired products in high yieldsand with suitable purities Since many reaction sequences require at least one ormore heating steps for extended time periods, these optimizations are often difficultand time-consuming Microwave-assisted heating under controlled conditions hasbeen shown to be an invaluable technology for medicinal chemistry and drugdiscovery applications since it often dramatically reduces reaction times, typicallyfrom days or hours to minutes or even seconds Many reaction parameters can beevaluated in a few hours to optimize the desired chemistry Compound libraries canthen be rapidly synthesized in either a parallel or (automated) sequential formatusing this new, enabling technology In addition, microwave synthesis allows thediscovery of novel reaction pathways that serve to expand “chemical space” in generaland “biologically relevant, medicinal chemistry space” in particular

Specifically, microwave synthesis has the potential to impact upon medicinalchemistry efforts in at least three major phases of the drug discovery process: leadgeneration, hit-to-lead efforts, and lead optimization Medicinal chemistry addresseswhat are fundamentally biological and clinical problems Focusing first on thepreparation of suitable molecular tools for mechanistic validation, efforts ultimatelyturn to the optimization of biochemical, pharmacokinetic, pharmacological, clinical,and competitive properties of drug candidates A common theme throughout thisdrug discovery and development process is speed Speed equals competitive advan-tage, more efficient use of expensive and limited resources, faster exploration ofstructure–activity relationship, enhanced delineation of intellectual property, moretimely delivery of critically needed medicines, and ultimately determines positioning

in the marketplace To the pharmaceutical industry and the medicinal chemist, timetruly does equal money, and microwave chemistry has become a central tool in thisfast-paced, time-sensitivefield

Chemistry, like all sciences, consists of never-ending iterations of hypotheses andexperiments, with results guiding the progress and development of projects Theshort reaction times provided by microwave synthesis make it ideal for rapid reactionscouting and optimization, allowing very rapid progress through the “hypotheses–experiment–results” iterations, resulting in more decision points per time unit Inorder to fully benefit from microwave synthesis, one has to “be prepared to fail inorder to succeed.” While failure could cost a few minutes, success would gain manyhours 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 anafter lunch discussion of “What were the results?” (the “let’s talk after lunch”mantra) [1] Not surprisingly, therefore, most pharmaceutical, agrochemical, andbiotechnology companies are already heavily using microwave synthesis as frontlinemethodology in their chemistry programs, both for library synthesis and for leadoptimization, as they realize the ability of this enabling technology to speed chemicalreactions and therefore the drug discovery process

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

Whilefire is now rarely used in synthetic chemistry, it was not until Robert Bunseninvented the burner in 1855 that the energy from this heat source could be applied to areaction vessel in a focused manner The Bunsen burner was later superseded by theisomantle, the oil bath, or the hot plate as a means of applying heat to a chemicalreaction In the past few years, heating and driving chemical reactions by microwaveenergy has been an increasingly popular theme in the scientific community [1, 2].Microwave energy, originally applied for heating foodstuff by Percy Spencer in the1940s, has found a variety of technical applications in the chemical and relatedindustries since the 1950s, in particular in food processing, drying, and polymerindustries 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 implemen-ted in organic synthesis since the mid-1980s Thefirst reports on the use of microwaveheating to accelerate organic chemical transformations (MAOS) were published 25years ago by the groups of Gedye et al (Scheme 1.1) [6] and Giguere et al [7] in 1986 Inthose early days, experiments were typically carried out in sealed Teflon or glass vessels

in a domestic household microwave oven without any temperature or pressuremeasurements The results were often violent explosions due to the rapid uncon-trolled heating of organic solvents under closed-vessel conditions In the 1990s,several groups started to experiment with solvent-free microwave chemistry (so-calleddry media reactions), which eliminated the danger of explosions [8] Here, thereagents were preadsorbed onto either a more or less microwave-transparent (i.e.,silica, alumina, or clay) or strongly absorbing (i.e., graphite) inorganic support thatadditionally may have been doped with a catalyst or reagent Particularly in the earlydays 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 largenumber of interesting transformations using “dry media” reactions have beenpublished in the literature [8], technical difficulties relating to nonuniform heating,mixing, and the precise determination of the reaction temperature remainedunsolved, in particular when scale-up issues needed to be addressed

O

NH2 20% H2SO4

MW or thermal

O OH

thermal: 1 h, 90 % (reflux)

MW: 10 min, 99 % (sealed vessel)

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 standardorganic solvents under open-vessel conditions If solvents are heated by microwaveirradiation at atmospheric pressure in an open vessel, the boiling point of the solventtypically limits the reaction temperature that can be achieved Nonetheless, in order

to achieve high reaction rates, high-boiling microwave-absorbing solvents have beenfrequently used in an open-vessel microwave synthesis [9] However, the use of thesesolvents presented serious challenges in relation to product isolation and recycling ofthe solvent Because of the recent availability of modern microwave reactors withonline monitoring of both temperature and pressure, MAOS in dedicated sealedvessels using standard solvents– a technique pioneered by Christopher R Strauss inthe mid-1990s [10]– has been celebrating a comeback in recent years This is clearlyevident surveying the recently published (since 2001) literature in the area ofcontrolled microwave-assisted organic synthesis (Figure 1.1) In addition to theprimary and patent literature, many review articles, several books, special issues ofjournals, feature articles, online databases, information on the World Wide Web, andeducational publications provide extensive coverage of the subject (see Section 5.1 for

a comprehensive survey) Among the approximately 1000 original publications thatappeared in 2010 describing microwave-assisted reactions under controlled condi-tions, a careful analysis demonstrates that in about 90% of all cases, sealed-vesselprocessing (autoclave technology) in dedicated single-mode microwave instrumentshas been employed A 2007 survey has however found that as many as 30% of allpublished MAOS papers still employ kitchen microwave ovens [11], a practice

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.

banned by most of the respected scientific journals today For example, the AmericanChemical Society (ACS) organic chemistry journals will typically not considermanuscripts describing the use of kitchen microwave ovens or the absence of areaction temperature as specified in the relevant author guidelines [12].

Since the early days of microwave synthesis, the observed rate accelerations andsometimes altered product distributions compared to oil bath experiments have led

to speculation on the existence of so-called “specific” or “nonthermal” microwaveeffects [13] Historically, such effects were claimed when the outcome of a synthesisperformed under microwave conditions was different from that of the conventionallyheated counterpart at the same apparent temperature Reviewing the presentliterature [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, aconsequence of the high reaction temperatures that can rapidly be attained whenirradiating polar materials in a microwavefield, although effects that are caused bythe unique nature of the microwave dielectric heating mechanism (specific micro-wave effects) also need to be considered While for the medicinal chemist in industry,this discussion may seem futile, the debate on “microwave effects” is undoubtedlygoing to continue for a few years in the academic world Regardless of the nature ofthe observed rate enhancements (for further details on microwave effects, seeSection 2.5), microwave synthesis has now truly matured and has moved from alaboratory 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 beenattributed to its lack of controllability and reproducibility, coupled with a general lack

of understanding of the basics of microwave dielectric heating The risks associatedwith theflammability of organic solvents in a microwave field and the lack of availablededicated microwave reactors allowing adequate temperature and pressure controlwere major concerns Important instrument innovations (see Chapter 3) now allow acareful control of time, temperature, and pressure profiles, paving the way forreproducible protocol development, scale-up, and transfer from laboratory to labo-ratory and scientist to scientist Today, microwave chemistry is as reliable as the vastarsenal of synthetic methods that preceded it Since 2001, therefore, the number ofpublications related to MAOS has increased dramatically (Figure 1.1) to such a levelthat it might be assumed that in a few years, many more chemists than today willprobably 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 arecent survey has found that less than 10% of all publications in synthetic organicchemistry currently make use of microwave technology [15]

Recent innovations in microwave reactor technology now allow controlled paralleland automated sequential processing under sealed-vessel conditions and the use ofcontinuous or stop-flow reactors for scale-up purposes In addition, dedicated vesselsfor solid-phase synthesis, for performing transformations using pre-pressurizedconditions and for a variety of other special applications, have been developed Today,there are four major instrument vendors that produce microwave instrumentationdedicated toward organic synthesis All those instruments offer temperature and

pressure sensors, built-in magnetic stirring, power control, software operation, andsophisticated safety controls The number of users of dedicated microwave reactors istherefore growing at a rapid rate, and it appears only to be a question of time untilmost laboratories will be equipped with suitable microwave instrumentation.

In the past, microwave chemistry was often used only when all other options toperform a particular reaction failed or when exceedingly long reaction times or hightemperatures were required to complete a reaction This practice is now slowlychanging and due to the growing availability of microwave reactors in manylaboratories, routine synthetic transformations are also now being carried out bymicrowave heating One of the major drawbacks of this relatively new technology still

is equipment cost While prices for dedicated microwave reactors for organicsynthesis have come down considerably since theirfirst introduction in the late1990s, the current price range for microwave reactors is still many times higher thanthat of conventional heating equipment As with any new technology, the currentsituation is bound to change over the next several years and less expensive equipmentshould become available By then, microwave reactors will have truly become the

“Bunsen burners of the twentyfirst century” and will be a standard equipment inevery chemical laboratory

1.3

Scope and Organization of the Book

Today, a large body of work on microwave-assisted synthesis exists in the publishedand patent literature Many review articles, several books, and information on theWorld 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 practicalinformation for advanced practitioners of microwave-assisted organic synthesis.Special emphasis is placed on concepts and chemical transformations that are ofimportance to medicinal chemists, and that have been reported in the most recentliterature (2002–2010) The extensive literature survey is limited to reactions thathave been performed using controlled microwave heating conditions, that is,where dedicated microwave reactors for synthetic applications with adequatetemperature and pressure measurements have been employed After a discussion

of microwave dielectric heating theory and microwave effects (Chapter 2), a review ofthe existing equipment for performing MAOS will be presented (Chapter 3) This isfollowed by a chapter outlining the different processing techniques in a microwave-heated experiment (Chapter 4) Finally, a literature survey with more than 1500references will be presented in Chapters 5–8

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

1 Leadbeater, N (2004) Chemistry World, 1,

38 –41.

2 (a) Adam, D (2003) Nature, 421, 571–572;

(b) Marx, V (2004) Chemical and

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

Mathe, 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.,

11 Moseley, J.D., Lenden, P., Thomson, A.D., and Gilday, J.P (2007) Tetrahedron Letters,

(c) de la Hoz, A., D ıaz-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,

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

Microwave Theory

The physical principles behind and the factors determining the successful tion of microwaves in organic synthesis are not widely familiar to chemists.Nevertheless, it is essential for the synthetic chemist involved in microwave-assistedorganic synthesis to have at least a basic knowledge of the underlying principles ofmicrowave–matter interactions and of the nature of microwave effects The basicunderstanding of macroscopic microwave interactions with matter was formulated

applica-by von Hippel in the mid-1950s [1] In this chapter, a brief summary of the currentunderstanding of microwaves and their interactions with matter is given For morein-depth discussion on this quite complexfield, the reader is referred to recent reviewarticles [2–5]

2.1

Microwave Radiation

Microwave irradiation is an electromagnetic irradiation in the frequency range of0.3–300 GHz, corresponding to wavelengths of 1 mm–1 m The microwave region ofthe electromagnetic spectrum (Figure 2.1) therefore lies between infrared (IR) andradio frequencies The major use of microwaves is either for transmission ofinformation (telecommunication) or for transmission of energy Wavelengthsbetween 1 mm and 25 cm are extensively used for RADAR transmissions and theremaining wavelength range is used for telecommunications All domestic “kitchen”microwave ovens and all dedicated microwave reactors for chemical synthesis thatare 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 frequencyallocations for microwave heating applications (ISM (industrial, scientific, andmedical) frequencies (see Table 2.1) [6], but these are generally not employed indedicated reactors for synthetic chemistry Indeed, published examples of organicsynthesis carried out with microwave heating at frequencies other than 2.45 GHz areextremely rare [7]

Microwaves in Organic and Medicinal Chemistry, Second Edition.

C Oliver Kappe, Alexander Stadler, and Doris Dallinger.

Ó 2012 Wiley-VCH Verlag GmbH & Co KGaA Published 2012 by Wiley-VCH Verlag GmbH & Co KGaA.

From comparison of the data presented in Table 2.2 [8], it is obvious thatthe energy of the microwave photon at a frequency of 2.45 GHz (about 105eV)

is too low to cleave molecular bonds and is also lower than Brownian motion It istherefore clear that microwaves cannot “induce” chemical reactions by directabsorption of electromagnetic energy, as opposed to ultraviolet and visible radiation(photochemistry)

Figure 2.1 The electromagnetic spectrum.

Table 2.1 ISM microwave frequencies.

Data from Ref [6].

Table 2.2 Comparison of radiation types and bond energies.

Radiation type Frequency

(MHz)

Quantum energy (eV)

Bond type Bond

Microwave Dielectric Heating

Microwave chemistry is based on the efficient heating of materials by “microwavedielectric 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 andconvert it into heat Microwaves are electromagnetic waves that consist of an electricand a magneticfield component (Figure 2.2) For most practical purposes related tomicrowave synthesis, it is the electric component of the electromagneticfield that is

of importance for wave–material interactions, although in some instances magneticfield interactions (e.g., with metals or metal oxides) can also be of relevance [9, 10].The electric component of an electromagneticfield causes heating by two mainmechanisms: dipolar polarization and ionic conduction The interaction of theelectricfield 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 withmicrowaves, it must possess a dipole moment When exposed to microwavefrequencies, the dipoles of the sample align with the applied electricfield As thefield oscillates, the dipole field attempts to realign itself with the alternating electricfield and, in the process, energy is lost in the form of heat through molecular frictionand dielectric loss The amount of heat generated by this process is directly related tothe ability of the matrix to align itself with the frequency of the appliedfield If thedipole does not have enough time to realign (high-frequency irradiation) or itreorients too quickly (low-frequency irradiation) with the appliedfield, no heatingoccurs The allocated frequency of 2.45 GHz, used in all commercial systems, liesbetween these two extremes and gives the molecular dipole time to align in thefieldbut not to follow the alternatingfield precisely Therefore, as the dipole reorients toalign itself with the electric field, the field is already changing and generates aphase difference between the orientation of thefield and that of the dipole Thisphase difference causes energy to be lost from the dipole by molecular friction andcollisions, giving rise to dielectric heating In summary,field energy is transferred tothe medium and electrical energy is converted into kinetic or thermal energy andultimately into heat It should be emphasized that the interaction between microwave

radiation and the polar solvent, which occurs when the frequency of the radiationapproximately matches the frequency of the rotational relaxation process, is not aquantum mechanical resonance phenomenon Transitions between quantized rota-tional bands are not involved and the energy transfer is not a property of a specificmolecule but the result of a collective phenomenon involving the bulk [4, 5] The heat

is generated by frictional forces occurring between the polar molecules whoserotational 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 crystallattice and cannot move as freely as in the liquid state

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 microwavefield, they collide with their neighboring molecules or atoms These collisions causeagitation or motion, creating heat Thus, if two samples containing equal amounts ofdistilled water and tap water, respectively, are heated by microwave irradiation at afixed radiation power, more rapid heating will occur for the tap water sample due to itsionic content Such ionic conduction effects are particularly important when con-sidering the heating behavior of ionic liquids in a microwavefield (see Section 4.5.2).The conductivity principle is a much stronger effect than the dipolar rotationmechanism with regard to the heat-generating capacity

A related heating mechanism exists for strongly conducting or semiconductingmaterials such as metals, where microwave irradiation can induce aflow 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 becomesimportant for heating strongly microwave-absorbing materials, such as thin metalFigure 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.

films (Pd and Au), graphite supports (see Section 4.1), or so-called passive heatingelements made of silicon carbide (see Section 4.6).

It has to be emphasized that a low tan d value does not preclude a particular solventfrom 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 thereaction medium will, in most cases, allow sufficient heating by microwaves

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

Data from Ref [12].

Furthermore, polar additives (such as alcohols or ionic liquids) or passive heatingelements can be added to otherwise low-absorbing reaction mixtures in order toincrease the absorbance level of the medium (see Sections 4.5.2 and 4.6).

The loss tangent values are both frequency and temperature dependent Figure 2.4shows the dielectric properties of distilled water as a function of frequency at 25C[1, 4, 5] It is apparent that appreciable values of the dielectric loss e00exist over a widefrequency range The dielectric loss e00goes through a maximum as the dielectricconstant e0 falls The heating, as measured by e00, reaches its maximum around

18 GHz, while all domestic microwave ovens and dedicated reactors for chemicalsynthesis operate at a much lower frequency of 2.45 GHz The practical reason for thelower frequency is the necessity to heat food efficiently throughout its interior Ifthe frequency is optimal for a maximum heating rate, the microwaves are absorbed inthe outer regions of the food and penetrate only a short distance (skin effect) [4].According to definition, the penetration depth is the point where 37% (1/e) of theinitially irradiated microwave power is still present [6] The penetration depth isinversely proportional to tan d and, therefore, critically depends on factors such astemperature and irradiation frequency Materials with relatively high tan d values arethus characterized by low values of penetration depth and, therefore, microwaveirradiation may be totally absorbed within the outer layers of these materials For asolvent such as water (tan d ¼ 0.123 at 25C and 2.45 GHz), the penetration depth atroom temperature is only on the order of a few centimeters (Table 2.4) Beyond thispenetration depth, volumetric heating due to absorption of microwave energybecomes negligible This means that during microwave experiments on a largerscale, only the outer layers of the reaction mixture may be directly heated bymicrowave irradiation via dielectric heating mechanisms The inner part of thereaction mixture will, to a large extent, be heated by conventional heat convectionFigure 2.4 Dielectric properties of water as a function of frequency at 25C [13].

and/or conduction mechanisms Issues relating to the penetration depthare therefore critically important when considering the scale-up of MAOS (seeSection 4.8).

The dielectric loss and loss tangent of pure water and most other organic solventsdecrease with increasing temperature (Figure 2.5) The absorption of microwaveradiation in water therefore decreases at higher temperatures While it is relativelyeasy to heat water from room temperature to 100C by 2.45 GHz microwaveirradiation, it is significantly more difficult to heat water further to 200C andbeyond in a sealed vessel In fact, supercritical water (T> 374C) is transparent tomicrowave irradiation (see Section 4.5.1)

Most organic materials and solvents behave like that of water, in the sense that thedielectric loss e00will decrease with increasing temperature [2–5] From the practicalpoint of view, this may be somewhat inconvenient, since microwave heating at highertemperatures may often be compromised On the other hand, from the standpoint of

Table 2.4 Penetration depth of some common materials.

Data from Ref [11].

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

safety, it should be stressed that the opposite situation may lead to a scenario where amaterial will become a stronger microwave absorber with increasing temperature.This is the case for some inorganic/polymeric materials [4], and will lead to thedanger of a thermal runaway during microwave heating Another notable exception

of more practical relevance to synthetic chemistry is ionic liquid, which is heated viathe ionic conduction mechanism rather than by dipolar polarization As the tem-perature increases, the dielectric loss e00sometimes 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 ofmicrowaves and consequently to a rapid heating of the medium (tan d 0.05–1)(Table 2.3) Nonpolar microwave-transparent materials exhibit only small interac-tions with penetrating microwaves (tan d < 0.01) (Table 2.5) and can thus be used asconstruction materials (insulators) for reactors because of their high penetrationdepth values (Table 2.4) If microwave radiation is reflected by the materialsurface, there is no, or only small, coupling of energy into the system Thetemperature increases in the material only marginally This holds true especiallyfor metals with high conductivity, although in some cases resistance heating for thesematerials can occur [10]

2.4

Microwave versus Conventional Thermal Heating

Traditionally, organic synthesis is carried out by conductive heating with an externalheat source (e.g., an oil bath or heating mantle) This is a comparatively slow andinefficient method for transferring energy into the system since it depends onconvection currents and on the thermal conductivity of the various materials that

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

must be penetrated, and generally results in the temperature of the reaction vesselbeing higher than that of the reaction mixture (Figure 2.7) This is particularly true ifreactions are performed under reflux conditions, whereby the temperature of thebathfluid is typically kept at 10–30C above the boiling point of the reaction mixture

in order to ensure an efficient reflux In addition, a temperature gradient can developwithin the sample and local overheating can lead to product, substrate, or reagentdecomposition

In contrast, microwave irradiation produces efficient internal heating (in corevolumetric heating) by direct coupling of microwave energy with the molecules(solvents, reagents, and catalysts) that are present in the reaction mixture Microwaveirradiation, therefore, raises the temperature of the whole volume simultaneously(bulk heating), whereas in the conventionally heated vessel, the reaction mixture incontact with the vessel wall is heatedfirst (Figure 2.7a) Since the reaction vesselsemployed in modern microwave reactors are typically made of (nearly) microwave-transparent materials such as borosilicate glass, quartz, or Teflon (Table 2.5), theradiation passes through the walls of the vessel and an inverted temperaturegradient 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 wallFigure 2.7 Comparison of conventional (a) and microwave heating (b).

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

Data from Ref [11].

effects (no hot vessel surface) that may in principle lead to the observation of so-calledspecific microwave effects (see Section 2.5.3), for example, in the context ofdiminished catalyst deactivation It should be emphasized that microwave dielectricheating and thermal heating by convection are totally different processes, and thatany 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 irradi-ation and microwave–matter interactions, the exact reasons why and how micro-waves enhance chemical processes are still a matter of debate Since the early days ofmicrowave synthesis, the observed rate accelerations and sometimes altered productdistributions compared to conventionally heated experiments have led to specula-tions 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 undermicrowave conditions was different from the conventionally heated counterpart atthe same measured reaction temperature Today it is generally agreed that in moststandard cases, the observed enhancements in microwave-heated reactions are in factthe result of purely thermal/kinetic effects; in other words, they are a consequence ofthe high reaction temperatures that can rapidly be attained when irradiating polarmaterials/reaction mixtures under closed-vessel conditions in a microwavefield (seeSection 2.5.2) Similarly, the possible existence of so-called specific microwave effectsthat cannot be duplicated by conventional heating and result from the uniqueness ofthe microwave dielectric heating phenomenon is largely undisputed [15, 16] In thiscategory fall, for example (i) the superheating effect of solvents at atmosphericpressure, (ii) the selective heating of, for example, strongly microwave-absorbingheterogeneous catalysts or reagents in a less polar reaction medium, and (iii) theelimination of wall effects caused by inverted temperature gradients (seeSection 2.5.3)

In contrast, the subject of “nonthermal microwave effects” (also referred to asathermal effects) is highly controversial and has led to heated debates in the scientificcommunity [17] Essentially, nonthermal effects have been postulated to result from aproposed direct interaction of the electricfield with specific molecules in the reactionmedium 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 electricfield leads toorientation effects of dipolar molecules or intermediates and hence changes thepreexponential factor A or the activation energy (entropy term) in the Arrheniusequation for certain types of reactions Furthermore, a similar effect has beenproposed for polar reaction mechanisms, where the polarity is increased going fromthe ground state to the transition state, resulting in an enhancement of reactivity bylowering of the activation energy Significant nonthermal microwave effects havebeen 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

instrumen-tation 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 b-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

Essentially, one can envision three different possibilities for rationalizing rate

enhancements observed in a microwave-assisted chemical reaction [20]:

MW: 80-98%

Δ: 0%

11 examples N

. Thermal effects (kinetics)

. Specific microwave effects

. Nonthermal (athermal) microwave effects

Clearly, a combination of two or all three contributions may be responsible for theobserved phenomena, which makes the investigation of microwave effects anextremely complex subject Before discussing the above-mentioned effects in detail,

it is important to have an understanding of how the reaction temperature in amicrowave-heated reaction can be adequately determined In order to obtain repro-ducible and reliable results from a microwave-assisted reaction, it is absolutelyessential to have an accurate way of directly measuring the temperature of thereaction 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 isselected by the user (see Chapter 3) By coupling the feedback from a suitabletemperature probe to the modulation of magnetron output power, the reactionmixture is heated and kept at the preselected value (see, for example, Figures 2.12and 2.13) This process requires a reliable way of rapidly monitoring the reactiontemperature online during the microwave irradiation process The correct temper-ature measurement in microwave-assisted reactions, however, often presents aproblem since classical temperature sensors such as thermometers or metal-basedthermocouples will fail as they will couple with the electromagneticfield [6] In themost popular single-mode microwave reactors (Biotage Initiator, CEM Discover, seeSection 3.4), the reaction temperature is generally determined by a calibrated externalinfrared sensor, integrated into the cavity, that detects the surface temperature of thereaction vessel from a predefined distance It is assumed that the measuredtemperature on the outside of the reaction vessel will correspond more or less tothe temperature of the reaction mixture contained inside Unfortunately, this is notalways the case and extreme care must be taken relying on these data [6, 21–26] Thereactor wall is typically the coldest spot of the reaction system due to the inverted heatflux in comparison to conventional heating as the energy conversion using micro-wave irradiation takes place directly in the reaction mixture (Figure 2.7) [6]

A more accurate way is to determine the temperature of the reaction mixturedirectly by an internal probe such as afiber-optic sensor [21–26], as implemented inthe Anton Paar Monowave 300 reactor, that allows both external temperaturemeasurement by an IR sensor and internal temperature monitoring by a ruby-basedimmersing fiber-optic probe (see Section 3.4) [26] Fiber-optic probes are moreaccurate than IR sensors, but are also more expensive Another disadvantage,compared to other temperature measurement systems, is the generally more narrowoperating range of 0–300C In addition, for some types of probes, permanent aging

phenomena can already be observed above 250C after a few hours [6] These probesare also very sensitive toward mechanical stress and one reason for the lowertemperature resistance is the unavoidable use of polymers during their fabrication,for example, for gluing the sensor crystal to the opticalfiber Until recently, theroutine use offiber-optic probes in microwave-assisted synthesis was therefore oftennot practical Fiber-optic probes are also available to monitor internal reactiontemperatures in the CEM Discover system and are used in some of the multimodereactors discussed in Chapter 3 In certain instances, it can also be of interest toinvestigate the temperature of a microwave-heated reaction mixture or vessel surfacewith the aid of a thermovision camera [27–29].

For routine synthetic applications in single-mode microwave reactors, the use ofstandard IR probes is often acceptable, mainly because of the convenience, the robustnature, 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 ofthese external probes is not appropriate In general, external IR sensors will onlyrepresent the internal reaction temperature properly if efficient agitation of thehomogeneous reaction mixture is ensured Inefficient agitation can lead to temper-ature gradients within the reaction mixture due tofield inhomogeneities in the high-density single-mode microwave cavities [25, 26, 30] Extreme care must therefore betaken with heterogeneous reactions, such as solvent-free, dry media, or highlyviscous systems (see Section 4.1)

In addition, it has to be emphasized that in the three most popular single-modemicrowave reactors, the temperature is measured at different positions of theotherwise more or less identical microwave vessels (Figure 2.8) Taking into accountinherentfield inhomogeneities that likely exist in all these cavities [25], this fact initself can lead to discrepancies when comparing the results obtained from runningthe exact same chemical reaction in these systems [30] It has to be noted that in the

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

Biotage microwave systems, a certain minimumfilling volume must be used in order

to ensure a proper temperature reading These differences are aggravated whenbiphasic mixtures are concerned, where one of the phases is strongly microwaveabsorbing and the other phase is only weakly absorbing A case in point are, forexample, unstirred biphasic mixtures of ionic liquids and nonpolar organic solventswhere a strong differential heating (see Section 2.5.3) of the ionic liquid phase willoccur [23] Depending on the microwave system used, either the temperature of thevery hot ionic liquid phase (IR from the bottom) or the temperature of the coolerorganic layer (IR from the side) will be recorded

Importantly, external IR sensors should never be used in conjunction withsimultaneous external cooling of the reaction vessel Using this patented technique,the reaction vessel is cooled from the outside by compressed air while beingirradiated by microwaves [31] This allows a higher level of microwave power to bedirectly administered to the reaction mixture, but will prevent overheating bycontinuously removing latent heat [32] It has been demonstrated by several researchgroups that by using this technique the internal reaction temperatures will besignificantly higher than recorded by the IR sensor on the outside [6, 21, 22, 24,25] When using simultaneous external cooling, an internalfiber-optic probe devicemust therefore be employed Even without using external cooling, one should beaware of the fact that the IR sensor will need some time until it reflects the actualinternal reaction temperature This is because it will take a certain time for thereaction vessel, made of glass, to be warmed “from the inside” by microwavedielectric heating of its polar contents Although this delay is typically only onthe order of a few seconds, it may suffice to lead to an undetected smallovershooting of the internal reaction temperature, in particular in case of stronglymicrowave-absorbing reaction mixtures that are rapidly heated by microwave irra-diation [25, 26, 33]

In case of low-absorbing or nearly microwave-transparent reaction mixtures, theopposite phenomenon may occur Since the glass used for making the comparativelylow-cost microwave process vials used in single-mode reactors is not completelymicrowave 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, willoccur under these circumstances (Figure 2.9) In contrast, no detectable heating ofthe microwave-transparent reaction mixture is seen when a custom-made reactionvessel made of high-purity quartz is employed (Figure 2.9) Heating of the micro-wave-transparent solvent, when using the standard glass vessel, is the result ofindirect heating by conduction and convection phenomena via the hot surface of theself-absorbing glass Since an IR sensor directly monitors the surface temperature ofthe glass (rather than of its contents), the observed effects are more pronounced usingthis type of monitoring method [23] It is important to note, however, that in case ofmedium or strongly microwave-absorbing reaction mixtures, the heating of the glassreaction vessel can be considered negligible and is therefore of little practical concern

in microwave synthesis [23]

From a practical point of view, it should be highlighted that IR sensors need to bere-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 aproper temperature measurement This is particularly important when the IR sensor

is housed at the bottom of the microwave cavity where debris can more easilyaccumulate (Figure 2.8)

Based on the information provided above, it is evident that more accuratetemperature measurements in conjunction with microwave-assisted reactions can

be obtained using internaloptic probes In contrast to thermocouples, optic sensors are immune to electromagnetic interference and high voltage, do notrequire shielding, and do not spark or transmit current Although different types ofsensing technologies exist, most microwave reactor manufacturers that providefiber-optic temperature sensors rely on probes that use semiconductor bandgaptechnology (CEM, Milestone) or ruby-based probes (Anton Paar) These devicestypically have an accuracy of1.5C

fiber-Although internalfiber-optic temperature probes are more accurate than external

IR sensors, their use is also not without complications This is, in part, because themechanically sensitive sensor crystal needs to be protected, requiring the use ofappropriate protective immersion wells for thefiber-optic probes In some fiber-opticprobes, 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 Delaytimes of up to 13 s have been measured for some commercially availablefiber-opticprobes/immersion wells [25] In other, “faster,” probes, the GaAs crystal is unpro-tected and can in fact be seen at the tip of the probe, but at the same time it is moreprone to destruction In some commercial systems, a very fast probe is used incombination with an inert immersion well that slows down the response timesignificantly Care must therefore be taken in selecting a fiber-optic probe with a shortresponse time for a particular measurement problem [25, 33]

Recent evidence suggests that in fact the use of one singlefiber-optic probe maynot suffice to represent the temperature profile of a microwave-heated reaction

Figure 2.9 Heating profiles for microwave-transparent CCl 4 in Pyrex and quartz reaction vessels at constant 150 W magnetron output power (CEM Discover, IR sensor) Reproduced with permission from Ref [23].

mixture [25] If efficient stirring/agitation cannot be ensured, temperature gradientsmay develop as a consequence of inherentfield inhomogeneities inside a single-mode microwave cavity (Figure 2.10) In contrast to an oil bath experiment, evencompletely 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 standardmagnetic stirring is not effective, as in the synthesis of polymers

The temperature monitoring studies shown in Figure 2.10 demonstrate thatmicrowave heating in high field density single-mode cavities is in fact not ashomogeneous as often portrayed, and that extreme care must be taken in determin-ing the proper reaction temperature in these experiments, especially in those caseswhere adequate mixing cannot be ensured

It should be stressed that when studying differences between microwave heatingand conventional heating (microwave effects), it is particularly important to usehighly accurate and fast responding temperature monitoring devices In order toaccurately compare the results obtained by direct microwave heating with theoutcome of a conventionally heated reaction, a reactor system should be used thatallows to perform both types of transformations in the identical reaction vessel and tomonitor the internal reaction temperature in both experiments directly with the samefiber-optic probe device Such a reactor setup, originally introduced by Maes andcoworkers for the CEM Discover reactor (Figure 2.11) [34], can be immersed eitherinto the cavity of the microwave reactor or into a preheated and temperature-equilibrated oil or metal bath placed on a magnetic stirrer/hot plate In both cases,

POWER = 0 (NO cooling) Stirring OFF

Figure 2.10 Temperature profiles for a sample

of 5 mL of NMP contained in a 10 mL quartz

vessel equipped with three internal fiber-optic

sensors positioned at different heights The

sample was irradiated with constant 50 W

magnetron output power (CEM Discover).

Shown are the profiles for the three internal

fiber-optic probes and the external IR sensor Magnetic stirring reduces the temperature differences between the individual fiber-optic probes from max 36C to less than 6C The temperature of the IR sensor deviates by 12C from the top fiber-optic probe with stirring Adapted from Ref [25].

the software of the microwave instrument is recording the internal temperature.Such a system has the advantage that the same reaction vessel and the same method

of temperature measurement are used In this way, all parameters apart from themode of heating are identical and, therefore, a fair comparison between microwaveheating and thermal heating can generally be made [24, 25, 34, 35]

A more recent and much simpler concept to carefully simulate a microwave-heatedexperiment using conventional heating conditions is to employ a microwavereaction vessel made of strongly microwave-absorbing silicon carbide (SiC) (seeFigure 3.5) [36, 37] Microwave irradiation will induce aflow of electrons in thesemiconducting SiC ceramic that heats the material very efficiently through resis-tance heating mechanisms The use of SiC reaction vessels in combination with asingle-mode microwave reactor (Anton Paar Monowave 300) provides an almostcomplete shielding of the contents inside from the electromagneticfield Therefore,these “microwave” experiments do not involve electromagneticfield effects on thechemistry since the semiconducting ceramic vial is effectively preventingmicrowave irradiation to penetrate into the reaction mixture The involvement ofelectromagneticfield effects (specific/nonthermal microwave effects) on a number

of chemical transformations was evaluated by comparing the results obtained inFigure 2.11 Setup for monitoring internal reaction temperatures with fiber-optic probes

in microwave and oil bath experiments (CEM Discover).

microwave-transparent Pyrex vials with experiments performed in SiC vials at thesame reaction temperature (see Section 2.5.4) [36, 37].

Unfortunately, at the time when most of the early work on microwave effects waspublished, many of the complications and subtleties of accurate online temperaturemeasurement under microwave irradiation conditions were not known [15, 16] Theconclusions of these studies should therefore be treated with extreme skepticism.The following sections provide an overview of the currently existing hypotheses ondifferent types of microwave effects

2.5.2

Thermal Effects (Kinetics)

Reviewing the present literature, it appears that today many scientists would agree that

in the majority of cases, the reason for the observed rate enhancements seen inmicrowave chemistry is a purely thermal/kinetic effect, that is, a consequence of thehigh reaction temperatures that can rapidly be attained when irradiating polarmaterials in a microwavefield As shown in Figure 2.12, even a moderately strongmicrowave-absorbing solvent such as 1-methyl-2-pyrrolidone (NMP, bp 202–204C,tan d ¼ 0.275) (Table 2.3) can be heated very rapidly (microwave flash heating) in amicrowave cavity As indicated in Figure 2.12, a sample of NMP can be heated to 200Cwithin about 40 s, depending on the maximum output power of the magnetron [38].Today, most of the published microwave-assisted reactions are performed undersealed-vessel conditions in the relatively small, so-called single-mode microwavereactors with high power density (see Chapter 3) Under these autoclave-type

heated under open-vessel microwave

irradiation conditions [38] Multimode

microwave heating (MicroSYNTH, Milestone)

at different maximum power levels for 6 min

with temperature control using the feedback

from a fiber-optic probe After the set temperatures of 200C (700 W), 150C (500 W), 120C (300 W), and 100C (100 W) are reached, the power regulates itself down to an appropriate level (not shown) Reproduced with permission from Ref [38].

conditions, microwave-absorbing solvents with a comparatively low boiling pointsuch as methanol (bp 65C, tan d ¼ 0.659) can be rapidly superheated to tempera-tures more than 130C in excess of their boiling points when irradiated undermicrowave conditions (Figure 2.13) The rapid increase in temperature can be evenmore pronounced for media with extreme loss tangents such as ionic liquids (seeSection 4.5.2), where temperature jumps of 200C within a few seconds are notuncommon [26] Naturally, such temperature profiles are very difficult if notimpossible to reproduce by standard thermal heating Therefore, comparisons withconventionally heated processes are inherently troublesome.

The temperature, power, and pressure profiles shown in Figure 2.13 nicelyillustrate the operating principles of a modern dedicated microwave reactor such

as the Anton Paar Monowave 300 (see Section 3.4.1.1) After the set temperature of

195C is reached (about 40 s), the microwave magnetron power regulates itself down

to about 30 W, which is all that is needed to keep the sample of methanol superheated

at 195C, 130C above its boiling point at atmospheric pressure Depending on theinitially selected heating mode (as fast as possible or ramp heating), the temperaturecontrol algorithm properly adjusts the magnetron power to ensure that the desired settemperature is reached as fast as possible, at the same time trying not to overheat thesample Since the reaction is performed in a sealed microwave process vial, anautogenic internal pressure of about 29 bar develops in the vessel, which is controlledand monitored by the pressure measurement system of the instrument (see Section3.4.1.1) At the end of the microwave irradiation period (after 210 s), the reactionmixture is rapidly cooled to a temperature of typically about 50C by a stream ofcompressed air (active gas jet cooling) This allows the user to remove the processedmicrowave reaction vial from the cavity in a reasonably short time period, which isparticularly important when processing several reactions in sequence using roboticvial handling (see Section 4.7.1)

It appears obvious that a specific reaction performed under the conditions depicted

in Figure 2.13 utilizing superheated methanol as solvent at 195C will occur at amuch faster rate than when carried out in refluxing methanol at 65C Dramatic rateenhancements when comparing reactions that are performed under standard oilbath conditions (heating under reflux) with high-temperature microwave-heatedprocesses are therefore not uncommon As Baghurst and Mingos [4] have pointedout, based on simply applying the Arrhenius law [k¼ A exp(Ea/RT)], a transfor-mation that requires 68 days to reach 90% conversion at 27C will show the samedegree of conversion within 1.61 s (!) when performed at 227C (Table 2.6) Due tothe very rapid heating and extreme temperatures observable in microwave chemistry,

it appears obvious that many of the reported rate enhancements can be rationalized

by purely thermal/kinetic effects In the absence of any “specific” or “nonthermal”effects, however, one would also expect the reactions carried out under open-vessel,reflux conditions to proceed at the same reaction rate, regardless of whether they areheated by microwaves or in a thermal process (see Section 4.3) It should beemphasized that for these strictly thermal effects, the preexponential factor A andthe energy term (activation energy Ea) in the Arrhenius equation are not affected, onlythe temperature term changes (see Section 2.5.4)

It should also be noted that the rapid heating and cooling typical of small-scalemicrowave-assisted transformations (see Figure 2.13) may lead to altered productdistributions compared to a conventional oil bath reflux experiment, where heating(and cooling) typically is not as fast and the reaction temperature is generally lower Ithas been argued that the very different heating profiles experienced in microwave andconventional heating can actually lead to different reaction products if the reactionproduct distribution is controlled by complex temperature-dependent kinetic pro-files [3] This may be the reason why in many cases microwave-assisted reactions havebeen found to be cleaner, leading to less by-products compared to the conventionallyheated processes [30]

At the same time, it is obvious that microwave heating will not always favor thedesired reaction pathway and that there may be cases where, because of the higherreaction temperatures, unwanted reaction products (e.g., isomers), not seen during aconventionally heated experiment performed at a lower temperature, will be formed.Table 2.6 Relationship between temperature and time for a typical first-order reaction (A ¼ 4  10 10