Chemistry Books

Book SynopsisIncreasing environmental regulations have resulted in the need for new methods of analysis for environmental samples. As an updated version to Extraction Methods for Environmental Analysis published in 1998, Extraction Techniques in Analytical Science provides the fundamentals of extraction methods in environmental organic contaminants.Trade Review"This book should prove valuable to undergraduate and graduate students who are using such extraction techniques in their research projects, especially those who wish to gain an understanding of a wide range of sample preparation and purification methods. The affordable price of this book is appealing, and its size should encourage its regular use . . . Extraction techniques in analytical sciences is a valuable book that discusses state-of-the-art extraction techniques that are employed in various laboratories, including those devoted to analytical chemistry." (Anal Bioanal Chem, 2010) "Written as a self-study guide, the book is an ideal text for undergraduate and postgraduate students, but also for newcomers in the field interested in obtaining a general but complete overview of modern extraction techniques in use for the analysis of organic compounds in complex environmental samples." (Chromatographia, 1 December 2010)Table of ContentsSeries Preface. Preface. Acknowledgements. Acronyms, Abbreviations and Symbols. About the Author. 1 Pre and Post-Extraction Considerations. AQUEOUS SAMPLES. 2 Classical Approaches for Aqueous Extraction. 3 Solid Phase Extraction. 4 Solid Phase Microextraction. 5 New Developments in Microextraction. SOLID SAMPLES. 6 Classical Approaches for Solid-Liquid Extraction. 7 Pressurized Fluid Extraction. 8 Microwave-Assisted Extraction. 9 Matrix Solid Phase Dispersion. 10 Supercritical Fluid Extraction. GASEOUS SAMPLES. 11 Air Sampling. COMPARISON OF EXTRACTION METHODS. 12 Comparison of Extraction Methods. RESOURCES. 13 Resources for Extraction Techniques. Responses to Self-Assessment Questions. Glossary of Terms. SI Units and Physical Constants. Periodic Table. General Index. Application Index.

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Book SynopsisComing to a conclusion, this wonderful, informative and very interesting book presents an excellent overview of small volatile organic compounds and their role in our life and environment. Really fascinating is the entirety of scientific disciplines which were addressed by this book.Trade Review"Coming to a conclusion, this wonderful, informative and very interesting book presents an excellent overview of small volatile organic compounds and their role in our life and environment. Really fascinating is the entirety of scientific disciplines which were addressed by this book." (Flavour and Fragrance Journal, 2011) "In spite of its few shortcomings, this book deserves to be a well-used reference in the library of any laboratory specialising in VOC". (Chemistry World, 1 May 2011) "The Chemistry and Biology of Volatiles takes an interdisciplinary approach to volatile molecules". (Small Business VoIP, 14 December 2010)Table of ContentsForeword xiii List of Contributors xv Acknowledgements xvii Abbreviations xix 1 Volatiles – An Interdisciplinary Approach 1 Andreas Herrmann 1.1 Introduction 1 1.2 Geraniol – A Typical Example 2 1.3 Conclusion 8 References 8 2 Biosynthesis and Emission of Isoprene, Methylbutanol and Other Volatile Plant Isoprenoids 11 Hartmut K. Lichtenthaler 2.1 Introduction 11 2.2 Plant Isoprenoids 12 2.3 Two IPP-Yielding Pathways in Plants 15 2.4 Prenyl Chain Formation and Elongation 16 2.5 Compartmentation of Plant Isoprenoid Biosynthesis 16 2.6 The Enzyme Steps of the Plastidic DOXP/MEP Pathway of IPP Formation 17 2.7 Cross-Talk Between the Two IPP Biosynthesis Pathways 19 2.8 Biosynthesis and Emission of Volatile Isoprene at High Irradiance 22 2.8.1 Regulation of Isoprene Emission 25 2.9 Inhibition of Isoprene Biosynthesis 26 2.9.1 Fosmidomycin and 5-Ketoclomazone 26 2.9.2 Diuron 27 2.10 Inhibition of Carotenoid and Chlorophyll Biosynthesis by Fosmidomycin and 5-Ketoclomazone 27 2.11 Biosynthesis and Emission of Methylbutenol at High Irradiance 28 2.12 Source of Pyruvate for Isoprene and Methylbutenol Biosynthesis 29 2.13 Branching Point of DOXP/MEP Pathway with Other Metabolic Chloroplast Pathways 30 2.14 Is There a Physiological Function of Isoprene and MBO Emission? 31 2.15 Biosynthesis and Emission of Monoterpenes, Sesquiterpenes and Diterpenes 33 2.15.1 Monoterpenes 35 2.15.2 Diterpenes 36 2.15.3 Sesquiterpenes 36 2.16 Some General Remarks on the Regulation of Terpene Biosynthesis in Plants 36 2.17 Volatile Terpenoids as Aroma Compounds of Wine 37 2.18 Function of Terpenes in Plant Defence 38 2.19 Conclusion 38 Acknowledgements 39 References 40 3 Analysis of the Plant Volatile Fraction 49 Patrizia Rubiolo, Barbara Sgorbini, Erica Liberto, Chiara Cordero and Carlo Bicchi 3.1 Introduction 49 3.2 Sample Preparation 50 3.2.1 ‘Liquid’ Phase Sampling 51 3.2.2 Headspace Sampling 51 3.2.3 Headspace–Solid Phase Microextraction 52 3.2.4 In-Tube Sorptive Extraction 54 3.2.5 Headspace Sorptive Extraction 55 3.2.6 Static and Trapped Headspace 56 3.2.7 Solid-Phase Aroma Concentrate Extraction 56 3.2.8 Headspace Liquid-Phase Microextraction 56 3.2.9 Large Surface Area High Concentration Capacity Headspace Sampling 59 3.3 Analysis 59 3.3.1 Fast-GC and Fast-GC-qMS EO Analysis 61 3.3.2 Qualitative Analysis 65 3.3.3 Quantitative Analysis 66 3.3.4 Enantioselective GC 70 3.3.5 Multidimensional GC Techniques 75 3.4 Further Developments 76 3.5 Conclusion 85 Acknowledgements 87 References 87 4 Plant Volatile Signalling: Multitrophic Interactions in the Headspace 95 Andre Kessler and Kimberly Morrell 4.1 Introduction 95 4.2 The Specificity and Complexity of Herbivore-Induced VOC Production 97 4.2.1 Plant Endogenous Wound Signalling 99 4.2.2 Herbivore-Derived Elicitors of VOC Emission 102 4.3 Ecological Consequences of VOC Emission 104 4.3.1 Within-Plant Defence Signalling 104 4.3.2 Herbivore-Induced VOC Emission as Part of a Metabolic Reconfiguration of the Plant 105 4.3.3 Herbivores Use VOCs to Select Host Plants 107 4.3.4 VOCs as Indirect Defences Against Herbivores 108 4.3.5 VOCs in Plant–Plant Interactions 111 4.4 Conclusion 112 Acknowledgements 114 References 114 5 Pheromones in Chemical Communication 123 Kenji Mori 5.1 Introduction 123 5.1.1 Definition of Pheromones 123 5.1.2 Classification of Pheromones 123 5.2 History of Pheromone Research 125 5.3 Research Techniques in Pheromone Science 127 5.3.1 The Collecting of Pheromones 127 5.3.2 Bioassay-Guided Purification 128 5.3.3 Structure Determination and Synthesis 128 5.3.4 Field Bioassay 129 5.3.5 Structure Elucidation of the Male-Produced Aggregation Pheromone of the Stink Bug Eysarcoris lewisi – A Case Study 129 5.4 Structural Diversity Among Pheromones 132 5.5 Complexity of Multicomponent Pheromones 137 5.6 Stereochemistry and Pheromone Activity 139 5.6.1 Only a Single Enantiomer is Bioactive and its Opposite Enantiomer Does Not Inhibit the Response to the Active Isomer 139 5.6.2 Only One Enantiomer is Bioactive, and its Opposite Enantiomer Inhibits the Response to the Pheromone 139 5.6.3 Only One Enantiomer is Bioactive, and its Diastereomer Inhibits the Response to the Pheromone 139 5.6.4 The Natural Pheromone is a Single Enantiomer, and its Opposite Enantiomer or Diastereomer is Also Active 140 5.6.5 The Natural Pheromone is a Mixture of Enantiomers or Diastereomers, and Both of the Enantiomers, or All of the Diastereomers are Separately Active 141 5.6.6 Different Enantiomers or Diastereomers are Employed by Different Species 141 5.6.7 Both Enantiomers are Necessary for Bioactivity 141 5.6.8 One Enantiomer is More Active Than the Other, but an Enantiomeric or Diastereomeric Mixture is More Active Than the Enantiomer Alone 141 5.6.9 One Enantiomer is Active on Males, While the Other is Active on Females 142 5.6.10 Only the meso-Isomer is Active 142 5.7 Pheromones With Kairomonal Activities 142 5.8 Mammalian Pheromones 143 5.9 Invention of Pheromone Mimics 145 5.10 Conclusion 147 Acknowledgements 147 References 147 6 Use of Volatiles in Pest Control 151 J. Richard M. Thacker and Margaret R. Train 6.1 Introduction 151 6.2 Repellents (DEET, Neem, Essential Oils) 151 6.3 Volatile Synthetic Chemicals and Fumigants 154 6.4 Pheromones 158 6.5 Volatile Allelochemicals 165 6.6 Plant Volatiles and Behavioural Modification of Beneficial Insects 166 6.7 Concluding Comments 167 References 168 7 Challenges in the Synthesis of Natural and Non-Natural Volatiles 173 Anthony A. Birkbeck 7.1 Introduction – The Art of Organic Synthesis 173 7.2 Overcoming Challenges in the Small-Scale Synthesis of Natural Volatile Compounds 174 7.2.1 D,L-Caryophyllene (1964) 174 7.2.2 b-Vetivone (1973) 175 7.3 Overcoming Challenges in the Large-Scale Synthesis of Nature Identical and Non-Natural Molecules 176 7.3.1 (Z)-3-Hexenol 176 7.3.2 Citral 177 7.3.3 (–)-Menthol 179 7.3.4 Habanolide 180 7.4 Remaining Challenges in the Large-Scale Synthesis of Natural and Non-Natural Volatiles 180 7.5 Design and Synthesis of Novel Odorants and Potential Industrial Routes to a Natural Product 182 7.5.1 Cassis (Blackcurrant) 182 7.5.2 Patchouli 184 7.5.3 Musk 187 7.5.4 Sandalwood 189 7.6 Other Challenges 193 7.7 Conclusion 193 Acknowledgements 194 Dedication 195 References 195 8 The Biosynthesis of Volatile Sulfur Flavour Compounds 203 Meriel G. Jones 8.1 Introduction: Flavours as Secondary Metabolites 203 8.2 Sulfur in Plant Biology 204 8.3 Sulfur Compounds as Flavour Volatiles 205 8.4 The Alk(en)yl Cysteine Sulfoxide Flavour Precursors 206 8.5 Biosynthesis of the Flavour Precursors of Allium 207 8.5.1 The Biosynthesis of Allium Flavour Precursors via g-Glutamyl Peptides 208 8.5.2 The Biosynthesis of Allium Flavour Precursors via Cysteine Synthases 209 8.6 Formation of Volatiles from CSOs 210 8.6.1 S-Methyl-L-cysteine sulfoxide 210 8.6.2 Release of the Allium CSOs 211 8.7 The Allium Flavour Volatiles 212 8.8 The Enzyme Alliinase 213 8.9 The Enzyme Lachrymatory Factor Synthase 214 8.10 The Biological Roles of the Flavour Precursors 215 8.11 The Glucosinolate Flavour Precursors 216 8.12 GS and Their Biosynthetic Pathways 216 8.13 Release of Volatile GS Hydrolysis Products 218 8.14 The Biological Role of Glucosinolates 220 8.15 Application of Transgenic Technology to Applied Aspects of GS Biosynthesis 222 8.16 Volatile Sulfur Compounds from Other Plants 222 8.16.1 Complex Organic Sulfur Volatiles 222 8.16.2 Simple Sulfur Volatiles 223 8.16.3 Hydrogen Sulfide 223 8.16.4 Methanethiol 224 8.17 Conclusion 224 References 224 9 Thermal Generation of Aroma-Active Volatiles in Food 231 Christoph Cerny 9.1 Introduction 231 9.2 The Maillard Reaction 233 9.2.1 The Amadori Rearrangement 234 9.2.2 Deoxyosones 235 9.2.3 Retro-Aldolization 235 9.3 Formation of Aroma Compounds in the Later Stages of the Maillard Reaction 237 9.3.1 2-Furfurylthiol 237 9.3.2 4-Hydroxy-2,5-dimethyl-3(2H)-furanone 239 9.3.3 Alkyl and Alkenylpyrazines 239 9.3.4 2-Acetyl-1-pyrroline 241 9.4 The Strecker Degradation 241 9.5 Caramelization 244 9.6 Thiamin Degradation 246 9.7 Ferulic Acid Degradation 246 9.8 Fat Oxidation 247 9.9 Conclusion 250 References 250 10 Human Olfactory Perception 253 Alan Gelperin 10.1 Introduction 253 10.2 Historical Perspective on Olfactory Perception 254 10.3 Human Olfactory Pathway 255 10.4 Functional Studies in Human Subjects 256 10.5 Functional Studies in Brain-Damaged Subjects 259 10.6 Single Odorants, Binary Mixtures and Complex Odour Objects 259 10.7 Olfactory Versus Trigeminal Odorant Identification 262 10.8 Orthonasal Versus Retronasal Odour Perception 263 10.9 Specific Anosmias 264 10.10 MHC-Correlated Odour Preferences in Human Subjects 265 10.11 Odour Deprivation and Odour Perception 266 10.12 Age-Related Decline in Olfactory Perception 267 10.13 New Neurons in Adult Brains 268 10.14 Epidemiological Studies of Human Olfaction 268 10.15 Active Sampling and Olfactory Perception 269 10.16 Human Olfactory Imagery 270 10.17 Top-Down Influences on Olfactory Perception 271 10.18 Reproductive State and Olfactory Sensitivity 272 10.19 Olfaction, Hunger and Satiety 273 10.20 Odour Perception Bias by Odour Names 274 10.21 Olfaction and Disease States 275 10.22 Prenatal and Postnatal Influences on Infant Odour/Flavour Preferences 276 10.23 Future Directions 277 Acknowledgements 277 References 278 11 Perfumery – The Wizardry of Volatile Molecules 291 Christophe Laudamiel 11.1 The Big Picture 291 11.2 Wizardry No. 1: Full Holograms Create Real Emotions 292 11.3 Volatiles Need a Language Wizard 296 11.4 Wizardry No. 2: The Perfumer in the Jungle of Volatiles to Create Emotions 298 11.5 Wizardry No. 3: End Results Are Music to the Nose 303 References 304 12 Microencapsulation Techniques for Food Flavour 307 Youngjae Byun, Young Teck Kim, Kashappa Goud H. Desai and Hyun Jin Park 12.1 Demands 307 12.2 Microencapsulation in the Food Industry 307 12.3 Techniques and Materials for Flavour Microencapsulation 308 12.3.1 Spray Drying 308 12.3.2 Extrusion 312 12.3.3 Cyclodextrin Inclusion Complexes 314 12.3.4 Helical Inclusion Complexes 316 12.3.5 Fluidized Bed Coating 318 12.3.6 Top Spray Fluidized Bed Coating 318 12.3.7 Bottom Spray System 318 12.3.8 Wurster System 320 12.3.9 Tangential Spray or Rotary Fluidized Bed Coating 320 12.3.10 Coacervation 320 12.3.11 Double or Multiple Emulsion with Freeze Drying 321 12.3.12 Co-Crystallization 322 12.3.13 Spray Chilling and Spray Cooling 322 12.3.14 Supercritical Fluids 323 12.3.15 Other Techniques 323 12.4 Conclusion and Future Trends 325 References 326 13 Profragrances and Properfumes 333 Andreas Herrmann 13.1 Introduction 333 13.2 Release of Alcohols 335 13.2.1 Enzymatic Hydrolysis 335 13.2.2 Neighbouring-Group-Assisted, Non-Enzymatic Hydrolysis 340 13.3 Release of Carbonyl Derivatives 346 13.3.1 Oxidations 346 13.3.2 Reversible Systems 350 13.3.3 Retro 1,4-Additions 354 13.4 Profragrance and Properfume Strategies 356 13.4.1 Performance and Cost Efficiency 356 13.4.2 Stability 357 13.5 Conclusion 357 Acknowledgements 358 References 358 14 Reactions of Biogenic Volatile Organic Compounds in the Atmosphere 363 Russell K. Monson 14.1 Introduction 363 14.2 The Relative Importance of Anthropogenic Versus Biogenic VOC Emissions to Atmospheric Chemistry 364 14.3 Overview of BVOC Oxidation 365 14.4 The Types of Emitted BVOCs and General Roles in Atmospheric Chemistry 370 14.5 Gas Phase Oxidation of BVOCs 372 14.6 Gas Phase Chemistry of BVOCs in Urban and Suburban Airsheds 374 14.7 Gas Phase Chemistry Within and Above Forests 375 14.8 BVOC Emissions and SOA Formation 377 14.9 Conclusion 381 References 381 Index 389

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Book SynopsisCumulenes are organic molecules with two or more cumulative (consecutive) double bonds. Their reactions often proceed at room temperature, with or without a catalyst, and are stereospecific, giving the reaction products in high yields - features characteristic of click reactions.Table of ContentsPreface Acknowledgements 1 General Introduction References 2 1-Carbon Cumulenes 2.1 Sulfines, R2C SO 2.2 Sulfenes, R2C S(O)O 2.3 Other 1-Carbon Cumulenes 3 2-Carbon Cumulenes 3.1 Carbon Oxides, O C O, :CO 3.2 Carbon Sulfides, S C S, S CO 3.3 Carbon Nitrides 3.4 Center Carbon Phosphorallenes, P C P 4 1,2-Dicarbon Cumulenes 4.1 Ketenes, R2C C O 4.2 Thioketenes, R2C C S 4.3 Ketenimines, R2C C NR 4.4 1-Silaallenes, R2C C Si 4.5 1-Phosphaallenes, R2C C P 4.6 Other Metal Allenes 5 1,3-Dicarbon Cumulenes 5.1 Thiocarbonyl S-ylides, R2C S CH2 5.2 2-Azaallenium Salts, R(Ce)C N+ C(Ce)R 5.3 1-Oxa-3-azoniabutatriene Salts, R2C N+ C O 5.4 1-Thia-3-azabutatriene Salts, R2C N+ C S 5.5 Phosphorus Ylides 6 1,2,3-Tricarbon Cumulenes 6.1 Allenes, R2C CR2 6.2 [3] Cumulenes, R2C C C CR2 6.3 [4] Cumulenes, R2C C C C CR2 6.4 [5] Cumulenes, R2C C C C C CR2 7 Noncarbon Cumulenes 7.1 Azides, RN N N 7.2 Triazaallenium Salts, RN N+ NR 7.3 Sulfur Oxides 7.4 Sulfur Nitrides 7.5 Cationic Boron Cumulenes, R2N B NR Index

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Book SynopsisIn-situ monitoring is the use of portable analytical instruments. This work evaluates the developments of the 1980s and 1990s which will form the basis of future sophisticated in situ-monitoring systems. The emphasis is on micro-analytical monitoring techniques and microtechnology.Table of ContentsList of Contributors. Series Preface. Preface. General Concepts (J. Buffle and G. Horvai). Electrochemical and Optical Oxygen Microsensors for In Situ Measurements (R.N. Glud, et al.). Sensors for In Situ pH and pCO2 Measurements in Seawater and at the Sediment-Water Interface (W.J. Cai and C.E. Reimers). Sensors for In Situ Analysis of Sulfide in Aquatic Systems (M. Kuhl and C. Steuckart). Potentiometric Microsensors for In Situ Measurements in Aquatic Environments (D. De Beer). Biosensors for Analysis of Water, Sludge and Sediments with Emphasis on Microscale Biosensors (N.P. Revsbech et al). Continuous Flow Techniques for On Site and In Situ Measurements of Metals and Nutrients in Sea Water (K.S. Johnson, et al.). Dynamic Aspects of In Situ Speciation Processes and Techniques (H.P. van Leeuwen). In Situ voltammetry: Concepts and Practice for Trace Analysis and Speciation (J. Buffle and M-L. Tercier-Waeber). Permeation Liquid Membranes for Field Analysis and Speciation of Trace Compounds in Waters (J. Buffle et al). Dialysis, DET and DGT: In Situ Diffusional Techniques for Studying Water, Sediments and Soils (W. Davison, et al.). Microtechnology for the Development of In Situ Microanalytical Systems (G.C. Fiaccabrino, et al.). Index.

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Book SynopsisAn introductory yet rigorous account of electrolyte solutions which emphasises the connection between the observable macroscopic experimental properties and the interpretations made at the molecular level.Trade Review"…will serve as a resource for chemistry and chemical engineering students…highly recommended." (CHOICE, December 2007)Table of ContentsPreface xix Preliminary Chapter Guidance to Student xxiii List of symbols xxv 1 Concepts and Ideas: Setting the Stage 1 1.1 Electrolyte solutions – what are they? 2 1.2 Ions – simple charged particles or not? 4 1.3 The solvent: structureless or not? 7 1.4 The medium: its structure and the effect of ions on this structure 8 1.5 How can these ideas help in understanding what might happen when an ion is put into a solvent? 9 1.6 Electrostriction 11 1.7 Ideal and non-ideal solutions – what are they? 11 1.8 The ideal electrolyte solution 14 1.9 The non-ideal electrolyte solution 14 1.10 Macroscopic manifestation of non-ideality 15 1.11 Species present in solution 17 1.12 Formation of ion pairs from free ions 17 1.13 Complexes from free ions 21 1.14 Complexes from ions and uncharged ligands 21 1.15 Chelates from free ions 22 1.16 Micelle formation from free ions 22 1.17 Measuring the equilibrium constant: general considerations 23 1.18 Base-lines for theoretical predictions about the behaviour expected for a solution consisting of free ions only, Debye-Hu¨ckel and Fuoss-Onsager theories and the use of Beer’s Law 24 1.19 Ultrasonics 26 1.20 Possibility that specific experimental methods could distinguish between the various types of associated species 29 1.21 Some examples of how chemists could go about inferring the nature of the species present 29 2 The Concept of Chemical Equilibrium: An Introduction 33 2.1 Irreversible and reversible reactions 34 2.2 Composition of equilibrium mixtures, and the approach to equilibrium 34 2.3 Meaning of the term ‘position of equilibrium’ and formulation of the equilibrium constant 35 2.4 Equilibrium and the direction of reaction 39 2.5 A searching problem 44 2.6 The position of equilibrium 45 2.7 Other generalisations about equilibrium 46 2.8 K and pK 46 2.9 Qualitative experimental observations on the effect of temperature on the equilibrium constant, K 47 2.10 Qualitative experimental observations on the effect of pressure on the equilibrium constant, K 49 2.11 Stoichiometric relations 49 2.12 A further relation essential to the description of electrolyte solutions – electrical neutrality 50 3 Acids and Bases: A First Approach 53 3.1 A qualitative description of acid–base equilibria 54 3.2 The self ionisation of water 56 3.3 Strong and weak acids and bases 56 3.4 A more detailed description of acid–base behaviour 57 3.5 Ampholytes 60 3.6 Other situations where acid/base behaviour appears 62 3.7 Formulation of equilibrium constants in acid–base equilibria 66 3.8 Magnitudes of equilibrium constants 67 3.9 The self ionisation of water 67 3.10 Relations between Ka and Kb: expressions for an acid and its conjugate base and for a base and its conjugate acid 68 3.11 Stoichiometric arguments in equilibria calculations 70 3.12 Procedure for calculations on equilibria 71 4 Equilibrium Calculations for Acids and Bases 73 4.1 Calculations on equilibria: weak acids 74 4.2 Some worked examples 80 4.3 Calculations on equilibria: weak bases 85 4.4 Some illustrative problems 90 4.5 Fraction ionised and fraction not ionised for a weak acid; fraction protonated and fraction not protonated for a weak base 97 4.6 Dependence of the fraction ionised on pKa and pH 98 4.7. The effect of dilution on the fraction ionised for weak acids lying roughly in the range: pKa ¼ 4.0 to 10.0 101 4.8 Reassessment of the two approximations: a rigorous expression for a weak acid 103 4.9 Conjugate acids of weak bases 104 4.10 Weak bases 105 4.11 Effect of non-ideality 105 5 Equilibrium Calculations for Salts and Buffers 107 5.1 Aqueous solutions of salts 108 5.2 Salts of strong acids/strong bases 108 5.3 Salts of weak acids/strong bases 108 5.4 Salts of weak bases/strong acids 109 5.5 Salts of weak acids/weak bases 117 5.6 Buffer solutions 119 6 Neutralisation and pH Titration Curves 139 6.1 Neutralisation 140 6.2 pH titration curves 141 6.3 Interpretation of pH titration curves 149 6.4 Polybasic acids 153 6.5 pH titrations of dibasic acids: the calculations 161 6.6 Tribasic acids 166 6.7 Ampholytes 168 7 Ion Pairing, Complex Formation and Solubilities 177 7.1 Ion pair formation 178 7.2 Complex formation 184 7.3 Solubilities of sparingly soluble salts 195 8 Practical Applications of Thermodynamics for Electrolyte Solutions 215 8.1 The first law of thermodynamics 216 8.2 The enthalpy, H 217 8.3 The reversible process 217 8.4 The second law of thermodynamics 217 8.5 Relations between q, w and thermodynamic quantities 218 8.6 Some other definitions of important thermodynamic functions 218 8.7 A very important equation which can now be derived 218 8.8 Relation of emfs to thermodynamic quantities 219 8.9 The thermodynamic criterion of equilibrium 220 8.10 Some further definitions: standard states and standard values 221 8.11 The chemical potential of a substance 221 8.12 Criterion of equilibrium in terms of chemical potentials 222 8.13 Chemical potentials for solids, liquids, gases and solutes 223 8.14 Use of the thermodynamic criterion of equilibrium in the derivation of the algebraic form of the equilibrium constant 224 8.15 The temperature dependence of DHu 230 8.16 The dependence of the equilibrium constant, K, on temperature 231 8.17 The microscopic statistical interpretation of entropy 236 8.18 Dependence of K on pressure 237 8.19 Dependence of DGu on temperature 242 8.20 Dependence of DSu on temperature 242 8.21 The non-ideal case 244 8.22 Chemical potentials and mean activity coefficients 247 8.23 A generalisation 251 8.24 Corrections for non-ideality for experimental equilibrium constants 258 8.25 Some specific examples of the dependence of the equilibrium constant on ionic strength 263 8.26 Graphical corrections for non-ideality 270 8.27 Comparison of non-graphical and graphical methods of correcting for non-ideality 270 8.28 Dependence of fraction ionised and fractiion protonated on ionic strength 271 8.29 Thermodynamic quantities and the effect of non-ideality 271 9 Electrochemical Cells and EMFs 273 9.1 Chemical aspects of the passage of an electric current through a conducting medium 274 9.2 Electrolysis 275 9.3 Electrochemical cells 280 9.4 Some examples of electrodes used in electrochemical cells 285 9.5 Combination of electrodes to make an electrochemical cell 292 9.6 Conventions for writing down the electrochemical cell 293 9.7 One very important point: cells corresponding to a ‘net chemical reaction’ 298 9.8 Liquid junctions in electrochemical cells 298 9.9 Experimental determination of the direction of flow of the electrons, and measurement of the potential difference 305 9.10 Electrode potentials 305 9.11 Standard electrode potentials 306 9.12 Potential difference, electrical work done and DG for the cell reaction 308 9.13 DG for the cell process: the Nernst equation 312 9.14 Methods of expressing concentration 315 9.15 Calculation of standard emfs values for cells and DGu values for reactions 317 9.16 Determination of pH 320 9.17 Determination of equilibrium constants for reactions where K is either very large or very small 322 9.18 Use of concentration cells 324 9.19 ‘Concealed’ concentration cells and similar cells 326 9.20 Determination of equilibrium constants and pK values for reactions which are not directly that for the cell reaction 328 9.21 Use of concentration cells with and without liquid junctions in the determination of transport numbers 343 10 Concepts and Theory of Non-ideality 349 10.1 Evidence for non-ideality in electrolyte solutions 350 10.2 The problem theoretically 351 10.3 Features of the simple Debye-Hu¨ckel model 351 10.4 Aspects of electrostatics which are necessary for an understanding of the procedures used in the Debye-Hückel theory and conductance theory 353 10.5 The ionic atmosphere in more detail 360 10.6 Derivation of the Debye-Hückel theory from the simple Debye-Hückel model 363 10.7 The Debye-Hückel limiting law 380 10.8 Shortcomings of the Debye-Hückel model 382 10.9 Shortcomings in the mathematical derivation of the theory 384 10.10 Modifications and further developments of the theory 385 10.11 Evidence for ion association from Debye-Hückel plots 391 10.12 The Bjerrum theory of ion association 393 10.13 Extensions to higher concentrations 401 10.14 Modern developments in electrolyte theory 402 10.15 Computer simulations 402 10.16 Further developments to the Debye-Hückel theory 404 10.17 Statistical mechanics and distribution functions 409 10.18 Application of distribution functions to the determination of activity coefficients due to Kirkwood; Yvon; Born and Green; and Bogolyubov 414 10.19 A few examples of results from distribution functions 417 10.20 ‘Born-Oppenheimer level’ models 419 10.21 Lattice calculations for concentrated solutions 419 11 Conductance: The Ideal Case 421 11.1 Aspects of physics relevant to the experimental study of conductance in solution 422 11.2 Experimental measurement of the conductivity of a solution 425 11.3 Corrections to the observed conductivity to account for the self ionisation of water 427 11.4 Conductivities and molar conductivities: the ideal case 428 11.5 The physical significance of the molar conductivity, L 431 11.6 Dependence of molar conductivity on concentration for a strong electrolyte: the ideal case 432 11.7 Dependence of molar conductivity on concentration for a weak electrolyte: the ideal case 433 11.8 Determination of L0 436 11.9 Simultaneous determination of K and L0 438 11.10 Problems when an acid or base is so weak that it is never 100% ionised, even in very, very dilute solution 441 11.11 Contributions to the conductivity of an electrolyte solution from the cation and the anion of the electrolyte 441 11.12 Contributions to the molar conductivity from the individual ions 442 11.13 Kohlrausch’s law of independent ionic mobilities 443 11.14 Analysis of the use of conductance measurements for determination of pKas for very weak acids and pKbs for very weak bases: the basic quantities involved 447 11.15 Use of conductance measurements in determining solubility products for sparingly soluble salts 451 11.16 Transport numbers 453 11.17 Ionic mobilities 457 11.18 Abnormal mobility and ionic molar conductivity of H3Oþ(aq) 463 11.19 Measurement of transport numbers 464 12 Theories of Conductance: The Non-ideal Case for Symmetrical Electrolytes 475 12.1 The relaxation effect 476 12.2 The electrophoretic effect 480 12.3 Conductance equations for strong electrolytes taking non-ideality into consideration: early conductance theory 480 12.4 A simple treatment of the derivation of the Debye-Hu¨ckel-Onsager equation 1927 for symmetrical electrolytes 483 12.5 The Fuoss-Onsager equation 1932 488 12.6 Use of the Debye-Hu¨ckel-Onsager equation for symmetrical strong electrolytes which are fully dissociated 488 12.7 Electrolytes showing ion pairing and weak electrolytes which are not fully dissociated 490 12.8 Empirical extensions to the Debye-Hu¨ckel-Onsager 1927 equation 492 12.9 Modern conductance theories for symmetrical electrolytes – post 1950 493 12.10 Fuoss-Onsager 1957: Conductance equation for symmetrical electrolytes 493 12.11 A simple illustration of the effects of ion association on experimental conductance curves 500 12.12 The Fuoss-Onsager equation for associated electrolytes 500 12.13 Range of applicability of Fuoss-Onsager 1957 conductance equation for symmetrical electrolytes 503 12.14 Limitations of the treatment given by the 1957 Fuoss-Onsager conductance equation for symmetrical electrolytes 504 12.15 Manipulation of the 1957 Fuoss-Onsager equation, and later modifications by Fuoss and other workers 505 12.16 Conductance studies over a range of relative permittivities 506 12.17 Fuoss et al. 1978 and later 506 Appendix 1 512 Appendex 2 515 13 Solvation 517 13.1 Classification of solutes: a resume´ 518 13.2 Classification of solvents 518 13.3 Solvent structure 519 13.4 The experimental study of the structure of water 522 13.5 Diffraction studies 522 13.6 The theoretical approach to the radial distribution function for a liquid 526 13.7 Aqueous solutions of electrolytes 526 13.8 Terms used in describing hydration 528 13.9 Traditional methods for measuring solvation numbers 530 13.10 Modern techniques for studying hydration: NMR 533 13.11. Modern techniques of studying hydration: neutron and X-ray diffraction 538 13.12 Modern techniques of studying solvation: AXD diffraction and EXAFS 541 13.13 Modern techniques of studying solvation: computer simulations 542 13.14 Cautionary remarks on the significance of the numerical values of solvation numbers 543 13.15 Sizes of ions 544 13.16 A first model of solvation – the three region model for aqueous electrolyte solutions 544 13.17 Volume changes on solvation 551 13.18 Viscosity data 552 13.19 Concluding comment 552 13.20 Determination of DGu hydration 552 13 21 Determination of DHu hydration 553 13.22 Compilation of entropies of hydration from DGu hydration and DHu hydration 554 13.23 Thermodynamic transfer functions 554 13.24 Solvation of non-polar and apolar molecules – hydrophobic effects 554 13.25 Experimental techniques for studying hydrophobic hydration 556 13.26 Hydrophobic hydration for large charged ions 559 13.27 Hydrophobic interaction 560 13.28 Computer simulations of the hydrophobic effect 560 Subject Matter of Worked Problems 561 Index 563

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Book SynopsisThis is the first volume in the series to concentrate on organo-lithium compounds - the sub series The chemistry of the metal-carbon bond (5 vol) treated organometallics in general. It deals with theoretical/physical/computational apsects, as well as major spectroscopies, such as MS, NMR, IR/UV etc and both biological and industrial applications. * The core of the volume is the synthetic chapters with lots of examples for modern synthetic approaches * Written by key researchers in the field * An invaluable reference source to organic chemists working in academia and industry * Features important reagents in organic synthesisTable of Contents1. Theoretical studies in organolithium chemistry (Eluvathingal D. Jemmis and G. Gopakumar). 2. Lead structures in lithium organic chemistry (Thomas Stey and Dietmar Stalke). 3. Thermochemistry of organolithium compounds (Suzanne W. Slayden and Joel F. Liebman). 4. Solid state NMR spectroscopy in organolithium chemistry (Dan Johnels and Harald G¨unther). 5. Gas phase chemistry of organolithium compounds (Chagit Denekamp). 6. Vibrational spectroscopy of organolithium compounds (I. Pavel, W. Kiefer and D. Stalke). 7. Effects of structural variation on organolithium compounds (Marvin Charton). 8. Analytical aspects of organolithium compounds (Jacob Zabicky). 9. The preparation of organolithium reagents and intermediates (Frederic Leroux, Manfred Schlosser, Elinor Zohar and Ilan Marek). 10. Directed metallation of aromatic compounds (Jonathan Clayden). 11. Arene-catalyzed lithiation (Miguel Yus). 12. Rearrangements of organolithium compounds (Katsuhiko Tomooka). 13. Lithium carbenoids (Manfred Braun). 14. Addition of organolithium reagents to double bonds (Hiroshi Yamataka, K. Yamada and K. Tomioka). 15. Polylithium organic compounds: Syntheses and selected molecular structures (Carsten Strohmann and Daniel Schildbach). 16. alpha-Amino-organolithium compounds (Robert E. Gawley and Iain Coldham). 17. Asymmetric deprotonation with alkyllithium-(--)-sparteine (Dieter Hoppe and Guido Christoph). 18. Reactivity of oxiranes with organolithium reagents (Fabrice Chemla and Emmanuel Vrancken). Author index. Subject index.

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Book SynopsisBioelectrochemistry: Fundamentals, Experimental Techniques and Application, covers the fundamental aspects of the chemistry, physics and biology which underlie this subject area. It describes some of the different experimental techniques that can be used to study bioelectrochemical problems and it describes various applications of biolelectrochemisty including amperometric biosensors, immunoassays, electrochemistry of DNA, biofuel cells, whole cell biosensors, in vivo applications and bioelectrosynthesis. By bringing together these different aspects, this work provides a unique source of information in this area,approaching the subject from a cross-disciplinary viewpoint.Trade Review"All chapters are readable and packed with information, all are well referenced and up-to-date. The bookis highly recommended to those with interests in bioelectrochemistry and its applications." (Chromatographia, September 2010)Table of ContentsList of Contributors. Preface. 1 Bioenergetics and Biological Electron Transport (Philip N. Bartlett). 1.1 Introduction. 1.2 Biological Cells. 1.3 Chemiosmosis. 1.3.1 The Proton Motive Force. 1.3.2 The Synthesis of ATP. 1.4 Electron Transport Chains. 1.4.1 The Mitochondrion. 1.4.2 The NADH–CoQ Reductase Complex. 1.4.3 The Succinate–CoQ Reductase Complex. 1.4.4 The CoQH2–Cyt c Reductase Complex. 1.4.5 The Cyt c Oxidase Complex. 1.4.6 Electron Transport Chains in Bacteria. 1.4.7 Electron Transfer in Photosynthesis. 1.4.8 Photosystem II. 1.4.9 Cytochrome bf Complex. 1.4.10 Photosystem I. 1.4.11 Bacterial Photosynthesis. 1.5 Redox Components. 1.5.1 Quinones. 1.5.2 Flavins. 1.5.3 NAD(P)H. 1.5.4 Hemes. 1.5.5 Iron–Sulfur Clusters. 1.5.6 Copper Centres. 1.6 Governing Principles. 1.6.1 Spatial Separation. 1.6.2 Energetics: Redox Potentials. 1.6.3 Kinetics: Electron Transfer Rate Constants. 1.6.4 Size of Proteins. 1.6.5 One-Electron and Two-Electron Couples. 1.7 ATP Synthase. 1.8 Conclusion. References. 2 Electrochemistry of Redox Enzymes (James F. Rusling, Bingquan Wang and Sei-eok Yun). 2.1 Introduction. 2.1.1 Historical Perspective. 2.1.2 Examples of Soluble Mediators. 2.1.3 Development of Protein-Film Voltammetry and Direct Enzyme Electrochemistry. 2.2 Mediated Enzyme Electrochemistry. 2.2.1 Electron Mediation. 2.2.2 Wiring with Redox Metallopolymer Hydrogels. 2.2.3 Wiring with Conducting Polymers. 2.2.4 NAD(P)þ/NAD(P)H Dependent Enzymes. 2.2.5 Regeneration of NAD(P)H from NAD(P)þ. 2.2.6 Regeneration of NAD(P)þ from NAD(P)H. 2.3 Direct Electron Transfer between Electrodes and Enzymes. 2.3.1 Enzymes in Solution. 2.3.2 Enzyme-Film Voltammetry: Basic Theory. 2.3.3 Adsorbed and Coadsorbed Enzyme Monolayers. 2.3.4 Self-Assembled Monolayers and Covalently Attached Enzymes. 2.3.5 Enzymes on Carbon Nanotube Electrodes. 2.3.6 Enzymes in Lipid Bilayer Films. 2.3.7 Polyion Films and Layer-by-Layer Methods. 2.4 Outlook for the Future. Acknowledgements. References. 3 Biological Membranes and Membrane Mimics (Tibor Hianik). 3.1 Introduction. 3.2 Membrane Structure and Composition. 3.2.1 Membrane Structure. 3.2.2 Membrane Lipids. 3.2.3 Membrane Proteins. 3.3 Models of Membrane Structure. 3.3.1 Lipid Monolayers. 3.3.2 Bilayer Lipid Membranes (BLM). 3.3.3 Supported Bilayer Lipid Membranes. 3.3.4 Liposomes. 3.4 Ordering, Conformation and Molecular Dynamics of Lipid Bilayers. 3.4.1 Structural Parameters of Lipid Bilayers Measured by X-ray Diffraction. 3.4.2 Interactions between Bilayers. 3.4.3 Dynamics and Order Parameters of Bilayers Determined by EPR and NMR Spectroscopy and by Optical Spectroscopy Methods. 3.5 Phase Transitions of Lipid Bilayers. 3.5.1 Lyotropic and Thermotropic Transitions. 3.5.2 Thermodynamics of Phase Transitions. 3.5.3 Trans–Gauche Isomerization. 3.5.4 Order Parameter. 3.5.5 Cooperativity of Transition. 3.5.6 Theory of Phase Transitions. 3.6 Mechanical Properties of Lipid Bilayers. 3.6.1 Anisotropy of Mechanical Properties of Lipid Bilayers. 3.6.2 The Model of an Elastic Bilayer. 3.6.3 Mechanical Properties of Lipid Bilayers and Protein–Lipid Interactions. 3.7 Membrane Potentials. 3.7.1 Diffusion Potential. 3.7.2 Electrostatic Potentials. 3.7.3 Methods of Surface Potential Measurement. 3.8 Dielectric Relaxation. 3.8.1 The Basic Principles of the Measurement of Dielectric Relaxation. 3.8.2 Application of the Method of Dielectric Relaxation to BLMs and sBLMs. 3.9 Transport Through Membranes. 3.9.1 Passive Diffusion. 3.9.2 Facilitated Diffusion of Charged Species Across Membranes. 3.9.3 Mechanisms of Ionic Transport. 3.9.4 Active Transport Systems. 3.10 Membrane Receptors and Cell Signaling. 3.10.1 Physical Reception. 3.10.2 Principles of Hormonal Reception. 3.10.3 Taste and Smell Reception. 3.11 Lipid-Film Coated Electrodes. 3.11.1 Modification of Lipid-Film Coated Electrodes by Functional Macromolecules. 3.11.2 Bioelectrochemical and Analytical Applications of Lipid Coated Electrodes. Acknowledgements. References. 4 NAD(P)-Based Biosensors (L. Gorton and P. N. Bartlett). 4.1 Introduction. 4.2 Electrochemistry of NAD(P)þ/NAD(P)H. 4.3 Direct Electrochemical Oxidation of NAD(P)H. 4.3.1 General Observations. 4.3.2 Effect of Adsorption. 4.3.3 Mechanism and Kinetics. 4.4 Soluble Cofactors. 4.4.1 Implications of the Low Eo0 Value for Practical Applications. 4.4.2 Special Prerequisites for Biosensors Based on NAD(P)-Dependent Dehydrogenases. 4.5 Mediators for Electrocatalytic NAD(P)H Oxidation. 4.5.1 Other Mediating Functionalities and Metal Coated Electrodes. 4.5.2 Electropolymerisation. 4.5.3 Carbon Paste. 4.5.4 Gold Nanoparticles. 4.6 Construction of Biosensors from NAD(P)H-Dependent Dehydrogenases. 4.6.1 Entrapment Behind a Membrane. 4.6.2 Covalent Attachment to a Nylon Net or Membrane. 4.6.3 Cross-Linking. 4.6.4 Entrapment in a Polymer Film. 4.6.5 Carbon Paste. 4.6.6 Self-Assembled Monolayers. 4.7 Conclusions. Acknowledgements. References. 5 Glucose Biosensors (Josep M. Montornes, Mark S. Vreeke and Ioanis Katakis). 5.1 Introduction to Glucose Sensors. 5.2 Biosensors. 5.2.1 Types of Sensors. 5.2.2 Transduction Mode. 5.3 Application Areas. 5.3.1 Clinical. 5.3.2 Food and Fermentation. 5.4 Design Requirements. 5.4.1 Disposable Glucose Sensor. 5.4.2 Continuous Glucose Sensor. 5.4.3 Implantable Glucose Sensor. 5.5 Biosensor Construction. 5.5.1 Artificial Mediators. 5.5.2 Immobilization of GOx. 5.5.3 Inner and Outer Membrane Function. 5.6 From Product Design Requirements to Performance. 5.6.1 Design Exercise for the Disposable Glucose Sensor. 5.7 Conclusions. Acknowledgement. References. 6 Phenolic Biosensors (Ulla Wollenberger, Fred Lisdat, Andreas Rose and Katrin Streffer). 6.1 Introduction. 6.2 Enzymes Used for Phenol Biosensors. 6.2.1 Phenol Oxidation by Water-Producing Oxidases and Oxygenases. 6.2.2 Reducing Enzymes. 6.3 Design of Phenol Biosensors. 6.3.1 Oxygen Consumption. 6.3.2 Bioelectrocatalysis Based on Phenol-Oxidizing Enzymes. 6.3.3 Electrocatalytic Sensors Based on Quinone-Reducing Enzymes. 6.4 Applications. 6.4.1 Waste Water Treatment. 6.4.2 Sensitive Label Detectors. 6.4.3 Catecholamines. 6.5 Summary and Conclusions. Acknowledgements. References. 7 Whole-Cell Biosensors (H. Shiku, K. Nagamine, T. Kaya, T. Yasukawa and T. Matsue). 7.1 Introduction. 7.2 Whole-Cell Biosensors Probing Cellular Functions. 7.2.1 Redox Reactions in Whole Cells. 7.2.2 Responses on a Microbial Chip with Collagen Gel. 7.3 Whole-Cell Microdevices Fabricated Using Bio-MEMS Technologies. 7.3.1 Potentiometric Devices: LAPS and ISFET. 7.3.2 Other Electrochemical Devices: Amperometric and Impedance Sensors. 7.3.3 Improvement of Cell Culture within Microenvironments. 7.4 Genetically Engineered Whole-Cell Microdevices. 7.4.1 Sensors with Gene-Modified Bacteria. 7.4.2 Transcriptional Responses on a Microbial Chip with Collagen Gel. 7.4.3 Cellular Devices for High-Throughput Screening. 7.4.4 Microdevice for On-Chip Transfection and On-Chip Transformation. 7.5 Conclusions. References. 8 Modelling Biosensor Responses (P. N. Bartlett, C. S. Toh, E. J. Calvo and V. Flexer). 8.1 Introduction. 8.2 Enzyme Kinetics. 8.2.1 Equilibrium and Steady-State. 8.2.2 Analysis of Enzyme Kinetic Data. 8.2.3 The Significance of KMS for Biosensor Applications. 8.3 Modelling Enzyme Electrodes. 8.3.1 The Flux Diagram for the Membrane|Enzyme|Electrode. 8.3.2 Solving the Coupled Diffusion/Reaction Problem for the Membrane Enzyme|Electrode. 8.3.3 Deriving a Complete Kinetic Model. 8.3.4 Experimental Verification of Approximate Analytical Kinetic Models. 8.4 Numerical Simulation Methods. 8.4.1 Explicit Numerical Methods. 8.4.2 The Crank–Nicholson Method. 8.4.3 Other Simulation Methods. 8.5 Modelling Redox Mediated Enzyme Electrodes. 8.5.1 Steady-State Kinetics. 8.5.2 Homogeneous Mediated Enzyme Electrode. 8.6 Modelling Homogeneous Enzyme with Attached Redox Mediator. 8.7 Non-Steady-State Techniques for Homogeneous Enzyme Systems. 8.7.1 Extraction of Kinetic Parameters. 8.8 The Heterogeneous Mediated Mechanism. 8.8.1 Enzyme Monolayers with Soluble Redox Mediator. 8.8.2 Enzyme Multilayers. 8.9 Conclusions. Acknowledgements. References. 9 Bioelectrosynthesis–Electrolysis and Electrodialysis (Derek Pletcher). 9.1 Introduction. 9.2 Setting the Scene. 9.2.1 Electrolytic Production of Organic Compounds. 9.2.2 Technological Factors. 9.2.3 Enzymes in Organic Synthesis. 9.2.4 Combining Enzyme Chemistry and Electrosynthesis. 9.3 Mechanisms of and Approaches to Bioelectrosynthesis. 9.3.1 Homogeneous Systems. 9.3.2 Electrode Coatings. 9.4 Examples of Syntheses. 9.4.1 The Oxidation of Alcohols and Diols. 9.4.2 The Oxidation of 4-Alkylphenols. 9.4.3 The Synthesis of Dihydroxyacetone Phosphate. 9.4.4 The Site Specific Oxidation of Sugars. 9.4.5 Hydroxylation of Unactivated C–H Bonds. 9.4.6 Reduction of Carbonyl Compounds. 9.4.7 Hydrogenation. 9.4.8 Conclusions. 9.5 Electrodialysis. 9.6 Conclusions. References. 10 Biofuel Cells (G. Tayhas R. Palmore). 10.1 Introduction. 10.2 Fundamentals of Fuel Cells. 10.2.1 How Fuel Cells Work. 10.2.2 Equations that Govern the Performance of a Fuel Cell. 10.3 Economics of Conventional Fuel Cells and Biofuel Cells. 10.4 Biofuel Cells that use Micro-Organisms as the Catalytic Element. 10.5 Biofuel Cells that use Oxidoreductases as the Catalytic Element. 10.6 Future Directions in Biofuel Cell Research. Acknowledgements. References. 11 Electrochemical Immunoassays (Julia Yakovleva and Jenny Emneus). 11.1 Introduction. 11.2 Basic Concepts in Immunoassay. 11.2.1 Antibodies: Structure, Properties and Production. 11.2.2 Classification of Immunoassays. 11.3 Electrochemical Immunoassays (ECIA). 11.3.1 Labels in ECIAs. 11.3.2 Electrochemical Detection Principles. 11.4 Different Assay Formats and Applications. 11.4.1 Heterogeneous ECIA. 11.4.2 Homogeneous ECIAs. 11.4.3 Electrochemical Immunosensors. 11.5 Future Perspectives and Recent Trends. References. 12 Electrochemical DNA Assays (Ana Maria Oliveira-Brett). 12.1 Introduction. 12.2 Electrochemistry of DNA. 12.2.1 Reduction. 12.2.2 Oxidation. 12.3 Adsorption of DNA at Electrode Surfaces. 12.3.1 Guanine Adsorbates. 12.3.2 Adsorbed dsDNA and ssDNA. 12.4 Electrochemistry for Sensing/Probing DNA Interactions. 12.4.1 Biomarkers for DNA Damage. 12.4.2 DNA–Metal Interactions. 12.4.3 DNA–Drug Interactions. 12.5 DNA Electrochemical Biosensors. 12.5.1 In Situ DNA Oxidative Damage. 12.5.2 DNA Hybridisation. 12.5.3 DNA Microarrays. 12.6 Conclusions. Acknowledgements. References. 13 In Vivo Applications: Glucose Monitoring, Fuel Cells (P. Vadgama and M. Schoenleber). 13.1 Introduction. 13.2 Biocompatibility. 13.2.1 General Concepts. 13.2.2 Protein Constituents. 13.2.3 Blood. 13.2.4 Tissue. 13.3 Materials Interfacing Strategy. 13.4 Implanted Glucose Biosensors. 13.4.1 Electrode Designs for Tissue Monitoring. 13.4.2 Electrode Designs for Blood Monitoring. 13.4.3 Early Phase Tissue Response. 13.4.4 Open Microflow. 13.4.5 Bioelectrochemical Fuel Cells. 13.5 Conclusions. References. Index.

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Book SynopsisProvides the basic skills and information required to prepare an environmental sample for analysis. Divided into two sections, Inorganic Analysis and Organic Analysis, this book covers techniques such as atomic spectroscopy and chromatography.Trade Review"...covers one of the most neglected areas in environmental trace analysis, namely that of sample preparation." (Environment Times , January 2003) “…covers one of the most neglected areas in environmental trace analysis…very detailed, highly illustrated, and easy to read” (International Journal of Environmental Analytical Chemistry 2004)Table of ContentsSeries Preface. Preface. Acronyms, Abbreviations and Symbols. About the Author. Basic Laboratory Skills. Investigative Approach for Sample Preparation. Sampling. Storage of Samples. SAMPLE PREPARATION OF INORGANIC ANALYSIS. Solids. Liquids – Natural and Waste Waters. SAMPLE PREPARATION FOR ORGANIC ANALYSIS. Solids. Liquids. Volatile Compounds. Pre-Concentration Using Solvent Evaporation. Instrumental Techniques for Trace Analysis. Recording of Information in the Laboratory and Selected Resources. Responses to Self-Assessment Questions. Glossary of Terms. SI Units and Physical Constants. Periodic Table. Index.

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Book SynopsisProvides a systematic guide to unraveling structural information from the NMR spectra of unknown synthetic and natural compounds.Table of ContentsPreface. Preface to the First Edition. Symbols and Abbreviations. Short Introduction to Basic Principles and Methods. Recognition of Structural Fragments by NMR. Problems. Solutions to Problems. References. Formula Index of Solutions to Problems. Subject Index.

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Book SynopsisImproving upon excellence, this second edition of its best-selling predecessor brings to synthetic organic chemists the many applications of organopalladium chemistry, highlighting the most recent discoveries in this rapidly expanding field. This is an ideal text/reference book for those studying this topics.Trade Review"... covers the vast amount of innovation that has occurred in this important chemistry field in the last several years." (E-STREAMS, September 2005) "This book is beautifully illustrated, very well referenced and covers a wide range of exciting synthetic methods...." (Applied Organometallic Chemistry, March 2005) "...amazing that a single book of such scope could actually be written...achieved just the right balance..." (www.organische-chemie.ch, 08 June 2004) "...For the modest price, this book should find its way onto the shelves of all good chemistry libraries...." (Chemistry & Industry, No.22 15th November, 2004)Table of ContentsPreface. Abbreviations. 1 The Basic Chemistry of Organopalladium Compounds. 1.1 Characteristic Features of Pd-Promoted or –Catalyzed Reactions. 1.2 Palladium Compounds, Complexes, and Ligands Widely Used in Organic Synthesis. 1.3 Fundamental Reactions of Pd Compounds. 1.3.1 ‘Oxidative’ Addition. 1.3.2 Insertion. 1.3.3 Transmetallation. 1.3.4 Reductive Elimination. 1.3.5 β-H Elimination (β-Elimination, Dehydropalladation). 1.3.6 Elimination of β-Heteroatom Groups and β-Carbon. 1.3.7 Electrophilic Attack by Organopalladium Species. 1.3.8 Termination of Pd-Catalyzed or –Promoted Reactions and a Catalytic Cycle. 1.3.9 Reactions Involving Pd(II) Compounds and Pd(0) Complexes. References. 2 Oxidative Reactions with Pd(II) Compounds. 2.1 Introduction. 2.2 Reactions of Alkenes. 2.2.1 Introducti on. 2.2.2 Reaction with Water. 2.2.3 Reactions with Alcohols and Phenols. 2.2.4 Reactions with Carboxylic Acids. 2.2.5 Reactions with Amines. 2.2.6 Reactions with Carbon Nucleophiles. 2.2.7 Oxidative Carbonylation. 2.2.8 Reactions with Aromatic Compounds. 2.2.9 Coupling of Alkenes with Organometallic Compounds. 2.3 Stoichiometric Reactions of π-Allyl Complexes. 2.4 Reactions of Conjugated Dienes. 2.5 Reactions of Allenes. 2.6 Reaction of Alkynes. 2.7 Homocoupling and Oxidative Substitution Reactions of Aromatic Compounds. 2.8 Regioselective Reactions Based on Chelation and Participation of Heteroatoms. 2.9 Oxidative Carbonylation of Alcohols and Amines. 2.10 Oxidation of Alcohols. 2.11 Enone Formation from Ketones and Cycloalkenylation. References. 3 Pd(0)-Catalyzed Reactions of sp2Organic Halides and Pseudohalides. 3.1 Introduction. 3.2 Reactions with Alkenes (Mizoroki–Heck Reaction). 3.2.1 Introduction. 3.2.2 Catalysts and Ligands. 3.2.3 Reaction Conditions (Bases, Solvents, and Additives). 3.2.4 Halides and Pseudohalides. 3.2.5 Alkenes. 3.2.6 Formation of Neopentylpalladium and its Termination by Anion Capture. 3.2.7 Intramolecular Reactions. 3.2.8. Asymmetric Reactions. 3.2.9 Reactions with 1,2-, 1,3-, and 1,4-Dienes. 3.2.10 Amino Heck Reactions of Oximes. References. 3.3 Reactions of Aromatics and Heteroaromatics. 3.3.1 Arylation of Heterocycles. 3.3.2 Intermolecular Arylation of Phenols. 3.3.3 Intermolecular Polyarylation of Ketones. 3.3.4 Intramolecular Arylation of Aromatics. References. 3.4 Reactions with Alkynes. 3.4.1 Introduction. 3.4.2 Reactions of Terminal Alkynes to Form Aryl- and Alkenylalkynes (Sonogashira Coupling). References. 3.4.3 Reactions of Internal and Terminal Alkynes with Aryl and Alkenyl Halides via Insertion. References. 3.5 Carbonylation and Reactions of Acyl Chlorides. 3.5.1 Introduction. 3.5.2 Formation of Carboxylic Acids, Esters, and Amides. 3.5.3 Formation of Aldehydes and Ketones. 3.5.4 Reactions of Acyl Halides and Related Compounds. 3.5.5 Miscellaneous Reactions. References. 3.6 Cross-Coupling Reactions with Organometallic Compounds of the Main Group Metals via Transmetallation. 3.6.1 Introduction. 3.6.2 Organoboron Compounds (Suzuki–Miyaura Coupling). References. 3.6.3 Organostannanes (Kosugi–Migita–Stille Coupling). 3.6.4 Organozinc Compounds (Negishi Coupling). 3.6.5 Organomagnesium Compounds. 3.6.6 Organosilicon Compounds (Hiyama Coupling). References. 3.7 Arylation and Alkenylation of C, N, O, S, and P Nucleophiles. 3.7.1 α-Arylation and α-Alkenylation of Carbon Nucleophiles. 3.7.2 Intramolecular Attack of Aryl Halides on Carbonyl Groups. References. 3.7.3 Arylation of Nitrogen Nucleophiles. References. 3.7.4 Arylation of Phenols, Alcohols, and Thiols. References. 3.7.5 Arylation of Phosphines, Phosphonates, and Phosphinates. References. 3.8 Miscellaneous Reactions of Aryl Halides. 3.8.1 The Catellani Reactions using Norbornene as a Template for ortho-Substitution. References. 3.8.2 Reactions of Alcohols with Aryl Halides Involving β-Carbon Elimination. References. 3.8.3 Hydrogenolysis with Various Hydrides. 3.8.4 Homocoupling of Organic Halides (Reductive Coupling). References. 4 Pd(0)-Catalyzed Reactions of Allylic Compounds via Π-Allylpalladium Complexes. 4.1 Introduction and Range of Leaving Groups. 4.2 Allylation. 4.2.1 Stereo- and Regiochemistry of Allylation. 4.2.2 Asymmetric Allylation. 4.2.3 Allylation of Stabilized Carbon Nucleophiles. 4.2.4 Allylation of Oxygen and Nitrogen Nucleophiles. 4.2.5 Allylation with Bis-Allylic Compounds and Cycloadditions. 4.3 Reactions with Main Group Organometallic Compounds via Transmetallation. 4.3.1 Cross-Coupling with Main Group Organometallic Compounds. 4.3.2 Formation of Allylic Metal Compounds. 4.3.3 Allylation Involving Umpolung. 4.3.4 Reactions of Amphiphilic Bis-π -Allylpalladium Compounds. 4.4 Carbonylation Reactions. 4.5 Intramolecular Reactions with Alkenes and Alkynes. 4.6 Hydrogenolysis of Allylic Compounds. 4.6.1 Preparation of 1-Alkenes by Hydrogenolysis with Formates. 4.6.2 Hydrogenolysis of Internal and Cyclic Allylic Compounds. 4.7 Allyl Group as a Protecting Group. 4.8 1,4-Elimination. 4.9 Reactions via π -Allylpalladium Enolates. 4.9.1 Generation of π -Allylpalladium Enolates from Silyl and Tin Enolates. 4.9.2 Reactions of Allyl β-Keto Carboxylates and Related Compounds. 4.10 Pd(0) and Pd(II)-Catalyzed Allylic Rearrangement. 4.11 Reactions of 2,3-Alkadienyl Derivatives via Methylene-π -allylpalladiums. References. 5 Pd(0)-Catalyzed Reactions of 1,3-Dienes, 1,2-Dienes (Allenes), and Methylenecyclopropanes. 5.1 Reactions of Conjugated Dienes. 5.2 Reactions of Allenes. 5.2.1 Introduction. 5.2.2 Reactions with Pronucleophiles. 5.2.3 Carbonylation. 5.2.4 Hydrometallation and Dimetallation. 5.2.5 Miscellaneous Reactions. 5.3 Reactions of Methylenecyclopropanes. 5.3.1 Introduction. 5.3.2 Hydrostannation and Dimetallation. 5.3.3 Hydrocarbonation and Hydroamination. References. 6 Pd(0)-Catalyzed Reactions of Propargyl Compounds. 6.1 Introduction and Classification of Reactions. 6.2 Reactions via Insertion of Alkenes and Alkynes. 6.3 Carbonylations. 6.4 Reactions of Main Group Metal Compounds. 6.5 Reactions of Terminal Alkynes; Formation of 1,2-Alkadien-4-ynes. 6.6 Reactions of Nucleophiles on Central sp Carbon of Allenylpalladium Intermediates. 6.7 Hydrogenolysis and Elimination of Propargyl Compounds. References. 7 Pd(0)- and Pd(II)-Catalyzed Reactions of Alkynes and Benzynes. 7.1 Reactions of Alkynes. 7.1.1 Carbonylation. 7.1.2 Hydroarylation. 7.1.3 Hydroamination, Hydrocarbonation, and Related Reactions. 7.1.4 Hydrometallation and Hydro-Heteroatom Addition. 7.1.5 Dimetallation and Related Reactions. 7.1.6 Cyclization of 1,6-Enynes and 1,7-Diynes. 7.1.7 Benzannulation. 7.1.8 Homo- and Cross-Coupling of Alkynes. 7.1.9 Miscellaneous Reactions. 7.2 Reactions of Benzynes. 7.2.1 Cyclotrimerization and Cocyclization. 7.2.2 Addition Reactions of Arynes 595 References. 8 Pd(0)-Catalyzed Reactions of Alkenes. 8.1 Carbonylation. 8.2 Hydroamination. 8.3 Hydrometallation. 8.4 Miscellaneous Reactions. References. 9 Pd(0)-Catalyzed Miscellaneous Reactions of Carbon Monoxide. References. 10 Miscellaneous Reactions Catalyzed by Chiral and Achiral Pd(II) Complexes. References. Tables 1.1 to 1.18. Index.

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Book SynopsisThe statistics book for the non-statistician A practical handbook aimed at the working scientist, it covers the application of statistical and mathematical methods to the design of performance chemicals, such as pharmaceuticals, agrochemicals, fragrances, flavours and paints Highly qualified and internationally respected author.Trade Review“Written by a highly qualified internationally respected author this text is of practical use to chemists, biochemists, pharmacists, biologists and researchers from many other scientific disciplines in both industry and academia.” (International Journal Microstructure & Materials Properties, 1 October 2011) "At the same time, the highly detailed, thoughtful and readable explanation of statistical and data-mining concepts throughout the book will make it a valuable addition to the libraries of a wide range of researchers . . . It is definitely worth its purchase price and may be considered seriously as a textbook for nonmajor statistics students and research scientists in a wide variety of fields." (The American Statistician, 1 May 2011) "The book is recommended for readers interested, but not experienced, in data analysis methods used in drug design, pharmaceutical research or related areas. It provides an almost mathematical-free introduction to some multivariate statistical methods applied in these fields. Also the great experience and the personal views of a highly qualified author may be interesting for many scientists." (Zentralblatt Math, 2010) "This book should provide those engaged in multidimensional experimentation a relatively compact (under 400 pages) oversight of the relative merits of numerous techniques, all of which are heavily computer dependent, and will be of especial interest to those working in the field of pharmaceutical research. It should also draw their attention to the roots of complex methods by means of its introductory chapters." (Chromatographia, October 2010) "This book is a guide to the wide range of methods available. Not surprisingly given the author’s background, the examples in the book are all chemical and hence it will be of most interest and value to chemistry researchers.” (Chemistry World, May 2010)Table of ContentsPreface xi Abbreviations xiii 1 Introduction: Data and Its Properties, Analytical Methods and Jargon 1 1.1 Introduction 2 1.2 Types of Data 3 1.3 Sources of Data 5 1.3.1 Dependent Data 5 1.3.2 Independent Data 6 1.4 The Nature of Data 7 1.4.1 Types of Data and Scales of Measurement 8 1.4.2 Data Distribution 10 1.4.3 Deviations in Distribution 15 1.5 Analytical Methods 19 1.6 Summary 23 References 23 2 Experimental Design – Experiment and Set Selection 25 2.1 What is Experimental Design? 25 2.2 Experimental Design Techniques 27 2.2.1 Single-factor Design Methods 31 2.2.2 Factorial Design (Multiple-factor Design) 33 2.2.3 D-optimal Design 38 2.3 Strategies for Compound Selection 40 2.4 High Throughput Experiments 51 2.5 Summary 53 References 54 3 Data Pre-treatment and Variable Selection 57 3.1 Introduction 57 3.2 Data Distribution 58 3.3 Scaling 60 3.4 Correlations 62 3.5 Data Reduction 63 3.6 Variable Selection 67 3.7 Summary 72 References 73 4 Data Display 75 4.1 Introduction 75 4.2 Linear Methods 77 4.3 Nonlinear Methods 94 4.3.1 Nonlinear Mapping 94 4.3.2 Self-organizing Map 105 4.4 Faces, Flowerplots and Friends 110 4.5 Summary 113 References 116 5 Unsupervised Learning 119 5.1 Introduction 119 5.2 Nearest-neighbour Methods 120 5.3 Factor Analysis 125 5.4 Cluster Analysis 135 5.5 Cluster Significance Analysis 140 5.6 Summary 143 References 144 6 Regression Analysis 145 6.1 Introduction 145 6.2 Simple Linear Regression 146 6.3 Multiple Linear Regression 154 6.3.1 Creating Multiple Regression Models 159 6.3.1.1 Forward Inclusion 159 6.3.1.2 Backward Elimination 161 6.3.1.3 Stepwise Regression 163 6.3.1.4 All Subsets 164 6.3.1.5 Model Selection by Genetic Algorithm 165 6.3.2 Nonlinear Regression Models 167 6.3.3 Regression with Indicator Variables 169 6.4 Multiple Regression: Robustness, Chance Effects, the Comparison of Models and Selection Bias 174 6.4.1 Robustness (Cross-validation) 174 6.4.2 Chance Effects 177 6.4.3 Comparison of Regression Models 178 6.4.4 Selection Bias 180 6.5 Summary 183 References 184 7 Supervised Learning 187 7.1 Introduction 187 7.2 Discriminant Techniques 188 7.2.1 Discriminant Analysis 188 7.2.2 SIMCA 195 7.2.3 Confusion Matrices 198 7.2.4 Conditions and Cautions for Discriminant Analysis 201 7.3 Regression on Principal Components and PLS 202 7.3.1 Regression on Principal Components 203 7.3.2 Partial Least Squares 206 7.3.3 Continuum Regression 211 7.4 Feature Selection 214 7.5 Summary 216 References 217 8 Multivariate Dependent Data 219 8.1 Introduction 219 8.2 Principal Components and Factor Analysis 221 8.3 Cluster Analysis 230 8.4 Spectral Map Analysis 233 8.5 Models with Multivariate Dependent and Independent Data 238 8.6 Summary 246 References 247 9 Artificial Intelligence and Friends 249 9.1 Introduction 250 9.2 Expert Systems 251 9.2.1 LogP Prediction 252 9.2.2 Toxicity Prediction 261 9.2.3 Reaction and Structure Prediction 268 9.3 Neural Networks 273 9.3.1 Data Display Using ANN 277 9.3.2 Data Analysis Using ANN 280 9.3.3 Building ANN Models 287 9.3.4 Interrogating ANN Models 292 9.4 Miscellaneous AI Techniques 295 9.5 Genetic Methods 301 9.6 Consensus Models 303 9.7 Summary 304 References 305 10 Molecular Design 309 10.1 The Need for Molecular Design 309 10.2 What is QSAR/QSPR? 310 10.3 Why Look for Quantitative Relationships? 321 10.4 Modelling Chemistry 323 10.5 Molecular Fields and Surfaces 325 10.6 Mixtures 327 10.7 Summary 329 References 330 Index 333

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Book SynopsisMolecular Symmetry lays out the formal language in the area using illustrative examples of particular molecules throughout. It then applies the ideas of symmetry to describe molecular structure, bonding in molecules and consider the implications in spectroscopy.Trade Review"The work will prove to be a popular choice as a textbook or as an additional resource for group theory and advanced inorganic chemistry courses." (CHOICE, November 2009) “A major strength of this book is its accessibility to the practically and conceptually minded chemist; the reader is led into the subject through strong visual presentation of the ideas and although the mathematics is by no means ignored, it is presented within an applied context.“ (The Higher Education Academy Physical Sciences Centre Reviews, May 2009)Table of ContentsPreface. 1. Symmetry Elements and Operations. 1.1 Introduction. 1.2 Symmetry Elements and Operations. 1.3 Examples of the Impact of Geometric Symmetry on Chemistry. 1.4 Summary. 1.5 Self-Test Questions. Further Reading. 2. More Symmetry Operations and Products of Operations. 2.1 Introduction. 2.2 Background to Point Groups. 2.3 Closed Groups and New Operations. 2.4 Properties of Symmetry Operations. 2.5 Chirality and Symmetry. 2.6 Summary. 2.7 Completed Multiplication Tables. 2.8 Self-Test Questions. 3. The Point Groups Used with Molecules. 3.1 Introduction. 3.2 Molecular Classification Using Symmetry Operations. 3.3 Constructing Reference Models with Idealized Symmetry. 3.4 The Nonaxial Groups: Cs,Ci,C1. 3.5 The Cyclic Groups: Cn, Sn. 3.6 Axial Groups Containing Mirror Planes: Cnh and Cnv. 3.6.1 Examples of Axial Groups Containing Mirror Planes: Cnh and Cnv. 3.7 Axial Groups with Multiple Rotation Axes: Dn, Dnd and Dnh. 3.8 Special Groups for Linear Molecules: Cìv and Dìh. 3.9 The Cubic Groups: Td and Oh. 3.10 Assigning Point Groups to Molecules. 3.11 Example Point Group Assignments. 3.12 Self-Test Questions. 4. Point Group Representations, Matrices and Basis Sets. 4.1 Introduction. 4.2 Symmetry Representations and Characters. 4.3 Multiplication Tables for Character Representations. 4.4 Matrices and Symmetry Operations. 4.5 Diagonal and Off-Diagonal Matrix Elements. 4.6 The Trace of a Matrix as the Character for an Operation. 4.7 Noninteger Characters. 4.8 Reducible Representations. 4.9 Classes of Operations. 4.10 Degenerate Irreducible Representations. 4.11 The Labelling of Irreducible Representations. 4.12 Summary. 4.13 Completed Tables. 4.14 Self-Test Questions. Further Reading. 5. Reducible and Irreducible Representations. 5.1 Introduction. 5.2 Irreducible Representations and Molecular Vibrations. 5.3 Finding Reducible Representations. 5.4 Properties of Point Groups and Irreducible Representations. 5.5 The Reduction Formula. 5.6 A Complete Set of Vibrational Modes for H2O. 5.7 Choosing the Basis Set. 5.8 The d-Orbitals in Common Transition Metal Complex Geometries. 5.9 Linear Molecules: Groups of Infinite Order. 5.10 Summary. 5.11 Self-Test Questions. 6. Applications in Vibrational Spectroscopy. 6.1 Introduction. 6.2 Selection Rules. 6.3 General Approach to Analysing Vibrational Spectroscopy. 6.4 Symmetry-Adapted Linear Combinations. 6.5 Normalization. 6.6 The Projector Operator Method. 6.7 Linking Results for Symmetry-Inequivalent Sets of Atoms. 6.8 Additional Examples. 6.9 Summary. 6.10 Self-Test Questions. Further Reading. 7. Symmetry in Chemical Bonding. 7.1 Introduction. 7.2 Bond Energies. 7.3 The Relative Energies of Hydrogen-Like Atomic Orbitals. 7.4 The Molecules Formed by Other Second-Row Elements with Hydrogen. 7.5 The Second-Row Diatomic Molecules. 7.6 More Complex Polyatomic Molecules. 7.7 Metal Complexes. 7.8 Summary. 7.9 Self-Test Questions. Further Reading. Appendices. Appendix 1. H2O Models for Identifying the Results of Symmetry Operation Products. Appendix 2. Assignment of Chiral Centre Handedness using Cahn-Ingold-Prelog Rules. Appendix 3. Model of a Tetrahedron and the Related Cube. Appendix 4. Model of an Octahedron. Appendix 5. Matrices and Determinants. Appendix 6. The Mathematical Background to Infrared Selection Rules. Appendix 7. The Franck-Condon Principle. Appendix 8. Classical Treatment of Stokes/Anti-Stokes Absorption. Appendix 9. The Atomic Orbitals of Hydrogen. Appendix 10. The Origin of Chemical Bonding in H+2. Appendix 11. H2O Molecular Orbital Calculation in C2v Symmetry. Appendix 12. Character Tables. Index.

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Book SynopsisMolecular Symmetry lays out the formal language in the area using illustrative examples of particular molecules throughout. It then applies the ideas of symmetry to describe molecular structure, bonding in molecules and consider the implications in spectroscopy.Trade Review"The work will prove to be a popular choice as a textbook or as an additional resource for group theory and advanced inorganic chemistry courses." (CHOICE, November 2009) “A major strength of this book is its accessibility to the practically and conceptually minded chemist; the reader is led into the subject through strong visual presentation of the ideas and although the mathematics is by no means ignored, it is presented within an applied context.“ (The Higher Education Academy Physical Sciences Centre Reviews, May 2009)Table of ContentsPreface. 1. Symmetry Elements and Operations. 1.1 Introduction. 1.2 Symmetry Elements and Operations. 1.3 Examples of the Impact of Geometric Symmetry on Chemistry. 1.4 Summary. 1.5 Self-Test Questions. Further Reading. 2. More Symmetry Operations and Products of Operations. 2.1 Introduction. 2.2 Background to Point Groups. 2.3 Closed Groups and New Operations. 2.4 Properties of Symmetry Operations. 2.5 Chirality and Symmetry. 2.6 Summary. 2.7 Completed Multiplication Tables. 2.8 Self-Test Questions. 3. The Point Groups Used with Molecules. 3.1 Introduction. 3.2 Molecular Classification Using Symmetry Operations. 3.3 Constructing Reference Models with Idealized Symmetry. 3.4 The Nonaxial Groups: Cs,Ci,C1. 3.5 The Cyclic Groups: Cn, Sn. 3.6 Axial Groups Containing Mirror Planes: Cnh and Cnv. 3.6.1 Examples of Axial Groups Containing Mirror Planes: Cnh and Cnv. 3.7 Axial Groups with Multiple Rotation Axes: Dn, Dnd and Dnh. 3.8 Special Groups for Linear Molecules: Cìv and Dìh. 3.9 The Cubic Groups: Td and Oh. 3.10 Assigning Point Groups to Molecules. 3.11 Example Point Group Assignments. 3.12 Self-Test Questions. 4. Point Group Representations, Matrices and Basis Sets. 4.1 Introduction. 4.2 Symmetry Representations and Characters. 4.3 Multiplication Tables for Character Representations. 4.4 Matrices and Symmetry Operations. 4.5 Diagonal and Off-Diagonal Matrix Elements. 4.6 The Trace of a Matrix as the Character for an Operation. 4.7 Noninteger Characters. 4.8 Reducible Representations. 4.9 Classes of Operations. 4.10 Degenerate Irreducible Representations. 4.11 The Labelling of Irreducible Representations. 4.12 Summary. 4.13 Completed Tables. 4.14 Self-Test Questions. Further Reading. 5. Reducible and Irreducible Representations. 5.1 Introduction. 5.2 Irreducible Representations and Molecular Vibrations. 5.3 Finding Reducible Representations. 5.4 Properties of Point Groups and Irreducible Representations. 5.5 The Reduction Formula. 5.6 A Complete Set of Vibrational Modes for H2O. 5.7 Choosing the Basis Set. 5.8 The d-Orbitals in Common Transition Metal Complex Geometries. 5.9 Linear Molecules: Groups of Infinite Order. 5.10 Summary. 5.11 Self-Test Questions. 6. Applications in Vibrational Spectroscopy. 6.1 Introduction. 6.2 Selection Rules. 6.3 General Approach to Analysing Vibrational Spectroscopy. 6.4 Symmetry-Adapted Linear Combinations. 6.5 Normalization. 6.6 The Projector Operator Method. 6.7 Linking Results for Symmetry-Inequivalent Sets of Atoms. 6.8 Additional Examples. 6.9 Summary. 6.10 Self-Test Questions. Further Reading. 7. Symmetry in Chemical Bonding. 7.1 Introduction. 7.2 Bond Energies. 7.3 The Relative Energies of Hydrogen-Like Atomic Orbitals. 7.4 The Molecules Formed by Other Second-Row Elements with Hydrogen. 7.5 The Second-Row Diatomic Molecules. 7.6 More Complex Polyatomic Molecules. 7.7 Metal Complexes. 7.8 Summary. 7.9 Self-Test Questions. Further Reading. Appendices. Appendix 1. H2O Models for Identifying the Results of Symmetry Operation Products. Appendix 2. Assignment of Chiral Centre Handedness using Cahn-Ingold-Prelog Rules. Appendix 3. Model of a Tetrahedron and the Related Cube. Appendix 4. Model of an Octahedron. Appendix 5. Matrices and Determinants. Appendix 6. The Mathematical Background to Infrared Selection Rules. Appendix 7. The Franck-Condon Principle. Appendix 8. Classical Treatment of Stokes/Anti-Stokes Absorption. Appendix 9. The Atomic Orbitals of Hydrogen. Appendix 10. The Origin of Chemical Bonding in H+2. Appendix 11. H2O Molecular Orbital Calculation in C2v Symmetry. Appendix 12. Character Tables. Index.

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Book SynopsisProvides an introduction to those needing to use infrared spectroscopy for the first time, explaining the fundamental aspects of this technique, how to obtain a spectrum and how to analyse infrared data covering a wide range of applications. Includes instrumental and sampling techniques Covers biological and industrial applications Includes suitable questions and problems in each chapter to assist in the analysis and interpretation of representative infrared spectra Part of the ANTS (Analytical Techniques in the Sciences) Series.Table of ContentsSeries Preface. Preface. Acronyms, Abbreviations and Symbols. About the Author. 1. Introduction. 1.1 Electromagnetic Radiation. 1.2 Infrared Absorptions. 1.3 Normal Modes of Vibration. 1.4 Complicating Factors. 1.4.1 Overtone and Combination Bands. 1.4.2 Fermi Resonance. 1.4.3 Coupling. 1.4.4 Vibration–Rotation Bands. References. 2. Experimental Methods. 2.1 Introduction. 2.2 Dispersive Infrared Spectrometers. 2.3 Fourier-Transform Infrared Spectrometers. 2.3.1 Michelson Interferometers. 2.3.2 Sources and Detectors. 2.3.3 Fourier-Transformation. 2.3.4 Moving Mirrors. 2.3.5 Signal-Averaging. 2.3.6 Advantages. 2.3.7 Computers. 2.3.8 Spectra. 2.4 Transmission Methods. 2.4.1 Liquids and Solutions. 2.4.2 Solids. 2.4.3 Gases. 2.4.4 Pathlength Calibration. 2.5 Reflectance Methods. 2.5.1 Attenuated Total Reflectance Spectroscopy. 2.5.2 Specular Reflectance Spectroscopy. 2.5.3 Diffuse Reflectance Spectroscopy. 2.5.4 Photoacoustic Spectroscopy. 2.6 Microsampling Methods. 2.7 Chromatography–Infrared Spectroscopy. 2.8 Thermal Analysis–Infrared Spectroscopy. 2.9 Other Techniques. References. 3. Spectral Analysis. 3.1 Introduction. 3.2 Group Frequencies. 3.2.1 Mid-Infrared Region. 3.2.2 Near-Infrared Region. 3.2.3 Far-Infrared Region. 3.3 Identification. 3.4 Hydrogen Bonding. 3.5 Spectrum Manipulation. 3.5.1 Baseline Correction. 3.5.2 Smoothing. 3.5.3 Difference Spectra. 3.5.4 Derivatives. 3.5.5 Deconvolution. 3.5.6 Curve-Fitting. 3.6 Concentration. 3.7 Simple Quantitative Analysis. 3.7.1 Analysis of Liquid Samples. 3.7.2 Analysis of Solid Samples. 3.8 Multi-Component Analysis. 3.9 Calibration Methods. References. 4. Organic Molecules. 4.1 Introduction. 4.2 Aliphatic Hydrocarbons. 4.3 Aromatic Compounds. 4.4 Oxygen-Containing Compounds. 4.4.1 Alcohols and Phenols. 4.4.2 Ethers. 4.4.3 Aldehydes and Ketones. 4.4.4 Esters. 4.4.5 Carboxylic Acids and Anhydrides. 4.5 Nitrogen-Containing Compounds. 4.5.1 Amines. 4.5.2 Amides. 4.6 Halogen-Containing Compounds. 4.7 Heterocyclic Compounds. 4.8 Boron Compounds. 4.9 Silicon Compounds. 4.10 Phosphorus Compounds. 4.11 Sulfur Compounds. 4.12 Near-Infrared Spectra. 4.13 Identification. References. 5. Inorganic Molecules. 5.1 Introduction. 5.2 General Considerations. 5.3 Normal Modes of Vibration. 5.4 Coordination Compounds. 5.5 Isomerism. 5.6 Metal Carbonyls. 5.7 Organometallic Compounds. 5.8 Minerals. References. 6. Polymers. 6.1 Introduction. 6.2 Identification. 6.3 Polymerization. 6.4 Structure. 6.5 Surfaces. 6.6 Degradation. References. 7. Biological Applications. 7.1 Introduction. 7.2 Lipids. 7.3 Proteins and Peptides. 7.4 Nucleic Acids. 7.5 Disease Diagnosis. 7.6 Microbial Cells. 7.7 Plants. 7.8 Clinical Chemistry. References. 8. Industrial and Environmental Applications. 8.1 Introduction. 8.2 Pharmaceutical Applications. 8.3 Food Science. 8.4 Agricultural Applications. 8.5 Pulp and Paper Industries. 8.6 Paint Industry. 8.7 Environmental Applications. References. Responses to Self-Assessment Questions. Bibliography. Glossary of Terms. SI Units and Physical Constants. Periodic Table. Index.

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Book SynopsisA resource on inorganic polyphosphate metabolism. This book describes the structure and properties of these compounds and presents a comparative analysis of the traditional methods of their extraction from cells.Trade Review"This book is recommended for academic libraries supporting advanced biochemistry or related programs." (E-STREAMS, January 2005)Table of ContentsForeword to the First Edition. Preface. Acknowledgements. Introduction. 1 The Chemical Structures and Properties of Condensed Inorganic Phosphates. 1.1 The Structures of Condensed Phosphates. 1.1.1 Cyclophosphates. 1.1.2 Polyphosphates. 1.1.3 Branched Inorganic Phosphates, or ‘Ultraphosphates’. 1.2 Some Chemical Properties of Condensed Inorganic Polyphosphates. 1.3 Physico-Chemical Properties of Condensed Inorganic Polyphosphates. 2 Methods of Polyphosphate Assay in Biological Materials. 2.1 Methods of Extraction from Biological Materials. 2.2 Chromatographic Methods. 2.3 Colorimetric and Fluorimetric Methods. 2.4 Cytochemical Methods. 2.5 X-Ray Energy Dispersive Analysis. 2.6 31P Nuclear Magnetic Resonance Spectroscopy. 2.7 Other Physical Methods. 2.8 Gel Electrophoresis. 2.9 Enzymatic Methods. 3 The Occurrence of Polyphosphates in Living Organisms. 4 The Forms in which Polyphosphates are Present in Cells. 4.1 Polyphosphate–Cation Complexes. 4.2 Polyphosphate–Ca2+–Polyhydroxybutyrate Complexes. 4.3 Complexes of Polyphosphates with Nucleic Acids. 4.4 Binding of Polyphosphates with Proteins. 5 Localization of Polyphosphates in Cells of Prokaryotes and Eukaryotes. 5.1 Prokaryotes. 5.2 Eukaryotes. 6 Enzymes of Polyphosphate Biosynthesis and Degradation. 6.1 Enzymes of Polyphosphate Biosynthesis. 6.1.1 Polyphosphate Kinase (Polyphosphate:ADP Phosphotransferase, EC 2.7.4.1). 6.1.2 3-Phospho-D-Glyceroyl-Phosphate:Polyphosphate Phosphotransferase (EC 2.7.4.17). 6.1.3 Dolichyl-Diphosphate:Polyphosphate Phosphotransferase (EC 2.7.4.20). 6.2 Enzymes of Polyphosphate Degradation. 6.2.1 Polyphosphate-Glucose Phosphotransferase (EC 2.7.1.63). 6.2.2 NAD Kinase (ATP:NAD 2_-Phosphotransferase, EC 2.7.1.23). 6.2.3 Exopolyphosphatase (Polyphosphate Phosphohydrolase, EC 3.6.1.11). 6.2.4 Adenosine–Tetraphosphate Phosphohydrolase (EC 3.6.1.14). 6.2.5 Triphosphatase (Tripolyphosphatase, EC 3.6.1.25). 6.2.6 Endopolyphosphatase (Polyphosphate Depolymerase, EC 3.6.1.10). 6.2.7 PolyP:AMP Phosphotransferase. 7 The Functions of Polyphosphates and Polyphosphate-Dependent Enzymes. 7.1 Phosphate Reserve. 7.1.1 In Prokaryotes. 7.1.2 In Eukaryotes. 7.2 Energy Source. 7.2.1 Polyphosphates in Bioenergetics of Prokaryotes. 7.2.2 Polyphosphate in Bioenergetics of Eukaryotes. 7.3 Cations Sequestration and Storage. 7.3.1 In Prokaryotes. 7.3.2 In Eukaryotes. 7.4 Participation in Membrane Transport. 7.5 Cell Envelope Formation and Function. 7.5.1 Polyphosphates in the Cell Envelopes of Prokaryotes. 7.5.2 Polyphosphates in the Cell Envelopes of Eukaryotes. 7.6 Regulation of Enzyme Activities. 7.7 Gene Activity Control, Development and Stress Response. 7.7.1 In Prokaryotes. 7.7.2 In Lower Eukaryotes. 7.8 The Functions of Polyphosphates in Higher Eukaryotes. 8 The Peculiarities of Polyphosphate Metabolism in Different Organisms. 8.1 Escherichia coli. 8.1.1 The Dynamics of Polyphosphates under Culture Growth. 8.1.2 The Effects of Pi Limitation and Excess. 8.1.3 The Effects of Mutations on Polyphosphate Levels and Polyphosphate-Metabolizing Enzyme Activities. 8.1.4 The Effects of Nutrition Deficiency and Environmental Stress. 8.2 Pseudomonas aeruginosa. 8.3 Acinetobacter. 8.4 Aerobacter aerogenes (Klebsiella aerogenes). 8.5 Azotobacter. 8.6 Cyanobacteria (Blue–Green Algae) and other Photosynthetic Bacteria. 8.7 Mycobacteria and Corynebacteria. 8.8 Propionibacteria. 8.9 Archae. 8.10 Yeast. 8.10.1 Yeast Cells Possess Different Polyphosphate Fractions. 8.10.2 The Dynamics of PolyP Fractions during the Cell Cycle. 8.10.3 The Relationship between the Metabolism of Polyphosphates and other Compounds. 8.10.4 Polyphosphate Fractions at Growth on a Pi-Sufficient Medium with Glucose. 8.10.5 The Effects of Pi Limitation and Excess. 8.10.6 The Effects of other Conditions on the Polyphosphate Content in Yeast Cells. 8.10.7 The Effects of Inhibitors on the Polyphosphate Content in Yeast Cells. 8.10.8 The Effects of Mutations on the Content and Chain Lengths of Polyphosphate in Yeast. 8.11 Other Fungi (Mould and Mushrooms). 8.12 Algae. 8.12.1 Localization and Forms in Cells. 8.12.2 The Dynamics of Polyphosphates in the Course of Growth. 8.12.3 The Influence of Light and Darkness. 8.12.4 The Effects of Pi Limitation and Excess. 8.12.5 Changes in Polyphosphate Content under Stress Conditions. 8.13 Protozoa. 8.14 Higher Plants. 8.15 Animals. 9 Applied Aspects of Polyphosphate Biochemistry. 9.1 Bioremediation of the Environment. 9.1.1 Enhanced Biological Phosphate Removal. 9.1.2 Removal of Heavy Metals from Waste. 9.2 Polyphosphates and Polyphosphate-Metabolizing Enzymes in Assay and Synthesis. 9.3 Polyphosphates in Medicine. 9.3.1 Antiseptic and Antiviral Agents. 9.3.2 Polyphosphate Kinase as a Promising Antimicrobial Target. 9.3.3 Polyphosphates as New Biomaterials. 9.3.4 Polyphosphates in Bone Therapy and Stomathology. 9.4 Polyphosphates in Agriculture. 9.5 Polyphosphates in the Food Industry. 10 Inorganic Polyphosphates in Chemical and Biological Evolution. 10.1 Abiogenic Synthesis of Polyphosphates and Pyrophosphate. 10.2 Phosphorus Compounds in Chemical Evolution. 10.3 Polyphosphates and Pyrophosphates: Fossil Biochemical Reactions and the Course of Bioenergetic Evolution. 10.4 Changes in the Role of Polyphosphates in Organisms at Different Evolutionary Stages. References. Index of Generic Names. Subject Index.

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Book SynopsisCore Concepts in Supramolecular Chemistry and Nanochemistry: From Supramolecules to Nanotechnology provides a concise introduction to this fast developing subject. The book offers a modern up-to date approach and carefully explains the basics and essential theory behind the subject.Trade ReviewThe text is written with lucidity…. One of the attractions … is its aesthetic appeal. (Reviews, June 2008)Table of ContentsPreface. About the authors. 1 Introduction. 1.1 What is supramolecular chemistry? 1.2 Selectivity. 1.3 Supramolecular interactions. 1.4 Supramolecular design. References. Suggested further reading. 2 Solution host–guest chemistry. 2.1 Introduction: guests in solution. 2.2 Macrocyclic versus acyclic hosts. 2.3 Cation binding. 2.4 Anion binding. 2.5 Metal-containing receptors. 2.6 Simultaneous cation and anion receptors. 2.7 Neutral-molecule binding. 2.8 Supramolecular catalysis and enzyme mimics. References. 3 Self-assembly. 3.1 Introduction. 3.2 Biological self-assembly. 3.3 Ladders, polygons and helices . 3.4 Rotaxanes, catenanes and knots. 3.5 Self-assembling capsules. References. 4 Solid-state supramolecular chemistry. 4.1 Introduction. 4.2 Zeolites. 4.3 Clathrates. 4.4 Clathrate hydrates. 4.5 Crystal engineering. 4.6 Coordination polymers. References. 5 Nanochemistry. 5.1 Introduction. 5.2 Nanomanipulation. 5.3 Molecular devices. 5.4 Self-assembled monolayers (SAMs). 5.5 Soft lithography. 5.6 Nanoparticles. 5.7 Fullerenes and nanotubes. 5.8 Dendrimers. 5.9 Fibres, gels and polymers. 5.10 Nanobiology and biomimetic chemistry. References. Index.

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Book SynopsisAn update of Theory of Molecular Interactions, Intermolecular Interactions has been completely rewritten to contain all mathematical apparatus needed for its study, as well as a description of principal quantum-mechanical and quantum-chemical methods applied to many-electron systems.Trade Review"…worthy to be placed on the shelf of any researcher, teacher, or graduate student working in those fields of science." (Physics Today, July 2007) "This book is of interest for all those professionals that carry out experimental and theoretical studies of intermolecular interactions…" (Magazine of Modern Plastics, April 2007)Table of ContentsPreface. 1 Background Knowledge. 1.1 The Subject and its Specificity. 1.2 A Brief Historical Survey. 1.3 The Concept of Interatomic Potential and Adiabatic Approximation. 1.4 General Classification of Intermolecular Interactions. References. 2 Types of Intermolecular Interactions: Qualitative Picture. 2.1 Direct Electrostatic Interactions. 2.2 Resonance Interaction. 2.3 Polarization Interactions. 2.4 Exchange Interaction. 2.5 Retardation Effects in Long-Range Interactions and the Influence of Temperature. 2.6 Relativistic (Magnetic) Interactions. 2.7 Interaction Between Macroscopic Bodies. References. 3 Calculation of Intermolecular Interactions. 3.1 Large Distances. 3.2 Intermediate and Short Distances. References. 4 Nonadditivity of Intermolecular Interactions. 4.1 Physical Nature of Nonadditivity and the Definition of Many-Body Forces. 4.2 Manifestations of Nonadditive Effects. 4.3 Perturbation Theory and Many-Body Decomposition. 4.4 Many-Body Effects in Atomic Clusters. 4.5 Atom–Atom Potential Scheme and Nonadditivity. References. 5 Model Potentials. 5.1 Semiempirical Model Potentials. 5.2 Determination of Parameters in Model Potentials. 5.3 Reconstructing Potentials on the Basis of Experimental Data. 5.4 Global Optimization Methods. References. Appendix 1: Fundamental Physical Constants and Conversion Table of Physical Units. Appendix 2: Some Necessary Mathematical Apparatus. A2.1 Vector and Tensor Calculus. A2.1.1 Definition of vector; the addition law. A2.1.2 Scalar and vector products; triple scalar product. A2.1.3 Determinants. A2.1.4 Vector analysis; gradient, divergence and curl. A2.1.5 Vector spaces and matrices. A2.1.6 Tensors. A2.2 Group Theory. A2.2.1 Properties of group operations. A2.2.2 Representations of groups. A2.2.3 The permutation group. A2.2.4 The linear groups. The three-dimensional rotation group. A2.2.5 Point groups. A2.2.6 Irreducible tensor operators. Spherical tensors. References. Appendix 3: Methods of Quantum-Mechanical Calculations of Many-Electron Systems. A3.1 Adiabatic Approximation. A3.2 Variational Methods. A3.2.1 Self-consistent field method. A3.2.2 Methods taking into account the electron correlation. A3.2.2.1 r12-dependent wave functions. A3.2.2.2 Configuration interaction. A3.2.2.3 Coupled cluster method. A3.2.2.4 Density functional theory approach. A3.3 Perturbation Theory. A3.3.1 Rayleigh–Schr¨odinger perturbation theory. A3.3.2 Møller–Plesset perturbation theory. A3.3.3 Operator formalism and the Brillouin–Wigner perturbation theory. A3.3.4 Variational perturbation theory. A3.3.5 Asymptotic expansions; Padé approximants. References. Index.

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Book SynopsisA Practical Guide to Supramolecular Chemistry is an introductory manual of practical experiments for chemists with little or no prior experience of supramolecular chemistry.Trade Review"For undergraduate students dealing with synthetic supramolecular chemistry, this book will be compulsory reading…will have a definite place in every good library collection." (Synthesis, April 2006)Table of ContentsPreface ix Introduction 1 1 Linear components for supramolecular networks 9 1.1 Flexible components 9 1.2 Rigid components from Schiff bases 17 1.3 Flexible tripods 19 1.4 Simple anion hosts 23 1.5 Rigid platforms 30 2 Cyclic synthons 35 2.1 Planar macrocycles from nature 35 2.2 Artificial planar macrocycles – phthalocyanines and other cyclic systems 37 2.3 Serendipitous macrocycles 43 2.4 Adding functionality to the crowns 46 2.5 Azacrowns with sidearms 51 2.6 Water-soluble macrocycles 55 2.7 Catenanes and rotaxanes 60 3 Molecular baskets, chalices and cages 69 3.1 One for beginners 69 3.2 Calixarenes – essential supramolecular synthons 71 3.3 Adding lower rim functionality to the calixarenes 77 3.4 Adding upper rim functionality to the calixarenes 80 3.5 Oxacalix[3]arenes 84 3.6 Oxacalixarene derivatives 91 3.7 Azacalix[3]arenes 99 3.8 Calixarene variations 102 3.9 Molecular cages for cations and anions 107 4 Supramolecular assembly 115 4.1 Detection, measurement, prediction and visualization 115 4.2 X-ray crystallography 115 4.3 Spectroscopic and spectrometric techniques 120 4.4 Binding constant determination 122 4.5 Solid state vs. solution behaviour 127 4.6 Supramolecular chemistry in silico: molecular modelling and associated techniques 127 4.7 Computational approaches 129 4.8 A protocol for supramolecular computational chemistry 141 4.9 Examples of in silico supramolecular chemistry 142 5 Supramolecular phenomena 161 5.1 Clathrates 161 5.2 Stabilization of cation–anion pairs by crown ethers: liquid clathrates 162 5.3 Receptors for the ammonium ion 168 5.4 Purification of fullerenes 170 5.5 Making molecular boxes and capsules 172 5.6 Self-complementary species and self-replication 176 Appendix 1 Integrated undergraduate projects 185 Appendix 2 Reagents and solvents 189 Index 197

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Book SynopsisA Practical Guide to Supramolecular Chemistry is an introductory manual of practical experiments for chemists with little or no prior experience of supramolecular chemistry.Trade Review"…an introduction to supramolecular chemistry…recommended." (CHOICE, May 2006)Table of ContentsPreface ix Introduction 1 1 Linear components for supramolecular networks 9 1.1 Flexible components 9 1.2 Rigid components from Schiff bases 17 1.3 Flexible tripods 19 1.4 Simple anion hosts 23 1.5 Rigid platforms 30 2 Cyclic synthons 35 2.1 Planar macrocycles from nature 35 2.2 Artificial planar macrocycles – phthalocyanines and other cyclic systems 37 2.3 Serendipitous macrocycles 43 2.4 Adding functionality to the crowns 46 2.5 Azacrowns with sidearms 51 2.6 Water-soluble macrocycles 55 2.7 Catenanes and rotaxanes 60 3 Molecular baskets, chalices and cages 69 3.1 One for beginners 69 3.2 Calixarenes – essential supramolecular synthons 71 3.3 Adding lower rim functionality to the calixarenes 77 3.4 Adding upper rim functionality to the calixarenes 80 3.5 Oxacalix[3]arenes 84 3.6 Oxacalixarene derivatives 91 3.7 Azacalix[3]arenes 99 3.8 Calixarene variations 102 3.9 Molecular cages for cations and anions 107 4 Supramolecular assembly 115 4.1 Detection, measurement, prediction and visualization 115 4.2 X-ray crystallography 115 4.3 Spectroscopic and spectrometric techniques 120 4.4 Binding constant determination 122 4.5 Solid state vs. solution behaviour 127 4.6 Supramolecular chemistry in silico: molecular modelling and associated techniques 127 4.7 Computational approaches 129 4.8 A protocol for supramolecular computational chemistry 141 4.9 Examples of in silico supramolecular chemistry 142 5 Supramolecular phenomena 161 5.1 Clathrates 161 5.2 Stabilization of cation–anion pairs by crown ethers: liquid clathrates 162 5.3 Receptors for the ammonium ion 168 5.4 Purification of fullerenes 170 5.5 Making molecular boxes and capsules 172 5.6 Self-complementary species and self-replication 176 Appendix 1 Integrated undergraduate projects 185 Appendix 2 Reagents and solvents 189 Index 197

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Book SynopsisA guide to spectroscopy and inorganic materials. It introduces the different optical spectroscopic techniques, used in many laboratories, for material characterisation. It also meets the demand from academia and the science community for an introductory text.Trade Review"This is a useful book for an undergraduate or an early-stage postgraduate course in spectroscopy." (Reviews, June 2008) "[allows] students with a background in quantum physics and solid state physics, to interpret simple optical spectra…and obtain knowledge of the main instrumentation used in this field." (Chimie Nouvelle, March 2007)Table of ContentsPREFACE. ACKNOWLEDGEMENTS. SOME PHYSICAL CONSTANTS OF INTEREST IN SPECTROSCOPY. I FUNDAMENTALS. I.1 Origin of the Spectroscopy. I.2 Electromagnetic Spectrum. Optical Spectroscopy. I.3 Absorption. The Spectrophotometer. I.4 Luminescence. The Spectrofluorimeter. Time resolved luminescence. I.5 Scattering. The Raman effect. I.6 Advanced topic: The Fourier Transform Spectrophotometer. Exercises. II LIGHT SOURCES. II.1 Introduction. II.2 Lamps. II.3 The Laser. Basic principles. II.4 Types of Lasers. II.5 Tunability of laser radiation. The Optical Parametric Oscillator. II.6 Advanced Topic:1) Site Selective Spectroscopy. 2) Excited State Absorption. Exercises. III MONOCHROMATORS AND DETECTORS. III.1 Introduction. III.2 Monochromators. III.3 Types of detectors. Basic parameters. III.4 The Photomultiplier. III.5 Signal/noise ratio optimisation. III.6 Detection of pulses. III.7 Advanced Topic: Detection of very fast pulses; The Streak Camera; The Correlator. Exercises. IV. OPTICAL TRANSPARENCY OF SOLIDS. IV.1 Introduction. IV.2 Optical magnitudes and the dielectric constant. IV.3The Lorentz oscillator. IV.4 Metals. IV.5 Semiconductors and insulators. IV.6 Spectral shape of the fundamental absorption edge. IV.7 Excitons. IV.8 Advanced topic: The colour of metals. Exercises. V. OPTICALLY ACTIVE CENTRES. V.1 Introduction. V.2 Static interaction. The crystalline field. V.3 Band intensities. The oscillator strength. V.4 Dynamic interaction. The coordinate configuration diagram. V.5 Band shape. The Huang-Rhys factor. V.6 Non radiative transitions. Energy transfer. V.7 Advanced topic: Determination of quantum efficiencies. Exercises. VI. APPLICATIONS: RARE EARTH AND TRANSITION METAL IONS, COLOUR CENTERS. VI.1 Introduction. VI.2 Trivalent rare earth ions. Diagram of Dieke. VI.3 Non radiative transitions in rare earth ions; The "energy gap" law. VI.4 Transition metal ions. Tanabe- Sugano diagrams. VI.5 Colour centres. VI.6 Advanced topic: 1) The Judd and Ofelt method. 2) Optical cooling of solids. Exercises. VII. GROUP THEORY AND SPECTROSCOPY. VII.1 Introduction. VII.2 Symmetry operations and classes. VII.3 Representations. The character table. VII.4 Reduction in symmetry and splitting of energy levels. VII.5 Selection rules for optical transitions. VII.6 Illustrative examples. VII.7 Advanced topic: Applications to optical transitions of Kramers ions. Exercises. APPENDICES. APPENDIX A1.- The joint density of states. APPENDIX A2.- Effect of an octahedral field on a valence electron d1. APPENDIX A3.- Calculation of the spontaneous emission probability by the Einstein thermodynamic treatment. APPENDIX A4.- Determination of the Smakula´s formula. INDEX.

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Book SynopsisThis book presents the current carbonaceous fuel conversion technologies based on chemical looping concepts in the context of traditional or conventional technologies. The key features of the chemical looping processes, their ability to generate a sequestration-ready CO2 stream, are thoroughly discussed.

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Book SynopsisThe how''s and why''s of successful drug repositioning Drug repositioning, also known as drug reprofiling or repurposing, has become an increasingly important part of the drug development process. This book examines the business, technical, scientific, and operational challenges and opportunities that drug repositioning offers. Readers will learn how to perform the latest experimental and computational methods that support drug repositioning, and detailed case studies throughout the book demonstrate how these methods fit within the context of a comprehensive drug repositioning strategy. Drug Repositioning is divided into three parts: Part 1, Drug Repositioning: Business Case, Strategies, and Operational Considerations, examines the medical and commercial drivers underpinning the quest to reposition existing drugs, guiding readers through the key strategic, technical, operational, and regulatory decisions needed for successful drugTrade Review “Overall, this book is so complete that it is a must read for all the players in drug repositioning, not only researches or drug developers, but also business development specialist, investors, venture capital firms, academia and regulators that need a compressive description that will satisfy novice and more experienced professionals.” (ChemMedChem, 1 March 2013) Table of ContentsAbout the Editors xv Acknowledgments xvii Contributors xix Introduction 1 Michael J. Barratt and Donald E. Frail References 5 Part I. Drug Repositioning: Business Case, Strategies, and Operational Consideration 7 1. Drug Repositioning: The Business Case and Current Strategies to Repurpose Shelved Candidates and Marketed Drugs 9 John Arrowsmith and Richard Harrison 2. Opportunities and Challenges Associated with Developing Additional Indication for Clinical Development Candidates and Marketed Drugs 33 Donald E. Frail and Michael J. Barratt 3. Clinical and Operational Considerations in Repositioning Marketed Drugs and Drug Candidates 53 Damian O’Connell, David J. Sequeira, and Maria L. Miller 4. Regulatory Considerations and Strategies for Drug Repositioning 65 Ken Phelps Part II. Application of Technology Platforms to Uncover New Indications and Repurpose Existing Drugs 89 5. Computational and Bioinformatic Strategies for Drug Repositioning Drugs 91 Richard Mazzarella and Craig Webb 6. Mining Scientific and Clinical Databases to Identify Novel Uses for Existing Drugs 137 Christos Andronis, Anuj Sharma, Spyros Deftereos, Vassilis Virvilis, Ourania Konstanti, Andreas Persidis, and Aris Persidis 7. Predicting the Polypharmacology of Drugs: Identifying New Uses through Chemoinformatics, Structural Informatics, and Molecular Modeling-Based Approaches 163 Li Xie, Sarah L. Kinnings, Lei Xie, and Philip E. Bourne 8. Systematic Phenotypic Screening for Novel Synergistic Combinations: A New Paradigm for Repositioning Existing Drugs 207 Margaret S. Lee 9. Phenotypic In Vivo Screening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates 253 Michael S. Saporito, Christopher A. Lipinski, and Andrew G. Reaume 10. Old Drugs Yield New Discoveries: Examples from the Prodrug , Chiral Switch, and Site-Selective Deuteration Strategies 291 Adam J. Morgan, Bhaumik A. Pandya, Craig E. Masse, and Scott L. Harbeson Part III. Academic and Nonprofit Initiatives and the Role of Alliances in the Drug Repostioning Industry 345 11. Repurposing Drugs for Tropical Disease: Case Studies and Open-Source Screening Initiatives 347 Curtis R. Chong 12. Drug Repositioning Efforts by Nonprofit Foundations 389 13. Business Development Strategies in the Repositioning Industry 433 Aris Persidis and Elizabeth T. Stark 14. A Case Study in Drug Repositioning: Sosei 445 Akinori Mochizuki and Makiko Aoyama Appendix Additional Drug Repositioning Resources and Links 457 Mark A. Mitchell and Michael J. Barratt Index 469

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Book SynopsisAs the lifespan of humans increases, research into aging and its related pathological conditions is gaining momentum. This book is the first to explain protein oxidation and the aging process, focusing on the connection between protein disturbances and the oxidative stress that cells continually undergo.Trade Review“With its discussion of current concepts linked to protein oxidation and its impact on aging and the pathology of certain age-related diseases, this book is an important contribution to the field. Students, researchers, scientists, and even clinicians will benefit from it.” (Doody’s, 10 January 2013) “The format and compartmentalised writing style make this an excellent compendium of knowledge for any researcher interested in assessing our state of knowledge of protein oxidation and ageing. It is easy to find out about the current state of knowledge about a specific reaction, product, method, and/or disease and follow this up by accessing the extensive list of references.” (Chemistry & Industry, 1 July 2013)Table of ContentsIntroduction to the Wiley Series on Protein and Peptide Science xi Preface xiii 1 Oxidative Stress and Protein Oxidation 1 1.1 The Large Variety of Protein Oxidation Products, 7 1.1.1 Primary Protein Oxidation Products, 7 1.1.1.1 Carbon-Centered Radicals, 9 1.1.1.2 Thiyl Radicals, 13 1.1.1.3 Aromatic Ring-Derived Radicals, 13 1.1.1.4 Transfer between Sites, 16 1.1.2 Reactive Compounds Mediating in Protein Oxidation, 18 1.1.2.1 Hydroxyl Radical, 20 1.1.2.2 Superoxide Radicals, 21 1.1.2.3 Hydrogen Peroxide, 24 1.1.2.4 Lipid Peroxyl Radicals, 24 1.1.2.5 Alkoxyl Radicals, 24 1.1.2.6 •NO and Peroxynitrite, 25 1.1.2.7 Hypochlorous Acid, 30 1.1.3 Enzymatic Systems Playing a Role in Protein Oxidation, 31 1.1.3.1 NADPH Oxidase, 32 1.1.3.2 Lipoxygenases, 35 1.1.3.3 Protein Kinases, 35 1.1.3.4 Mixed-Function Oxidases, 36 1.1.3.5 Nitric Oxide Synthetase (NOS), 38 1.1.3.6 Myeloperoxidase, 41 1.1.3.7 Cyclooxygenase, 42 1.1.4 Protein Oxidation in Cells and Cellular Structures, 43 1.1.4.1 Protein Oxidation in Blood and Blood Cells, 43 1.1.4.2 Protein Oxidation of Glycolytic Enzymes and Mitochondria, 46 1.1.4.2.1 Glycolytic Enzymes, 48 1.1.4.2.2 Aconitase, 49 1.1.4.2.3 Carnitine Palmitoyltransferase-1, 49 1.1.4.3 Cytochrome P450 Enzymes, 49 1.1.4.4 Protein Oxidation in the Nucleus and Chromatin, 50 1.1.4.4.1 Histone Modifi cation, 50 1.1.4.5 Protein Oxidation in the Endoplasmic Reticulum, 52 1.1.4.6 Protein Oxidation in Peroxisomes, 54 1.2 Reversible Oxidative Modifi cations, 55 1.2.1 Methionine Sulfoxides and Methionine Modifi cations, 55 1.2.2 Cysteine Modifi cations and Disulfi de Bond Formation, 61 1.2.3 Surface Hydrophobicity Modifi cations, 64 1.3 Irreversible Oxidation Products, 64 1.3.1 Protein Oxidation and Enzymatic Posttranslational Modifications, 65 1.3.2 Deamidation and Transamination, 66 1.3.3 Protein Glycation and AGEs, 67 1.3.3.1 Receptor for Advanced Glycation End Products (RAGE), 75 1.3.3.2 Nε-Carboxymethyllysine and Nε-Carboxyethyllysine, 76 1.3.3.3 Pentosidine, 76 1.3.4 Racemization, 77 1.3.5 Nitrosylation, 77 1.3.6 Tyrosyl Radicals and Nitrotyrosines, 78 1.3.6.1 Dityrosines, 79 1.3.7 Protein Carbonyls, 80 1.3.8 Aldehyde–Protein Reactions, 81 1.3.8.1 MDA-Protein Adducts, 82 1.3.8.2 4-Hydroxy-2,3-Nonenal-Protein Adducts, 82 1.3.9 Cross-Linking of Proteins, 82 1.4 The Oxidation of Extracellular Matrix, Membrane and Cytoskeletal Proteins, 83 1.4.1 Collagen, 84 1.4.2 Elastin, 95 1.4.3 The Oxidation of Membrane Proteins, 97 1.4.4 Band 3, 97 1.4.5 Actin, 99 1.5 Mechanism and Factors Influencing the Formation of Protein Oxidation Products, 100 1.5.1 Redox Status, 101 1.5.2 Protein Turnover, 106 1.5.3 Metal-Catalyzed Oxidation (MCO), 107 1.5.4 Heat Shock Proteins, 109 1.6 Protein Aggregates: Formation and Specific Metabolic Effects, 111 1.6.1 Accumulation of Oxidized Proteins, 113 1.6.2 Lipofuscin and Ceroid, 115 1.7 Methods to Measure Protein Oxidation Products in Research Laboratories, 119 1.7.1 Determination of Methionine Sulfoxide Reduction and Methionine Oxidation, 120 1.7.2 Determination of Protein Glycation and Adducts, 121 1.7.3 Analysis of Isoaspartate Formation, 122 1.7.4 Measurement of Fragmentation, 122 1.7.5 Measurement of Tyrosine Oxidation, 123 1.7.6 Protein Carbonyl Measurement, 124 1.7.7 Radioactive Labeling Protocols for Proteolysis and Aggregation Measurements, 128 1.7.8 Standard Chromatographic Methods for the Measurement of Protein Modifi cations, 132 1.7.9 Liquid Chromatography Techniques Supported by Mass Spectrometry, 133 1.7.10 GC/MS, 134 1.7.11 Analysis of Protein-Bound 3-Nitrotyrosine by a Competitive ELISA Method, 134 1.7.12 Protein Oxidation Products as Biomarkers in Clinical Science, 135 References, 139 2 Removal of Oxidized Proteins 215 2.1 The Limited Repair of Some Oxidized Proteins, 216 2.1.1 Thiol Repair, 216 2.1.2 Methionine Sulfoxide Reductases, 219 2.2 Proteolysis, 221 2.2.1 The Proteasomal System and Its Role in the Degradation of Oxidized Proteins, 222 2.2.1.1 The Ubiquitin–Proteasome System (UPS), 222 2.2.1.2 The Components of the UPS, 222 2.2.1.2.1 The 20S Proteasome, 222 2.2.1.2.2 The Inducible Forms of the Proteasome and Their Function, 227 2.2.1.2.3 The 11S Regulator, 231 2.2.1.2.4 The 19S Regulator and the UPS, 233 2.2.1.2.5 The PA200 Regulator Protein, 238 2.2.1.2.6 Cellular Proteasome Inhibitors, 239 2.2.1.3 Low-Molecular-Weight Proteasome Inhibitors, 239 2.2.1.4 Cellular Function of the UPS, 241 2.2.1.5 The Degradation of Oxidized Proteins: A Function of the 20S Proteasome, 243 2.2.1.5.1 Early Studies on the Turnover of Oxidized Proteins, 244 2.2.1.5.2 In Vitro Studies and the Recognition of Oxidized Proteins by the Proteasome, 244 2.2.1.5.3 Cellular and In Vivo Studies of the Degradation of Oxidized Proteins, 248 2.2.1.5.4 The Inhibition of the Proteasome by Cross-Linked Oxidized Proteins and Proteasomal Regulation during Oxidative Stress, 251 2.3 The Role of Other Proteases in the Fate of Oxidized Proteins, 254 2.3.1 Lysosomal Degradation of Oxidized Proteins and the Role of Autophagy, 254 2.3.2 Mitochondrial Degradation of Oxidized Proteins and the Lon Protease, 256 2.3.3 The Uptake of Extracellular Oxidized Proteins and the Role of the Proteasome in Their Degradation, 258 2.3.4 Calpains and the Degradation of Oxidized Proteins, 259 2.4 Role of Heat Shock Proteins in Protein Degradation, 260 2.5 Conclusion, 262 References, 262 3 Protein Oxidation and Aging: Different Model Systems and Affecting Factors 295 3.1 Protein Oxidation during Aging: Lower Organisms and Cellular Model Systems, 297 3.1.1 Yeast, 297 3.1.1.1 Saccharomyces cerevisiae, 297 3.1.1.2 Schizosaccharomyces pombe, 301 3.1.2 Podospora anserina, 301 3.1.3 Bacteria, 302 3.1.3.1 Escherichia coli, 302 3.1.4 Cell Cultures, 304 3.2 Nonmammalian Model Systems and the Accumulation of Oxidized Proteins during Aging, 308 3.2.1 Caenorhabditis elegans, 308 3.2.2 Drosophila melanogaster, 310 3.2.3 Aquatic Systems, 313 3.2.4 Plants, 315 3.2.5 Amphibians, 317 3.3 Age-Related Protein Oxidation in Humans and Mammals, 317 3.3.1 Humans, 317 3.3.2 Animals, 319 3.3.2.1 Rabbits, 323 3.3.2.2 Mice, 324 3.3.2.3 Rats, 327 3.3.2.4 Gerbils, 329 3.3.2.5 Primates, 330 3.4 Inherited Factors Influencing Protein Oxidation during Aging, 331 3.4.1 Genetic Instability, Mutations, and Polymorphism, 331 3.4.2 Gender, 333 3.4.3 Vitagenes, 334 3.4.4 Signal Transduction and Transcription Factors, 335 3.4.5 Ion Channels, 340 3.5 Age-Related Protein Aggregate Formation in Model Systems, 341 3.6 Environmental Factors Affecting Healthy Aging, 342 3.6.1 UV-Induced Skin Photoaging and Skin Aging, 344 3.6.2 Pesticides, 348 3.6.3 Exercise, 349 3.6.4 Dietary Factors and Prevention Strategies, 351 3.6.4.1 Melatonin, 353 3.6.4.2 Growth Hormone, 354 3.6.4.3 Biotrace Metal Elements: Zinc, 356 3.6.4.4 Ascorbic Acid, 357 3.6.4.5 Vitamin E, 360 3.6.4.6 Carnitine and Acetyl-L-Carnitine, 361 3.6.4.7 Homocysteine, 362 3.6.4.8 Ubiquinone, Coenzyme Q10, 363 3.6.4.9 Carnosine, 363 3.6.4.10 Lipoic Acid, 364 3.6.4.11 N-Acetyl-L-Cysteine, 365 3.6.5 Pharmacological Response and Biotransformation in Aging, 365 3.6.5.1 Plant Extracts, 366 3.6.5.2 Polyphenols and Flavonoids, 366 3.6.5.3 Resveratrol, 367 3.6.5.4 AGE and ALE Inhibitors, 368 3.6.6 Caloric Restriction, 369 3.7 Repair and Degradation of Oxidized Proteins during Aging, 370 References, 372 4 Protein Oxidation in Some Age-Related Diseases 417 4.1 Protein Oxidation during Neurodegeneration and Neurological Diseases, 417 4.1.1 Brain Aging, 418 4.1.2 Alzheimer’s Disease, 420 4.1.3 Parkinson’s Disease, 424 4.1.4 Huntington’s Disease, 425 4.1.5 Stroke, 427 4.1.6 Amyotrophic Lateral Sclerosis, 427 4.2 Protein Oxidation in Cardiac Diseases, 429 4.2.1 Ischemia–Reperfusion, 429 4.2.2 Atherosclerosis, 430 4.3 Protein Oxidation in Diabetes, 431 4.4 Protein Oxidation in Degenerative Arthritis, 434 4.5 Protein Oxidation in Muscle Wasting and Sarcopenia, 435 4.6 Protein Oxidation in Destructive Eye Diseases, 437 4.6.1 Age-Related Macular Degeneration, 437 4.6.2 Cataract, 438 4.7 Protein Oxidation in Osteoporosis, 440 4.8 Protein Oxidation in Cancer, 441 4.8.1 Proteasome Inhibitors in Cancer Therapy, 444 4.9 Other Diseases, 446 4.9.1 Premature Aging Diseases Progeria and Werner’s Syndrome, 446 4.9.2 Renal Failure and Hemodialysis in Elderly People, 447 4.9.3 Obesity, 447 4.9.4 Idiopathic Pulmonary Fibrosis, 448 4.9.5 Presbycusis (Age-Related Hear Loss), 448 References, 448 List of Abbreviations 479 Index 493

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Book SynopsisAs the ability to produce nanomaterials advances, it becomes more important to understand how the energy of the atoms in these materials is affected by their reduced dimensions.Table of ContentsPREFACE ix CHAPTER 1 INTRODUCTION TO KINETICS IN NANOSCALE MATERIALS 1 1.1 Introduction 1 1.2 Nanosphere: Surface Energy is Equivalent to Gibbs–Thomson Potential 3 1.3 Nanosphere: Lower Melting Point 6 1.4 Nanosphere: Fewer Homogeneous Nucleation and its Effect on Phase Diagram 10 1.5 Nanosphere: Kirkendall Effect and Instability of Hollow Nanospheres 13 1.6 Nanosphere: Inverse Kirkendall Effect in Hollow Nano Alloy Spheres 17 1.7 Nanosphere: Combining Kirkendall Effect and Inverse Kirkendall Effect on Concentric Bilayer Hollow Nanosphere 18 1.8 Nano Hole: Instability of a Donut-Type Nano Hole in a Membrane 19 1.9 Nanowire: Point Contact Reactions Between Metal and Silicon Nanowires 21 1.10 Nanowire: Nanogap in Silicon Nanowires 22 1.11 Nanowire: Lithiation in Silicon Nanowires 26 1.12 Nanowire: Point Contact Reactions Between Metallic Nanowires 27 1.13 Nano Thin Film: Explosive Reaction in Periodic Multilayered Nano Thin Films 28 1.14 Nano Microstructure in Bulk Samples: Nanotwins 30 1.15 Nano Microstructure on the Surface of a Bulk Sample: Surface Mechanical Attrition Treatment (SMAT) of Steel 32 References 33 Problems 35 CHAPTER 2 LINEAR AND NONLINEAR DIFFUSION 37 2.1 Introduction 37 2.2 Linear Diffusion 38 2.2.1 Atomic Flux 39 2.2.2 Fick’s First Law of Diffusion 40 2.2.3 Chemical Potential 43 2.2.4 Fick’s Second Law of Diffusion 45 2.2.5 Flux Divergence 47 2.2.6 Tracer Diffusion 49 2.2.7 Diffusivity 51 2.2.8 Experimental Measurement of the Parameters in Diffusivity 53 2.3 Nonlinear Diffusion 57 2.3.1 Nonlinear Effect due to Kinetic Consideration 58 2.3.2 Nonlinear Effect due to Thermodynamic Consideration 59 2.3.3 Combining Thermodynamic and Kinetic Nonlinear Effects 62 References 63 Problems 64 CHAPTER 3 KIRKENDALL EFFECT AND INVERSE KIRKENDALL EFFECT 67 3.1 Introduction 67 3.2 Kirkendall Effect 69 3.2.1 Darken’s Analysis of Kirkendall Shift and Marker Motion 72 3.2.2 Boltzmann and Matano Analysis of Interdiffusion Coefficient 76 3.2.3 Activity and Intrinsic Diffusivity 80 3.2.4 Kirkendall (Frenkel) Voiding Without Lattice Shift 84 3.3 Inverse Kirkendall Effect 84 3.3.1 Physical Meaning of Inverse Kirkendall Effect 86 3.3.2 Inverse Kirkendall Effect on the Instability of an Alloy Nanoshell 88 3.3.3 Inverse Kirkendall Effect on Segregation in a Regular Solution Nanoshell 90 3.4 Interaction Between Kirkendall Effect and Gibbs–Thomson Effect in the Formation of a Spherical Compound Nanoshell 93 References 97 Problems 97 CHAPTER 4 RIPENING AMONG NANOPRECIPITATES 99 4.1 Introduction 99 4.2 Ham’s Model of Growth of a Spherical Precipitate (Cr is Constant) 101 4.3 Mean-Field Consideration 103 4.4 Gibbs–Thomson Potential 105 4.5 Growth and Dissolution of a Spherical Nanoprecipitate in a Mean Field 106 4.6 LSW Theory of Kinetics of Particle Ripening 108 4.7 Continuity Equation in Size Space 113 4.8 Size Distribution Function in Conservative Ripening 114 4.9 Further Developments of LSW Theory 115 References 115 Problems 116 CHAPTER 5 SPINODAL DECOMPOSITION 118 5.1 Introduction 118 5.2 Implication of Diffusion Equation in Homogenization and Decomposition 121 5.3 Spinodal Decomposition 123 5.3.1 Concentration Gradient in an Inhomogeneous Solid Solution 123 5.3.2 Energy of Mixing to Form a Homogeneous Solid Solution 124 5.3.3 Energy of Mixing to Form an Inhomogeneous Solid Solution 126 5.3.4 Chemical Potential in Inhomogeneous Solution 129 5.3.5 Coherent Strain Energy 131 5.3.6 Solution of the Diffusion Equation 134 References 136 Problems 136 CHAPTER 6 NUCLEATION EVENTS IN BULK MATERIALS, THIN FILMS, AND NANOWIRES 138 6.1 Introduction 138 6.2 Thermodynamics and Kinetics of Nucleation 140 6.2.1 Thermodynamics of Nucleation 140 6.2.2 Kinetics of Nucleation 143 6.3 Heterogeneous Nucleation in Grain Boundaries of Bulk Materials 148 6.3.1 Morphology of Grain Boundary Precipitates 150 6.3.2 Introducing an Epitaxial Interface to Heterogeneous Nucleation 151 6.3.3 Replacive Mechanism of a Grain Boundary 154 6.4 No Homogeneous Nucleation in Epitaxial Growth of Si Thin Film on Si Wafer 156 6.5 Repeating Homogeneous Nucleation of Silicide in Nanowires of Si 160 6.5.1 Point Contact Reactions in Nanowires 161 6.5.2 Homogeneous Nucleation of Epitaxial Silicide in Nanowires of Si 164 References 168 Problems 168 CHAPTER 7 CONTACT REACTIONS ON Si; PLANE, LINE, AND POINT CONTACT REACTIONS 170 7.1 Introduction 170 7.2 Bulk Cases 175 7.2.1 Kidson’s Analysis of Diffusion-Controlled Planar Growth 175 7.2.2 Steady State Approximation in Layered Growth of Multiple Phases 178 7.2.3 Marker Analysis 179 7.2.4 Interdiffusion Coefficient in Intermetallic Compound 182 7.2.5 Wagner Diffusivity 186 7.3 Thin Film Cases 187 7.3.1 Diffusion-Controlled and Interfacial-Reaction-Controlled Growth 187 7.3.2 Kinetics of Interfacial-Reaction-Controlled Growth 188 7.3.3 Kinetics of Competitive Growth of Two-Layered Phases 193 7.3.4 First Phase in Silicide Formation 194 7.4 Nanowire Cases 196 7.4.1 Point Contact Reactions 197 7.4.2 Line Contact Reactions 202 7.4.3 Planar Contact Reactions 208 References 208 Problems 209 CHAPTER 8 GRAIN GROWTH IN MICRO AND NANOSCALE 211 8.1 Introduction 211 8.2 How to Generate a Polycrystalline Microstructure 213 8.3 Computer Simulation of Grain Growth 216 8.3.1 Atomistic Simulation Based on Monte Carlo Method 216 8.3.2 Phenomenological Simulations 217 8.4 Statistical Distribution Functions of Grain Size 219 8.5 Deterministic (Dynamic) Approach to Grain Growth 221 8.6 Coupling Between Grain Growth of a Central Grain and the Rest of Grains 225 8.7 Decoupling the Grain Growth of a Central Grain from the Rest of Grains in the Normalized Size Space 226 8.8 Grain Growth in 2D Case in the Normalized Size Space 229 8.9 Grain Rotation 231 8.9.1 Grain Rotation in Anisotropic Thin Films Under Electromigration 232 References 237 Problems 238 CHAPTER 9 SELF-SUSTAINED REACTIONS IN NANOSCALE MULTILAYERED THIN FILMS 240 9.1 Introduction 240 9.2 The Selection of a Pair of Metallic Thin Films for SHS 243 9.3 A Simple Model of Single-Phase Growth in Self-Sustained Reaction 245 9.4 A Simple Estimate of Flame Velocity in Steady State Heat Transfer 250 9.5 Comparison in Phase Formation by Annealing and by Explosive Reaction in Al/Ni 251 9.6 Self-Explosive Silicidation Reactions 251 References 255 Problems 256 CHAPTER 10 FORMATION AND TRANSFORMATIONS OF NANOTWINS IN COPPER 258 10.1 Introduction 258 10.2 Formation of Nanotwins in Cu 260 10.2.1 First Principle Calculation of Energy of Formation of Nanotwins 260 10.2.2 In Situ Measurement of Stress Evolution for Nanotwin Formation During Pulse Electrodeposition of Cu 264 10.2.3 Formation of Nanotwin Cu in Through-Silicon Vias 266 10.3 Formation and Transformation of Oriented Nanotwins in Cu 269 10.3.1 Formation of Oriented Nanotwins in Cu 270 10.3.2 Unidirectional Growth of Cu–Sn Intermetallic Compound on Oriented and Nanotwinned Cu 270 10.3.3 Transformation of ⟨111⟩ Oriented and Nanotwinned Cu to ⟨100⟩ Oriented Single Crystal of Cu 274 10.4 Potential Applications of Nanotwinned Cu 276 10.4.1 To Reduce Electromigration in Interconnect Technology 276 10.4.2 To Eliminate Kirkendall Voids in Microbump Packaging Technology 277 References 278 Problems 278 APPENDIX A LAPLACE PRESSURE IN NONSPHERICAL NANOPARTICLE 280 APPENDIX B INTERDIFFUSION COEFFICIENT Þ D = CBMG′′ 282 APPENDIX C NONEQUILIBRIUM VACANCIES AND CROSS-EFFECTS ON INTERDIFFUSION IN A PSEUDO-TERNARY ALLOY 285 APPENDIX D INTERACTION BETWEEN KIRKENDALL EFFECT AND GIBBS–THOMSON EFFECT IN THE FORMATION OF A SPHERICAL COMPOUND NANOSHELL 289 INDEX 293

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Book SynopsisExplores the impact of the latest breakthroughs in cluster SIMS technology Cluster secondary ion mass spectrometry (SIMS) is a high spatial resolution imaging mass spectrometry technique, which can be used to characterize the three-dimensional chemical structure in complex organic and molecular systems. It works by using a cluster ion source to sputter desorb material from a solid sample surface. Prior to the advent of the cluster source, SIMS was severely limited in its ability to characterize soft samples as a result of damage from the atomic source. Molecular samples were essentially destroyed during analysis, limiting the method''s sensitivity and precluding compositional depth profiling. The use of new and emerging cluster ion beam technologies has all but eliminated these limitations, enabling researchers to enter into new fields once considered unattainable by the SIMS method. With contributions from leading mass spectrometry researchers around the world,Table of ContentsContributors xi About the Editor xiii 1 AN INTRODUCTION TO CLUSTER SECONDARY ION MASS SPECTROMETRY (CLUSTER SIMS) 1 Christine M. Mahoney and Greg Gillen 1.1 Secondary Ion Mass Spectrometry in a Nutshell 2 1.1.1 SIMS Imaging 4 1.1.2 SIMS Depth Profiling 4 1.2 Basic Cluster SIMS Theory 5 1.3 Cluster SIMS: An Early History 6 1.3.1 Nonlinear Sputter Yield Enhancements 6 1.3.2 Molecular Depth Profiling 7 1.4 Recent Developments 8 1.5 About this Book 9 Acknowledgment 11 References 11 2 CLUSTER SIMS OF ORGANIC MATERIALS: THEORETICAL INSIGHTS 13 Arnaud Delcorte, Oscar A. Restrepo, and Bartlomiej Czerwinski 2.1 Introduction 13 2.2 Molecular Dynamics Simulations of Sputtering with Clusters 15 2.2.1 The Cluster Effect 15 2.2.2 Computer Simulations and the Molecular Dynamics “Experiment” 18 2.2.3 Light and Heavy Element Clusters, and the Importance of Mass Matching 20 2.2.4 Structural Effects in Organic Materials 21 2.2.4.1 Amorphous Molecular Solids and Polymers 21 2.2.4.2 Organic Crystals 26 2.2.4.3 Thin Organic Layers on Metal Substrates 28 2.2.4.4 Hybrid Metal–Organic Samples 32 2.2.5 Induced Chemistry 34 2.2.6 Multiple Hits and Depth Profiling 36 2.2.7 From Small Polyatomic Projectiles to Massive Clusters 38 2.2.7.1 Light-Element Clusters 38 2.2.7.2 Large Argon Clusters 41 2.2.7.3 Massive Gold Clusters 45 2.3 Other Models 46 2.3.1 Analytical Models: From Linear Collision Cascades to Fluid Dynamics 46 2.3.2 Recent Developments and Hybrid Approaches 47 2.4 Conclusions 50 Acknowledgments 51 References 51 3 ION SOURCES USED FOR SECONDARY ION MASS SPECTROMETRY 57 Albert J. Fahey 3.1 Introduction 57 3.2 Research Needs that have Influenced the Development of Primary Ion Sources for Sputtering 58 3.3 Functional Aspects of Various Ion Sources 59 3.3.1 Energy Spread in the Beam 59 3.3.2 Point-Source Ionization 60 3.3.3 Stable Emission 60 3.3.4 Ion Reactivity 60 3.3.5 Source Lifetime 60 3.3.6 Penetration Depth and Surface Energy Spread of the Projectile 61 3.4 Atomic Ion Sources 61 3.4.1 Field Emission 61 3.4.2 Radio Frequency (RF) Ionization 62 3.4.3 Electron Impact 63 3.4.4 Thermal Ionization 64 3.4.5 DC-Glow Discharge 65 3.4.6 Sputtering 66 3.5 Molecular Ion Sources 66 3.5.1 Field Emission 66 3.5.2 Radio Frequency Discharge 67 3.5.3 Electron Impact 68 3.5.4 DC-Glow Discharge 69 3.5.5 Sputtering 69 3.6 Cluster Ion Sources 70 3.6.1 Jets and Electron Impact (Massive Gas Clusters) 71 3.6.2 Field Emission 72 3.7 Summary 73 References 74 4 SURFACE ANALYSIS OF ORGANIC MATERIALS WITH POLYATOMIC PRIMARY ION SOURCES 77 Christine M. Mahoney 4.1 Introduction 77 4.2 Cluster Sources in Static SIMS 78 4.2.1 A Brief Introduction to Static SIMS 78 4.2.2 Analysis beyond the Static Limit 79 4.2.3 Increased Ion Yields 80 4.2.4 Decreased Charging 81 4.2.5 Surface Cleaning 82 4.3 Experimental Considerations 83 4.3.1 When to Employ Cluster Sources as Opposed to Atomic Sources 83 4.3.2 Type of Cluster Source Used 84 4.3.2.1 Liquid Metal Ion Gun (LMIG) 84 4.3.2.2 C + 60 for Mass Spectral Analysis and Imaging Applications 85 4.3.2.3 The Gas Cluster Ion Beam (GCIB) 86 4.3.2.4 Au 4+ 400 86 4.3.2.5 Other Sources 88 4.3.3 Cluster Size Considerations 88 4.3.4 Beam Energy 90 4.3.5 Sample Temperature 92 4.3.6 Matrix-Enhanced and Metal-Assisted Cluster SIMS 92 4.3.7 Matrix Effects 95 4.3.8 Other Important Factors 96 4.4 Data Analysis Methods 96 4.4.1 Principal Components Analysis 96 4.4.1.1 Basic Principles of PCA 97 4.4.1.2 Examples of PCA in the Literature 98 4.4.2 Gentle SIMS (G-SIMS) 101 4.5 Other Relevant Surface Mass-Spectrometry-Based Methods 101 4.5.1 Desorption Electrospray Ionization (DESI) 103 4.5.2 Plasma Desorption Ionization Methods 105 4.5.3 Electrospray Droplet Impact Source for SIMS 107 4.6 Advanced Mass Spectrometers for SIMS 108 4.7 Conclusions 109 Appendix A: Useful Lateral Resolution 110 References 110 5 MOLECULAR DEPTH PROFILING WITH CLUSTER ION BEAMS 117 Christine M. Mahoney and Andreas Wucher 5.1 Introduction 117 5.2 Historical Perspectives 120 5.3 Depth Profiling in Heterogeneous Systems 123 5.3.1 Introduction 123 5.3.2 Quantitative Depth Profiling 125 5.3.3 Reconstruction of 3D Images 127 5.3.4 Matrix Effects in Heterogeneous Systems 128 5.4 Erosion Dynamics Model of Molecular Sputter Depth Profiling 130 5.4.1 Parent Molecule Dynamics 131 5.4.2 Constant Erosion Rate 134 5.4.3 Fluence-Dependent Erosion Rate 136 5.4.4 Using Mass Spectrometric Signal Decay to Measure Damage Parameters 138 5.4.5 Surface Transients 141 5.4.6 Fragment Dynamics 141 5.4.7 Conclusions 145 5.5 The Chemistry of Atomic Ion Beam Irradiation in Organic Materials 146 5.5.1 Introduction 146 5.5.2 Understanding the Basics of Ion Irradiation Effects in Molecular Solids 146 5.5.3 Ion Beam Irradiation and the Gel Point 147 5.5.4 The Chemistry of Cluster Ion Beams 150 5.5.5 Chemical Structure Changes and Corresponding Changes in Depth Profile Shapes 152 5.6 Optimization of Experimental Parameters for Organic Depth Profiling 156 5.6.1 Introduction 156 5.6.2 Organic Delta Layers for Optimization of Experimental Parameters 157 5.6.3 Sample Temperature 159 5.6.4 Understanding the Role of Beam Energy During Organic Depth Profiling 167 5.6.5 Optimization of Incidence Angle 171 5.6.6 Effect of Sample Rotation 174 5.6.7 Ion Source Selection 178 5.6.7.1 SF + 5 and Other Small Cluster Ions 178 5.6.7.2 C n+ 60 and Similar Carbon Cluster Sources 179 5.6.7.3 The Gas Cluster Ion Beam (GCIB) 180 5.6.7.4 Low Energy Reactive Ion Beams 188 5.6.7.5 Electrospray Droplet Impact (EDI) Source for SIMS 189 5.6.7.6 Liquid Metal Ion Gun Clusters (Bi + 3 and Au + 3 ) 193 5.6.8 C + 60 /Ar+ Co-sputtering 195 5.6.9 Chamber Backfilling with a Free Radical Inhibitor Gas 197 5.6.10 Other Considerations for Organic Depth Profiling Experiments 197 5.6.11 Molecular Depth Profiling: Novel Approaches and Methods 198 5.7 Conclusions 198 References 200 6 THREE-DIMENSIONAL IMAGING WITH CLUSTER ION BEAMS 207 Andreas Wucher, Gregory L. Fisher, and Christine M. Mahoney 6.1 Introduction 207 6.2 General Strategies 210 6.2.1 Three-Dimensional Sputter Depth Profiling 210 6.2.2 Wedge Beveling 216 6.2.3 Physical Cross Sectioning 217 6.2.4 FIB-ToF Tomography 219 6.3 Important Considerations for Accurate 3D Representation of Data 225 6.3.1 Beam Rastering Techniques 225 6.3.2 Geometry Effects 226 6.3.3 Depth Scale Calibration 228 6.4 Three-Dimensional Image Reconstruction 233 6.5 Damage and Altered Layer Depth 238 6.6 Biological Samples 242 6.7 Conclusions 243 References 244 7 CLUSTER SECONDARY ION MASS SPECTROMETRY (SIMS) FOR SEMICONDUCTOR AND METALS DEPTH PROFILING 247 Greg Gillen and Joe Bennett 7.1 Introduction 247 7.2 Primary Particle–Substrate Interactions 248 7.2.1 Collisional Mixing and Depth Resolution 248 7.2.2 Transient Effects 249 7.2.3 Sputter-Induced Roughening 251 7.3 Possible Improvements in SIMS Depth Profiling—The Use of Cluster Primary Ion Beams 253 7.4 Development of Cluster SIMS for Depth Profiling Analysis 255 7.4.1 CF + 3 Primary Ion Beams 255 7.4.2 NO + 2 and O + 3 Primary Ion Beams 256 7.4.3 SF + 5 Polyatomic Primary Ion Beams 257 7.4.4 CSC − 6 and C − 8 Depth Profiling 258 7.4.5 Os3(CO)12 and Ir4(CO)12 Primary Ion Beams 262 7.4.6 C + 60 Primary Ion Beams 263 7.4.7 Massive Gaseous Cluster Ion Beams 265 7.5 Conclusions and Future Prospects 266 References 266 8 CLUSTER TOF-SIMS IMAGING AND THE CHARACTERIZATION OF BIOLOGICAL MATERIALS 269 John Vickerman and Nick Winograd 8.1 Introduction 269 8.2 The Capabilities of TOF-SIMS for Biological Analysis 270 8.3 New Hybrid TOF-SIMS Instruments 270 8.3.1 Introduction 270 8.3.2 Benefits of New DC Beam Technologies 271 8.4 Challenges in the Use of TOF-SIMS for Biological Analysis 273 8.4.1 Sample Handling of Biological Samples for Analysis in Vacuum 273 8.4.2 Analysis is Limited to Small to Medium Size Molecules 274 8.4.3 Ion Yields Limit Useful Spatial Resolution for Molecular Analysis to not Much Better than 1 μm 275 8.4.4 Matrix Effects Inhibit Application in Discovery Mode and Greatly Complicates Quantification 275 8.4.5 The Complexity of Biological Systems can Result in Data Sets that Need Multivariate Analysis (MVA) to Unravel 276 8.5 Examples of Biological Studies Using Cluster-TOF-SIMS 276 8.5.1 Analysis of Tissue 277 8.5.2 Drug Location in Tissue 285 8.5.3 Microbial Mat—Surface and Subsurface Analysis in Streptomyces 289 8.5.4 Cells 291 8.5.5 Depth Scale Measurement 302 8.5.6 High Throughput Biomaterials Characterization 306 8.6 Final Thoughts and Future Directions 310 Acknowledgments 310 References 310 9 FUTURE CHALLENGES AND PROSPECTS OF CLUSTER SIMS 313 Peter Williams and Christine M. Mahoney 9.1 Introduction 313 9.2 The Cluster Niche 314 9.3 Cluster Types 314 9.4 The Challenge of Massive Molecular Ion Ejection 315 9.4.1 Comparing with MALDI: The Gold Standard 316 9.4.2 Particle Impact Techniques 317 9.5 Ionization 318 9.5.1 “Preformed” Ions 319 9.5.2 Radical Ions and Ion Fragments 319 9.5.3 Ionization Processes for Massive Clusters 320 9.6 Matrix Effects and Challenges in Quantitative Analysis 321 9.7 SIMS Instrumentation 322 9.7.1 Massive Cluster Ion Source Technology 323 9.8 Prospects for Biological Imaging 324 9.9 Conclusions 325 References 326 Index 329

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Book SynopsisThis series provides the most comprehensive and highly focused treatment of important organic reactions currently available. All volumes of Organic Reactions (including this one) are collections of chapters each devoted to a single reaction or a definitive phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method.Table of ContentsCHAPTER PAGE 1. HYDROCYANATION OF ALKENES AND ALKYNES T. V. RajanBabu1 2. INTERMOLECULAR C-H INSERTIONS OF CARBENOIDS Huw M. L. Davies and Phillip M. Pelphrey 75 3. CROSS-COUPLING WITH ORGANOSILICON COMPOUNDS Wen-Tau T. Chang, Russell C. Smith, Christopher S. Regens, Aaron D. Bailey, Nathan S. Werner, and Scott E. Denmark 213 4. THE AZA-COPE/MANNICH REACTION Larry E. Overman, Philip G. Humphreys, and Gregory S. Welmaker 747 CUMULATIVE CHAPTER TITLES BY VOLUME 821 AUTHOR INDEX, VOLUMES 1–75 835 CHAPTER AND TOPIC INDEX, VOLUMES 1–75 841

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Book SynopsisDrawing from thousands of original research articles, this book focuses on new and emerging applications of supercritical water as a green solvent, including the catalytic conversion of biomass into fuels and the oxidation of hazardous materials.Table of ContentsPreface ix List of Acronyms and Symbols xiii 1 Introduction 1 1.1 Phase Diagrams of Single Fluids 1 1.2 The Critical Point 3 1.3 Supercritical Fluids as Solvents 5 1.4 Gaseous and Liquid Water 8 1.5 Near-Critical Water 15 1.6 Summary 17 2 Bulk Properties of SCW 22 2.1 Equations of State(EoS) 22 2.1.1 PVT Data for SCW 22 2.1.2 Classical Equations of State of SCW 24 2.1.3 Scaling Equations of State for SCW 26 2.1.4 EoS of Supercritical Heavy Water 29 2.2 Thermophysical Properties of SCW 30 2.2.1 Heat Capacity 30 2.2.2 Enthalpy and Entropy 32 2.2.3 Sound Velocity 34 2.3 Electrical and Optical Properties 34 2.3.1 Static Relative Permittivity 34 2.3.2 Electrical Conductivity 37 2.3.3 Light Refraction 38 2.4 Transport Properties 39 2.4.1 Viscosity 39 2.4.2 Self-Diffusion 41 2.4.3 Thermal Conductivity 42 2.5 Ionic Dissociation of SCW 44 2.6 Properties Related to the Solvent Power of SCW 47 2.7 Summary 49 3 Molecular Properties of SCW 57 3.1 Diffraction Studies of SCW Structure 60 3.1.1 X-Ray Diffraction Studies of SCW Structure 61 3.1.2 Neutron Diffraction Studies of SCW Structure 62 3.2 Computer Simulations of SCW 66 3.2.1 Monte Carlo Simulations 67 3.2.2 Molecular Dynamics Simulations 70 3.3 Spectroscopic Studies of SCW 74 3.3.1 Infrared Absorption Spectroscopy 74 3.3.2 Raman Scattering Spectroscopy 77 3.3.3 Nuclear Magnetic Resonance 79 3.3.4 Dielectric Relaxation Spectroscopy 82 3.4 The Extent of Hydrogen Bonding in SCW 83 3.5 The Dynamics of Water Molecules in SCW 90 3.6 Summary 92 4 SCW as a “Green” Solvent 100 4.1 Solutions of Gases in SCW 101 4.1.1 Phase Equilibria 101 4.1.2 Interactions in the Solutions 104 4.2 Solutions of Organic Substances in SCW 106 4.2.1 Phase Equilibria 106 4.2.2 Interactions in the Solutions 111 4.3 Solutions of Salts and Ions in SCW 115 4.3.1 Solubilities of Salts and Electrolytes 115 4.3.2 Thermodynamic Properties 121 4.3.3 Transport Properties 123 4.3.4 Ion Association in SCW 129 4.3.5 Ion Hydration in SCW 134 4.4 Binary Mixtures of Cosolvents with SCW 138 4.5 Summary 141 5 Applications of SCW 151 5.1 Conversion of Organic Substances to Fuel 152 5.1.1 Conversion to Hydrogen and Natural Gas 152 5.1.2 Conversion to Liquid Fuel 156 5.2 Supercritical Water Oxidation 157 5.2.1 General Aspects of SCWO Process 158 5.2.2 Examples of SCWO Applications 160 5.3 Uses of SCW in Organic Synthesis 162 5.4 Uses in Powder Technology of Inorganic Substances 164 5.5 Geothermal Aspects of SCW 166 5.6 Application of SCW in Nuclear Reactors 169 5.7 Corrosion Problems with SCW 171 5.8 Summary 174 Author Index 183 Subject Index 199

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Book SynopsisThis book presents ways to analyze complex bioprocesses and drug delivery systems using control theory. Filled with detailed examples, case studies, computer projects, and step-by-step solutions to numerical problems using computational software, it addresses issues and solves problems that dominate both fields.Trade Review"This text — featuring examples from the biological sciences, including novel drug-delivery systems — will help students and pharmaceutical researchers to develop a better understanding of process dynamics and control theory, so that they can analyze and solve a variety of problems in bioprocess and drug-delivery systems." (Chemical Engineering Progress, 21 May 2013)Table of ContentsPreface xi Acknowledgments xv 1 Introduction 1 1.1 The Role of Process Dynamics and Control in Branches of Biology 1 1.2 The Role of Process Dynamics and Control in Drug-Delivery Systems 10 1.3 Instrumentation 12 1.4 Summary 18 Problems 18 References 19 2 Mathematical Models 21 2.1 Background 22 2.2 Dynamics of Bioreactors 27 2.3 One- and Two-Compartment Models 34 2.4 Enzyme Kinetics 37 2.5 Summary 39 Problems 39 References 41 3 Linearization and Deviation Variables 43 3.1 Computer Simulations 43 3.2 Linearization of Systems 44 3.3 Glycolytic Oscillation 55 3.4 Hodgkin–Huxley Model 57 3.5 Summary 60 Problems 61 References 63 4 Stability Considerations 65 4.1 Definition of Stability 65 4.2 Steady-State Conditions and Equilibrium Points 79 4.3 Phase-Plane Diagrams 80 4.4 Population Kinetics 80 4.5 Dynamics of Bioreactors 83 4.6 Glycolytic Oscillation 85 4.7 Hodgkin–Huxley Model 87 4.8 Summary 88 Problems 88 References 91 5 Laplace Transforms 93 5.1 Definition of Laplace Transforms 93 5.2 Properties of Laplace Transforms 95 5.3 Laplace Transforms of Functions, Derivatives, and Integrals 96 5.4 Laplace Transforms of Linear Ordinary Differential Equation (ODE) and Partial Differential Equation (PDE) 104 5.5 Continuous Fermentation 108 5.6 Two-Compartment Models 110 5.7 Gene Regulation 111 5.8 Summary 113 Problems 113 Reference 115 6 Inverse Laplace Transforms 117 6.1 Heaviside Expansions 117 6.2 Residue Theorem 126 6.3 Continuous Fermentation 134 6.4 Degradation of Plasmid DNA 136 6.5 Constant-Rate Intravenous Infusion 138 6.6 Transdermal Drug-Delivery Systems 139 6.7 Summary 146 Problems 146 References 148 7 Transfer Functions 149 7.1 Input–Output Models 149 7.2 Derivation of Transfer Functions 150 7.3 One- and Two-Compartment Models: Michaelis–Menten Kinetics 154 7.4 Controlled-Release Systems 157 7.5 Summary 158 Problems 158 8 Dynamic Behaviors of Typical Plants 163 8.1 First-, Second- and Higher-Order Systems 163 8.2 Reduced-Order Models 167 8.3 Transcendental Transfer Functions 169 8.4 Time Responses of Systems with Rational Transfer Functions 171 8.5 Time Responses of Systems with Transcendental Transfer Functions 190 8.6 Bone Regeneration 192 8.7 Nitric Oxide Transport to Pulmonary Arterioles 193 8.8 Transdermal Drug Delivery 194 8.9 Summary 194 Problems 195 References 197 9 Closed-loop Responses with P, Pi, and Pid Controllers 199 9.1 Block Diagram of Closed-Loop Systems 200 9.2 Proportional Control 203 9.3 PI Control 204 9.4 PID Control 206 9.5 Total Sugar Concentration in a Glutamic Acid Production 207 9.6 Temperature Control of Fermentations 209 9.7 DO Concentration 213 9.8 Summary 214 Problems 215 References 217 10 Frequency Response Analysis 219 10.1 Frequency Response for Linear Systems 219 10.2 Bode Diagrams 227 10.3 Nyquist Plots 229 10.4 Transdermal Drug Delivery 232 10.5 Compartmental Models 236 10.6 Summary 239 Problems 239 References 240 11 Stability Analysis of Feedback Systems 243 11.1 Routh–Hurwitz Stability Criterion 243 11.2 Root Locus Analysis 248 11.3 Bode Stability Criterion 249 11.4 Nyquist Stability Criterion 254 11.5 Cheyne–Stokes Respiration 257 11.6 Regulation of Biological Pathways 262 11.7 Pupillary Light Reflex 264 11.8 Summary 265 Problems 265 References 267 12 Design of Feedback Controllers 269 12.1 Tuning Methods for Feedback Controllers 269 12.2 Regulation of Glycemia 279 12.3 Dissolved Oxygen Concentration 282 12.4 Control of Biomass in a Chemostat 284 12.5 Controlled Infusion of Vasoactive Drugs 285 12.6 Bone Regeneration 286 12.7 Fed-Batch Biochemical Processes 288 12.8 Summary 289 Problems 289 References 291 13 Feedback Control of Dead-time Systems 293 13.1 Smith Predictor-Based Methods 294 13.2 Control of Biomass 300 13.3 Zymomonas mobilis Fermentation for Ethanol Production 302 13.4 Fed-Batch Cultivation of Acinetobacter calcoaceticus Rag-1 304 13.5 Regulation of Glycemia 304 13.6 Summary 306 Problems 306 References 309 14 Cascade and Feedforward Control Strategies 311 14.1 Cascade Control 311 14.2 Feedforward Control 317 14.3 Insulin Infusion 321 14.4 A Gaze Control System 323 14.5 Control of pH 326 14.6 Summary 330 Problems 331 References 333 15 Effective Time Constant 335 15.1 Linear Second-Order ODEs 335 15.2 Sturm–Liouville (SL) Eigenvalue Problems 337 15.3 Relaxation Time Constant 340 15.4 Implementation in Mathematica ® 342 15.5 Controlled-Release Devices 342 15.6 Summary 343 Problems 344 References 345 16 Optimum Control and Design 347 16.1 Orthogonal Collocation Techniques 348 16.2 Dynamic Programming 350 16.3 Optimal Control of Drug-Delivery Rates 350 16.4 Optimal Design of Controlled-Release Devices 351 16.5 Implementation in Mathematica ® 352 16.6 Summary 358 Problems 359 References 360 Index 361 Preface xi Acknowledgments xv 1 Introduction 1 1.1 The Role of Process Dynamics and Control in Branches of Biology 1 1.2 The Role of Process Dynamics and Control in Drug-Delivery Systems 10 1.3 Instrumentation 12 1.4 Summary 18 Problems 18 References 19 2 Mathematical Models 21 2.1 Background 22 2.2 Dynamics of Bioreactors 27 2.3 One- and Two-Compartment Models 34 2.4 Enzyme Kinetics 37 2.5 Summary 39 Problems 39 References 41 3 Linearization and Deviation Variables 43 3.1 Computer Simulations 43 3.2 Linearization of Systems 44 3.3 Glycolytic Oscillation 55 3.4 Hodgkin–Huxley Model 57 3.5 Summary 60 Problems 61 References 63 4 Stability Considerations 65 4.1 Definition of Stability 65 4.2 Steady-State Conditions and Equilibrium Points 79 4.3 Phase-Plane Diagrams 80 4.4 Population Kinetics 80 4.5 Dynamics of Bioreactors 83 4.6 Glycolytic Oscillation 85 4.7 Hodgkin–Huxley Model 87 4.8 Summary 88 Problems 88 References 91 5 Laplace Transforms 93 5.1 Definition of Laplace Transforms 93 5.2 Properties of Laplace Transforms 95 5.3 Laplace Transforms of Functions, Derivatives, and Integrals 96 5.4 Laplace Transforms of Linear Ordinary Differential Equation (ODE) and Partial Differential Equation (PDE) 104 5.5 Continuous Fermentation 108 5.6 Two-Compartment Models 110 5.7 Gene Regulation 111 5.8 Summary 113 Problems 113 Reference 115 6 Inverse Laplace Transforms 117 6.1 Heaviside Expansions 117 6.2 Residue Theorem 126 6.3 Continuous Fermentation 134 6.4 Degradation of Plasmid DNA 136 6.5 Constant-Rate Intravenous Infusion 138 6.6 Transdermal Drug-Delivery Systems 139 6.7 Summary 146 Problems 146 References 148 7 Transfer Functions 149 7.1 Input–Output Models 149 7.2 Derivation of Transfer Functions 150 7.3 One- and Two-Compartment Models: Michaelis–Menten Kinetics 154 7.4 Controlled-Release Systems 157 7.5 Summary 158 Problems 158 8 Dynamic Behaviors of Typical Plants 163 8.1 First-, Second- and Higher-Order Systems 163 8.2 Reduced-Order Models 167 8.3 Transcendental Transfer Functions 169 8.4 Time Responses of Systems with Rational Transfer Functions 171 8.5 Time Responses of Systems with Transcendental Transfer Functions 190 8.6 Bone Regeneration 192 8.7 Nitric Oxide Transport to Pulmonary Arterioles 193 8.8 Transdermal Drug Delivery 194 8.9 Summary 194 Problems 195 References 197 9 Closed-loop Responses with P, Pi, and Pid Controllers 199 9.1 Block Diagram of Closed-Loop Systems 200 9.2 Proportional Control 203 9.3 PI Control 204 9.4 PID Control 206 9.5 Total Sugar Concentration in a Glutamic Acid Production 207 9.6 Temperature Control of Fermentations 209 9.7 DO Concentration 213 9.8 Summary 214 Problems 215 References 217 10 Frequency Response Analysis 219 10.1 Frequency Response for Linear Systems 219 10.2 Bode Diagrams 227 10.3 Nyquist Plots 229 10.4 Transdermal Drug Delivery 232 10.5 Compartmental Models 236 10.6 Summary 239 Problems 239 References 240 11 Stability Analysis of Feedback Systems 243 11.1 Routh–Hurwitz Stability Criterion 243 11.2 Root Locus Analysis 248 11.3 Bode Stability Criterion 249 11.4 Nyquist Stability Criterion 254 11.5 Cheyne–Stokes Respiration 257 11.6 Regulation of Biological Pathways 262 11.7 Pupillary Light Reflex 264 11.8 Summary 265 Problems 265 References 267 12 Design of Feedback Controllers 269 12.1 Tuning Methods for Feedback Controllers 269 12.2 Regulation of Glycemia 279 12.3 Dissolved Oxygen Concentration 282 12.4 Control of Biomass in a Chemostat 284 12.5 Controlled Infusion of Vasoactive Drugs 285 12.6 Bone Regeneration 286 12.7 Fed-Batch Biochemical Processes 288 12.8 Summary 289 Problems 289 References 291 13 Feedback Control of Dead-time Systems 293 13.1 Smith Predictor-Based Methods 294 13.2 Control of Biomass 300 13.3 Zymomonas mobilis Fermentation for Ethanol Production 302 13.4 Fed-Batch Cultivation of Acinetobacter calcoaceticus Rag-1 304 13.5 Regulation of Glycemia 304 13.6 Summary 306 Problems 306 References 309 14 Cascade and Feedforward Control Strategies 311 14.1 Cascade Control 311 14.2 Feedforward Control 317 14.3 Insulin Infusion 321 14.4 A Gaze Control System 323 14.5 Control of pH 326 14.6 Summary 330 Problems 331 References 333 15 Effective Time Constant 335 15.1 Linear Second-Order ODEs 335 15.2 Sturm–Liouville (SL) Eigenvalue Problems 337 15.3 Relaxation Time Constant 340 15.4 Implementation in Mathematica ® 342 15.5 Controlled-Release Devices 342 15.6 Summary 343 Problems 344 References 345 16 Optimum Control and Design 347 16.1 Orthogonal Collocation Techniques 348 16.2 Dynamic Programming 350 16.3 Optimal Control of Drug-Delivery Rates 350 16.4 Optimal Design of Controlled-Release Devices 351 16.5 Implementation in Mathematica ® 352 16.6 Summary 358 Problems 359 References 360 Index 361

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Book SynopsisAfter a multi-decade hiatus, it appears that nuclear power again may become a viable option for new electrical generation facilities in the United States. Due to regulations, every utility that operates a nuclear power plant will require risk and reliability assessment.Table of ContentsPreface xii Permissions and Copyrights xiv List of Tables xvi List of Figures xviii 1 Risk and Safety of Engineered Systems 1 1.1 Risk and Its Perception and Acceptance 1 1.2 Overview of Risk and Safety Analysis 6 1.3 Two Historical Reactor Accidents 8 1.4 Definition of Risk 9 1.5 Reliability, Availability, Maintainability, and Safety 10 1.6 Organization of the Book 12 References 13 2 Probabilities of Events 15 2.1 Events 15 2.2 Event Tree Analysis and Minimal Cut Sets 17 2.3 Probabilities 19 2.3.1 Interpretations of Probability 19 2.3.2 Axiomatic Approach to Probabilities 20 2.3.3 Intersection of Events 21 2.3.4 Union of Events 22 2.3.5 Decomposition Rule for Probabilities 25 2.4 TimeIndependent Versus TimeDependent Probabilities 25 2.5 TimeIndependent Probabilities 26 2.5.1 Introduction 26 2.5.2 TimeIndependent Probability Distributions 27 2.6 Normal Distribution 31 2.7 Reliability Functions 35 2.8 TimeDependent Probability Distributions 41 2.8.1 Erlangian and Exponential Distributions 42 2.8.2 Gamma Distribution 43 2.8.3 Lognormal Distribution 44 2.8.4 Weibull Distribution 46 2.8.5 Generalized “Bathtub” Distribution 47 2.8.6 Selection of a TimeDependent Probability Distribution 48 2.9 ExtremeValue Probability Distributions 50 2.10 Probability Models for Failure Analyses 52 References 53 Exercises 53 3 Reliability Data 59 3.1 Estimation Theory 59 3.1.1 Moment Estimators 60 3.1.2 Maximum Likelihood Estimators 61 3.1.3 Maximum Entropy Estimators 64 3.1.4 Comparison of Estimators 65 3.2 Bayesian Updating of Data 65 3.2.1 Bayes Equation 65 3.2.2 Applications of the Bayes Equation 67 3.3 Central Limit Theorem and Hypothesis Testing 70 3.3.1 Interpretation of the Central Limit Theorem 71 3.3.2 Hypothesis Testing with the Central Limit Theorem 72 3.4 Reliability Quantification 74 3.4.1 Central Limit Theorem for Reliability Quantification 74 3.4.2 Engineering Approach for Reliability Quantification 76 3.4.3 ­2Distribution for Reliability Quantification 77 3.4.4 ThreeWay Comparison and Concluding Remarks 78 References 80 Exercises 80 4 Reliability of MultipleComponent Systems 85 4.1 Series and ActiveParallel Systems 86 4.1.1 Systems with Independent Components 86 4.1.2 Systems with Redundant Components 88 4.1.3 FailtoSafety and FailtoDanger Systems 90 4.2 Systems with Standby Components 93 4.3 Decomposition Analysis 96 4.4 Signal Flow Graph Analysis 100 4.5 Cut Set Analysis 101 References 104 Exercises 104 5 Availability and Reliability of Systems with Repair 109 5.1 Introduction 109 5.2 Markov Method 111 5.2.1 Markov Governing Equations 111 5.2.2 Solution of Markov Governing Equations 113 5.2.3 An Elementary Example 116 5.3 Availability Analyses 118 5.3.1 Rules for Constructing Transition Rate Matrices 118 5.3.2 Availability Transition Rate Matrices 119 5.3.3 TimeDependent Availability Examples 123 5.3.4 SteadyState Availability 127 5.4 Reliability Analyses 128 5.4.1 Reliability Transition Rate Matrices 129 5.4.2 TimeDependent Reliability Examples 130 5.4.3 Mean Time to Failure 130 5.5 Additional Capabilities of Markov Models 133 5.5.1 Imperfect Switching Between System States 134 5.5.2 Systems with Nonconstant Hazard Rates 136 References 137 Exercises 137 6 Probabilistic Risk Assessment 141 6.1 Failure Modes 142 6.2 Classification of Failure Events 143 6.2.1 Primary, Secondary, and Command Failures 143 6.2.2 Common Cause Failures 144 6.2.3 Human Errors 148 6.3 Failure Data 150 6.3.1 Hardware Failures 150 6.3.2 Human Errors 150 6.4 Combination of Failures and Consequences 152 6.4.1 Inductive Methods 152 6.4.2 Event Tree Analysis 154 6.5 Fault Tree Analysis 156 6.5.1 Introduction 156 6.5.2 Fault Tree Construction 157 6.5.3 Qualitative Fault Tree Analysis 157 6.5.4 Quantitative Fault Tree Analysis 160 6.5.5 Common Cause Failures and Fault Tree Analysis 165 6.6 Master Logic Diagram 165 6.7 Uncertainty and Importance Analysis 168 6.7.1 Types of Uncertainty in PRAs 168 6.7.2 Stochastic Uncertainty Analysis 169 6.7.3 Sensitivity and Importance Analysis 170 References 172 Exercises 172 7 Computer Programs for Probabilistic Risk Assessment 179 7.1 Fault Tree Methodology of the SAPHIRE Code 179 7.1.1 Gate Conversion and Tree Restructuring 180 7.1.2 Simplification of the Tree 180 7.1.3 Fault Tree Expansion and Reduction 182 7.2 Fault and Event Tree Evaluation with the SAPHIRE Code 183 7.3 Other Features of the SAPHIRE Code 185 7.4 Other PRA Codes 185 7.5 Binary Decision Diagram Algorithm 187 7.5.1 Basic Formulation of the BDD Algorithm 187 7.5.2 Generalization of the BDD Formulation 189 7.5.3 Zero Suppressed BDD Algorithm and the FTREX Code 193 References 194 Exercises 195 8 Nuclear Power Plant Safety Analysis 197 8.1 Engineered Safety Features of Nuclear Power Plants 197 8.1.1 Pressurized Water Reactor 198 8.1.2 Boiling Water Reactor 210 8.2 Accident Classification and General Design Goals 215 8.2.1 Plant Operating States 217 8.2.2 Accident Classification in 10 CFR 50 217 8.2.3 General Design Criteria and Safety Goals 219 8.3 Design Basis Accident: LargeBreak LOCA 220 8.3.1 Typical Sequence of a ColdLeg LBLOCA in PWR 221 8.3.2 ECCS Specifications 225 8.3.3 Code Scaling, Applicability, and Uncertainty Evaluation 227 8.4 Severe (Class 9) Accidents 231 8.5 Anticipated Transients Without Scram 233 8.5.1 History and Background of the ATWS Issue 233 8.5.2 Resolution of the ATWS Issues 235 8.5.3 Power Coefficients of Reactivity in LWRs 237 8.6 Radiological Source and Atmospheric Dispersion 241 8.6.1 Radiological Source Term 242 8.6.2 Atmospheric Dispersion of Radioactive Plume 243 8.6.3 Simple Models for Dose Rate Calculation 247 8.7 Biological Effects of Radiation Exposure 250 References 252 Exercises 254 9 Major Nuclear Power Plant Accidents and Incidents 259 9.1 Three Mile Island Unit 2 Accident 260 9.1.1 Sequence of the Accident—March 1979 260 9.1.2 Implications and FollowUp of the Accident 260 9.2 PWR InVessel Accident Progression 263 9.2.1 Core Uncovery and Heatup 265 9.2.2 Cladding Oxidation 266 9.2.3 Clad Melting and Fuel Liquefaction 268 9.2.4 Molten Core Slumping and Relocation 270 9.2.5 Vessel Breach 271 9.3 Chernobyl Accident 272 9.3.1 Cause and Nature of the Accident—April 1986 272 9.3.2 Sequence of the Accident 274 9.3.3 Estimate of Energy Release in the Accident 275 9.3.4 Accident Consequences 275 9.3.5 Comparison of the TMI and Chernobyl Accidents 276 9.4 Fukushima Station Accident 277 9.4.1 Overview of the Accident–March 2011 277 9.4.2 Radiological Consequences of the Accident 278 9.4.3 Implications and FollowUp of the Fukushima Accident 279 9.5 Salem Anticipated Transient Without Scram 281 9.5.1 Chronology and Cause of the Salem Incident 281 9.5.2 Implications and FollowUp of the Salem ATWS Event 282 9.6 LaSalle Transient Event 284 9.6.1 LaSalle NuclearCoupled DensityWave Oscillations 284 9.6.2 Simple Model for NuclearCoupled DensityWave Oscillations 287 9.6.3 Implications and FollowUp of the LaSalle Incident 292 9.7 DavisBesse Potential LOCA Event 292 9.7.1 Background and Chronology of the Incident 292 9.7.2 NRC Decision to Grant DB Shutdown Delay 293 9.7.3 Causes for the DavisBesse Incident and FollowUp 298 References 298 Exercises 301 10 PRA Studies of Nuclear Power Plants 303 10.1 WASH1400 Reactor Safety Study 304 10.2 Assessment of Severe Accident Risks: NUREG1150. 311 10.2.1 Background and Scope of the NUREG1150 Study 311 10.2.2 Overview of NUREG1150 Methodology 313 10.2.3 Accident Frequency Analysis 315 10.2.4 Accident Progression Analysis 320 10.2.5 Radionuclide Transport Analysis 324 10.2.6 Offsite Consequence Analysis 327 10.2.7 Uncertainty Analysis 330 10.2.8 Risk Integration 331 10.2.9 Additional Perspectives and Comments on NUREG1150. 337 10.3 Simplified PRA in the Structure of NUREG1150. 340 10.3.1 Description of the Simplified PRA Model 340 10.3.2 Parametric Studies and Comments on the Simplified PRA Model 344 References 345 Exercises 347 11 Passive Safety and Advanced Nuclear Energy Systems 349 11.1 Passive Safety Demonstration Tests at EBRII 349 11.1.1 EBRII Primary System and Simplified Model 350 11.1.2 Unprotected LossofFlow and LossofHeatSink Tests 357 11.1.3 Simplified Fuel Channel Analysis 361 11.1.4 Implications of EBRII Passive Safety Demonstration Tests 362 11.2 Safety Characteristics of Generation III+ Plants 364 11.2.1 AP1000 Design Features 364 11.2.2 SmallBreak LOCA Analysis for AP1000 366 11.2.3 Economic Simplified Boiling Water Reactor 371 11.2.4 Reliability Quantification of SBWR Passive Safety Containment 375 11.3 Generation IV Nuclear Power Plants 382 11.3.1 SodiumCooled Fast Reactor 383 11.3.2 Hypothetical Core Disruptive Accidents for Fast Reactors 387 11.3.3 VHTR and Phenomena Identification and Ranking Table 393 References 396 Exercises 399 12 RiskInformed Regulations and ReliabilityCentered Maintenance 401 12.1 Risk Measures for Nuclear Plant Regulations 402 12.1.1 Principles of RiskInformed Regulations and Licensing 402 12.1.2 Uncertainties in RiskInformed Decision Making 405 12.1.3 Other Initiatives in RiskInformed Regulations 406 12.2 ReliabilityCentered Maintenance 406 12.2.1 Optimization Strategy for Preventive Maintenance 407 12.2.2 ReliabilityCentered Maintenance Framework 409 12.2.3 CostBenefit Considerations 410 References 413 Exercises 415 13 Dynamic Event Tree Analysis 417 13.1 Basic Features of Dynamic Event Tree Analysis 418 13.2 Continuous Event Tree Formulation 421 13.2.1 Derivation of the Stochastic Balance Equation 421 13.2.2 Integral Form of the Stochastic Balance Equation 423 13.2.3 Numerical Solution of the Stochastic Balance Equation 425 13.3 CelltoCell Mapping for Parameter Estimation 426 13.3.1 Derivation of the Bayesian Recursive Relationship 427 13.3.2 CCM Technique for Dynamic Event Tree Construction 430 13.4 Diagnosis of Component Degradations 434 13.4.1 Bayesian Framework for Component Diagnostics 434 13.4.2 Implementation of the Probabilistic Diagnostic Algorithm 437 References 441 Exercises 442 Appendix A: Reactor Radiological Sources 443 A.1 Fission Product Inventory and Decay Heat 443 A.2 Health Effects of Radiation Exposure 446 References 448 Appendix B: Some Special Mathematical Functions 449 B.1 Gamma Function 449 B.2 Error Function 451 References 451 Appendix C: Some Failure Rate Data 453 Appendix D: Linear Kalman Filter Algorithm 457 References 461 Answers to Selected Exercises 462 Index and Acronyms 467

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Book SynopsisThis books format follows an applications-oriented text and serves as a training tool for individuals in education and industry involved directly, or indirectly, with chemical reactors. It addresses both technical and calculational problems in this field.Trade Review“The book also reviews Accreditation Board for Engineering and Technology (ABET) topics as they apply to chemical reactors, making it beneficial for engineers who are preparing to take the Professional Engineer (PE) exam.” (Chemical Engineering Progress, 1 April 2013) Table of ContentsPreface xi Overview xiii Part I. Introduction 1. History of Chemical Reactions 3 2. The Field of Chemistry 11 3. Process Variables 19 4. Kinetic Principles 45 5. Stoichiometry and Conversion Variables 73 Part II. Traditional Reactor Analysis 6. Reaction and Reactor Classification 111 7. The Conservation Laws 127 8. Batch Reactors 147 9. Continuous Stirred Tank Reactors (CSTRs)181 10. Tubular Flow Reactors 209 11. Reactor Comparisons 243 Part III. Reactor Applications 12. Thermal Effects 273 13. Interpretation of Kinetic Data 14. Non-Ideal Reactors 357 15. Reactor Design Considerations 383 Part IV. Other Reactor Topics 16. Catalysts 413 17. Catalytic Reactions 429 18. Fluidized and Fixed Bed Reactors 445 19. Biochemical Reactors 475 20. Open-Ended Problems 505 21. Abet-Related Topic 519 Appendix. SI Units

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Book SynopsisCan academia save the pharmaceutical industry? The pharmaceutical industry is at a crossroads. The urgent need for novel therapies cannot stem the skyrocketing costs and plummeting productivity plaguing R&D, and many key products are facing patent expiration. Dr. Rathnam Chaguturu presents a case for collaboration between the pharmaceutical industry and academia that could reverse the industry''s decline.Collaborative Innovation in Drug Discovery: Strategies for Public and Private Partnershipsprovides insight into the potential synergy of basing R&D in academia while leaving drug companies to turn hits into marketable products.As Founder and CEO of iDDPartners, focused on pharmaceutical innovation, Founding president of the International Chemical Biology Society, and Senior Director-Discovery Sciences, SRI International, Dr. Chaguturu has assembled a panel of experts from around the world to weigh in on issues that affect the two driving forces in medical advancement.Table of ContentsForeword xv by Ferid Murad Preface xix About the Book xxv About the Editor xxvii Contributors xxix PART I: PERSPECTIVES ON COLLABORATIVE INNOVATION 1 If I have seen further it is by standing on the shoulders of giants. —Isaac Newton 1 PRODUCTIVE RELATIONSHIPS IN RESEARCH AND DEVELOPMENT BETWEEN GOVERNMENT, INDUSTRY, AND UNIVERSITIES 3 Wyatt R. Hume 2 DIVIDED WE FALL 11 William B. Mattes 3 INNOVATION: OPEN SOURCE AND NONPROFIT MODELS IN DRUG DISCOVERY 21 James M. Shaeffer and Sarah MacDonald 4 THE CHANGING FACE OF INNOVATION IN DRUG DISCOVERY 31 Litao Zhang and Carl Decicco 5 CURRENT TRENDS IN COLLABORATIVE DRUG DISCOVERY AND STRATEGIES TO DE-RISK PRECOMPETITIVE INITIATIVES 57 Anuradha Roy and Rathnam Chaguturu 6 A PERSPECTIVE ON THE EVOLUTION OF COLLABORATIVE DRUG DISCOVERY AND FUTURE CHALLENGES 75 Christopher A. Lipinski PART II: GOVERNMENTAL INITIATIVES ACCELERATE PRECOMPETITIVE COLLABORATION 85 Governments will always play a huge part in solving big problems. . . . They also fund basic research, which is a crucial component of the innovation that improves life for everyone. —Bill Gates 7 THE VALUE OF UNIVERSITY–INDUSTRY PARTNERSHIPS 87 Anthony M. Boccanfuso 8 TRENDS IN THE PUBLIC SECTOR ADOPTION OF TRANSLATIONAL RESEARCH APPROACHES 99 Mark A. Scheideler 9 PARTNERSHIPS FOR DRUG REPOSITIONING: LESSONS FROM THE CTSA PHARMACEUTICAL ASSETS PORTAL 115 Kate Marusina, Dean J. Welsch, Lynn Rose, Doug Brock, Nathan Bahr, Aaron M. Cohen, Rafael A. Gacel-Sinclair, Pakou Vang, Peter G. Ruminski, Bruce E. Bloom, Pamela Nagasawa, and Betty P. Guo 10 DEVELOPMENT PROGRAMS AT THE U.S. NATIONAL CANCER INSTITUTE: USE OF PUBLIC–PRIVATE PARTNERSHIPS AS A CATALYST TO ADVANCE CANCER THERAPY 135 Jason V. Cristofaro 11 NONINDUSTRIAL PHARMACEUTICAL RESEARCH IN THE BRIC COUNTRIES: LESSONS FOR DRUG DISCOVERY PARTNERSHIPS WITH ACADEMIC AND GOVERNMENTAL INSTITUTIONS 159 John Watson 12 DEATH OF DRUGS AND REBIRTH OF HEALTH CARE: INDIAN RESPONSE TO DISCOVERY IMPASSE 173 Bhushan Patwardhan PART III: A GAME CHANGER FOR AVERTING FUTURE PHARMA CLIFF 195 Coming together is a beginning, staying together is progress, and working together is success. —Henry Ford 13 ACCELERATING INNOVATION IN THE BIOSCIENCE REVOLUTION 197 Bernard H. Munos 14 VALUE-DRIVEN DRUG DEVELOPMENT: UNLOCKING THE VALUE OF YOUR PIPELINE 213 Valentina Sartori, Michael Steinmann, Petra Jantzer, and Matthias Evers 15 UNLOCKING THE MARKET POTENTIAL OF ACADEMIC RESEARCH 221 Assem S. el Baghdady and Yasser M.S. el Baghdady 16 COLLABORATIVE INNOVATION IN PHARMACEUTICAL INDUSTRY: APPROACHES AND REQUIREMENTS 255 Monika Lessl and Khusru Asadullah 17 CLOSE CONTACT: A COLOCATION MODEL FOR ACADEMIC–INDUSTRIAL PARTNERSHIPS IN DRUG DISCOVERY 267 Peter A. Covitz and Terrence D. Ruddy 18 SUCCESS FACTORS AND OBSTACLES IN ACADEMIA–INDUSTRY PARTNERSHIPS: A CASE STUDY OF A GRADUATE PROGRAM WITHIN THE BAYER–UNIVERSITY OF COLOGNE “PRIVILEGED PARTNERSHIP” 279 Stefan Herzig, Marion Rozowski, and Ingo Flamme 19 ACADEMIC, COMMERCIAL, AND BIODEFENSE CASE STUDIES FOR COLLABORATIVE DRUG DISCOVERY: POTENTIAL FOR DISRUPTING DRUG DISCOVERY 303 Barry A. Bunin and Sean Ekins 20 ACCESS PLATFORM: A STREAMLINED INTEGRATIVE PARTNERING PROCESS AT SANOFI TO COMMERCIALIZE UNIVERSITY-BASED INTELLECTUAL PROPERTY 319 Paul R. Eynott and Carole Fages 21 ENTREPRENEURSHIP: DRUG DISCOVERY INNOVATION AT START-UP AND MEDIUM-SIZED BIOTECHNOLOGY COMPANIES 341 Allen B. Reitz and Kathleen M. Czupich 22 CHEMICAL CONSULTING 355 Lester A. Mitscher PART IV: NONPROFITS DRIVE BENCH-TO-BEDSIDE INNOVATION 367 Can’t afford to innovate? Open up! —Henry Chesbrough 23 OPEN SOURCE DRUG DISCOVERY FOR NEGLECTED DISEASES 369 Tonny Johnson and Sanchayita Kar 24 THE MYELIN REPAIR FOUNDATION ACCELERATED RESEARCH COLLABORATIONTM MODEL: INNOVATIVE DISRUPTION IN BIOMEDICAL RESEARCH 385 Gali Hagel 25 FROM CATALYSIS TO MASS ACTION: THE EVOLUTION OF CHDI FOUNDATION, A DRUG-DEVELOPMENT ORGANIZATION DEVOTED TO HUNTINGTON’S DISEASE 411 Allan J. Tobin 26 LESSONS FROM THE PAST AS A MEANS TO THE FUTURE: INSTITUT PASTEUR AS A MODEL STRATEGY 437 Spencer L. Shorte 27 SEEDING OPEN INNOVATION DRUG DISCOVERY AND TRANSLATIONAL COLLABORATIONS TO LEVERAGE GOVERNMENT FUNDING: A CASE STUDY OF STRATEGIC PARTNERSHIP BETWEEN SANFORD-BURNHAM AND MAYO CLINIC 451 Thomas D.Y. Chung, Sundeep Khosla, Andrew D. Badley, and Michael R. Jackson PART V: ACADEMIC SCREENING CENTERS COME OF AGE 487 Open access high-throughput drug discovery in the public domain is a Mount Everest in the making. —Rathnam Chaguturu 28 FINDING THE MIDDLE GROUND: DRUG DISCOVERY TECHNOLOGY IN THE ERA OF ACADEMIC SCREENING CENTERS 489 Nathan S. Blow 29 OPEN INNOVATION-BASED DRUG DISCOVERY IN EUROPE: SOME EXAMPLES OF NATIONAL AND TRANSNATIONAL EUROPEAN INITIATIVES INTEGRATING CHEMISTRY, BIOLOGY, AND TECHNOLOGY PLATFORMS 499 Philip Gribbon 30 IN SICKNESS AND IN HEALTH: A SHOTGUN MARRIAGE THAT IS FLOURISHING 517 Horst Flotow and Alex Matter 31 A FLEXIBLE MODEL FOR COMPOUND MANAGEMENT FACILITIES TO STIMULATE COLLABORATIONS IN THE LIFE SCIENCES 533 David Camp PART VI: INTELLECTUAL PROPERTY AND TECHNOLOGY TRANSFER 563 Everything that can be invented has been invented. —Charles Duell 32 SUCCESSFUL TECHNOLOGY TRANSFER: LESSONS FROM THE TRANSLATIONAL MEDICINE RESEARCH COLLABORATION 565 Assem S. el Baghdady 33 CHALLENGES AND OPPORTUNITIES IN COMMERCIALIZING ACADEMIC DRUG DISCOVERIES 577 Christopher Paschall 34 THE PIVOTAL ROLE OF THE ACADEMIC ENTREPRENEUR AND THE ENTREPRENEURIAL UNIVERSITY IN GLOBAL LIFE SCIENCES 609 Donna Marie De Carolis PART VII: THE FINAL FRONTIER 621 No one can whistle a symphony; it takes a whole orchestra to play it. —Halford E. Luccock 35 THE CORE MODEL: DRUG DISCOVERY AND DEVELOPMENT VIA EFFECTIVE TRANSLATIONAL SCIENCE AND PUBLIC–PRIVATE COLLABORATION 623 Ibis Sánchez-Serrano 36 USING MARKET-DRIVEN COLLABORATION TO ACCELERATE INNOVATION IN BIOMEDICINE 653 Elizabeth Iorns 37 THE COST OF TAKING EYES OFF THE TRUE END USER: FOCUS ON PATIENT NEEDS AND OUTCOMES 663 Deborah E. Collyar 38 TO LEASH OR UNLEASH THE POWER OF PUBLIC–PRIVATE COLLABORATION: IN HEALTH AND DISEASE 679 Hakim Djaballah Index 687

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Book SynopsisEMERGENCY RESPONSE MANAGEMENT OF OFFSHORE Examines the Deepwater Horizon disaster and offers processes for safety and environmental protection Though renewable energy is a growing piece of the energy pie, fossil fuels still dominate our energy supplies and will continue to do so for decades. This makes offshore drilling, especially in places like the Gulf of Mexico and North Sea, extremely important for the future of the world's energy supply. Unfortunately, the world has been witnessing, over and over again, accidents, deadly explosions, spills, and environmental disasters that could have been avoided with proper safety and environmental processes put in place. The Deepwater Horizon catastrophe is the largest offshore oil spill in U.S. history and an ecological nightmare of epic proportions. Emergency Response Management of Offshore Oil Spills aids in the response of this and future disasters by providing this handy reference volume for engineers, manTable of ContentsPreface ix 1. Toxic Nature of Crude Oil 1 1.1 High Risk Areas 1 1.2 Potential Impacts 7 1.3 Definitions 8 1.4 Examples of Historical Oil Spills and Their Impacts 10 2. Origins of Spills 37 2.1 Offshore Drilling 37 2.2 Case Study 44 3. Use of Chemical Dispersants 55 3.1 Dispersants 55 3.2 Methods of Applicaion 60 3.3 Types of Dispensants and Commerical Products 62 4. Combating Spills at the Shoreline 93 4.1 Chemical Warfare 93 4.2 Booms and Barriers 157 5. Emerging Technologies 237 5.1 Clean World Innovations and EncapSol 237 5.2 Centrifuges 243 5.3 Skimmers and Response Vessels 244 6. Spill Response and Worker Protection 247 6.1 Countermeasure Options 247 6.2 Spill Response Protocols and Strategies 271 6.3 Worker Protection 336 6.4 The Oil Spill Response Plan 420 6.5 Air Monitoring 429 7. Standard of Care and The BP Oil Spill 443 7.1 The Impacts 443 7.2 The Waxman/Stupak Letter 449 7.3 Standard of Care 462 Index 509 About the Authors 531

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Book SynopsisEnables researchers to assess the effects of endocrine disrupters as well as comply with new environmental regulations Endocrine disrupters are chemicals?both man-made and natural?that interfere with the body''s endocrine system, potentially resulting in adverse developmental, reproductive, neurological, and immune effects. In recent years, a number of regulatory authorities around the world have drafted or enacted legislation that requires the detection and assessment of the effects of endocrine disrupters on both humans and wildlife. In response, this book provides comprehensive, up-to-date information on the latest tested and proven methods used to detect and assess the environmental hazards posed by endocrine-disrupting chemicals. Endocrine Disrupters is divided into chapters covering each major taxon as well as chapters dedicated to hazard assessment and regulation. The book covers testing methods for all the vertebrate groups and several invertebratTable of ContentsPreface ix Contributors xi 1 Ecotoxicity Test Methods for Endocrine-Disrupting Chemicals: An Introduction 1 Peter Matthiessen 1.1 Background 1 1.2 Regulatory Concerns 2 1.3 Invertebrates 2 1.4 Vertebrates 3 1.5 Testing Schemes for EDCs 5 Reference 6 2 Endocrine Disruption inWildlife: Background, Effects, and Implications 7 Dick Vethaak and Juliette Legler 2.1 Background to Endocrine Disruption 8 2.2 Effects of EDCs on Wildlife 19 2.3 Weight of Evidence and Ecological Significance of ED Effects 32 2.4 Implications for Effect Assessment and Toxicity Testing 36 2.5 Need for More Field Studies and an Integrated Approach 38 2.6 Concluding Points 39 References 40 3 The Regulatory Need for Tests to Detect EDCs and Assess Their Hazards toWildlife 59 Hans-Christian Stolzenberg, Tobias Frische, Vicki L. Dellarco, Gary Timm, Anne Gourmelon, Taisen Iguchi, Flemming Ingerslev, and Mike Roberts 3.1 Emerging Concerns and Policy Responses: Focusing on EDCs as a Large Pseudo-Uniform Group of Substances 60 3.2 General Approaches in Substance-Related Regulatory Frameworks (EU) 80 3.3 How to Make EDC Definitions Operational for Substance-Related Regulatory Work 87 3.4 Future Perspectives 91 3.5 Conclusions 92 References 93 4 Techniques for Measuring Endocrine Disruption in Insects 100 Lennart Weltje 4.1 Introduction 100 4.2 Methods 105 4.3 Discussion 108 4.4 Conclusion 110 4.5 Acknowledgments 110 References 110 5 Crustaceans 116 Magnus Breitholtz 5.1 Introduction 116 5.2 Background to Crustacean Endocrinology 118 5.3 State of the Art: What Do We Know About Endocrine Disruption in Crustaceans? 121 5.4 Available Subchronic/Chronic Standard Test Protocols 128 5.5 Complementary Tools for Identification of Endocrine Disruption 129 5.6 Summary and Conclusions 132 References 134 6 Endocrine Disruption in Molluscs: Processes and Testing 143 Patricia D. McClellan-Green 6.1 Background and Introduction 143 6.2 What Constitutes the Endocrine System in Molluscs? 145 6.3 End Points and Biomarkers of Endocrine Disruption 154 6.4 Current Test Methods Using Molluscs 164 6.5 Proposed Test Methods 167 6.6 Conclusions 171 References 172 7 Using Fish to Detect Endocrine Disrupters and Assess Their Potential Environmental Hazards 185 Peter Matthiessen 7.1 Introduction 185 7.2 International Efforts to Standardize Fish-Based Methods for Screening and Testing Endocrine-Disrupting 7.3 Fish-Based Screens Developed by OECD for Endocrine-Disrupting Chemicals 189 7.4 Progress with Developing Fish Partial Life Cycle Tests for Endocrine Disrupters 194 7.5 Prospects for the Standardization of Fish Full Life Cycle and Multigeneration Tests 195 7.6 Strengths and Weaknesses of a Hazard Evaluation Strategy Based Partly on Available and Proposed Fish Screens and Tests 197 7.7 Conclusions 198 References 198 8 Screening and Testing for Endocrine-Disrupting Chemicals in Amphibian Models 202 Daniel B. Pickford 8.1 Introduction 202 8.2 Potential Uses of Amphibians in Endocrine Disrupter Screening and Testing Programs 203 8.3 Embryonic Development 205 8.4 Hatching 208 8.5 Larval Development 209 8.6 Higher-Tier Tests with Amphibians 224 8.7 Other and Emerging Test Methods 227 8.8 Summary and Conclusions 229 References 232 9 Endocrine Disruption and Reptiles: Using the Unique Attributes of Temperature-Dependent Sex Determination to Assess Impacts 245 Satomi Kohno and Louis J. Guillette, Jr. 9.1 Introduction 245 9.2 Approaches to Examine Effects of EDCs 252 9.3 Induction of Sex Reversal In Ovo 255 9.4 Analysis of Sex-Reversed Animals 260 9.5 Conclusions 265 References 266 10 Birds 272 Paul D. Jones, Markus Hecker, Steve Wiseman, and John P. Giesy 10.1 Introduction 272 10.2 Differences Between Birds and Mammals and Among Bird Species 275 10.3 In Vitro Techniques 278 10.4 Studies with Embryos 280 10.5 In Vivo Techniques 280 10.6 Examples of EDC Effects from Field Studies 285 10.7 Proposed Two-Generation Test 288 10.8 Conclusions 291 References 292 11 Mammalian Methods for Detecting and Assessing Endocrine-Active Compounds 304 M. Sue Marty 11.1 Introduction 304 11.2 Mammalian Tier 1 Screening Assays 306 11.3 Tier 2 Tests 326 11.4 Human and Wildlife Relevance of Estrogen, Androgen, and Thyroid Screening Assays 329 11.5 Potential Future Assays for Endocrine Screening 330 References 332 12 Application of the OECD Conceptual Framework for Assessing the Human Health and Ecological Effects of Endocrine Disrupters 341 Thomas H. Hutchinson, Jenny Odum, and Anne Gourmelon 12.1 Introduction 342 12.2 Overview of the OECD Revised CF 343 12.3 Application of the Klimisch Criteria to the EE2 and VIN Case Studies 346 12.4 Case Study: Data Examples for 17-Ethynylestradiol 346 12.5 Case Study: Data Examples for Vinclozolin 357 12.6 Conclusions 367 References 368 13 The Prospects for Routine Testing of Chemicals for Endocrine-Disrupting Properties and Potential Ecological Impacts 373 Peter Matthiessen 13.1 Introduction 373 13.2 Are There Gaps in the Test Suite for EDCs? 374 13.3 “New” Modes of Endocrine-Disrupting Action 376 13.4 How Should Tests for EDCs Be Deployed in an Integrated Fashion? 377 13.5 Use of Weight of Evidence when Assessing Possible EDCs 380 13.6 Conclusions 382 References 382 Index 385

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Book SynopsisThe essential new edition of the book that put hypercarbon chemistry on the map A comprehensive and contemporary treatment of the chemistry of hydrocarbons (alkanes, alkenes, alkynes, and aromatics) towards electrophiles, Hypercarbon Chemistry, Second Edition deals with all major aspects of such chemistry involved in hydrocarbon transformations, and of the structural and reaction chemistry of carboranes, mixed hydrides in which both carbon and boron atoms participate in the polyhedral molecular frameworks. Despite the firmly established tetravalency, carbon can bond simultaneously to five or more other atoms. Hypercarbon bonding permeates much organic, inorganic and organometallic chemistry, and the book serves as the compendium for this phenomenon. Copious diagrams illustrate the rich variety of hypercarbon structures now known, and patterns therein. Individual chapters deal with specific categories of compound (e.g. organometallics, carboranes, carbocaTrade Review“Highly recommended. Upper-division undergraduates through professionals.” (Choice, 1 March 2012)Table of ContentsForeword to the First Edition xiii Preface to the Second Edition xv Preface to the First Edition xvii 1. Introduction: General Aspects 1 1.1. Aims and Objectives 1 1.2. Some Definitions 2 1.3. Structures of Some Typical Hypercarbon Systems 5 1.4. The Three-Center Bond Concept: Types of Three-Center Bonds 10 1.5. The Bonding in More Highly Delocalized Systems 21 1.6. Reactions Involving Hypercarbon Intermediates 26 References 31 2. Carbon-Bridged (Associated) Metal Alkyls 37 2.1. Introduction 37 2.2. Bridged Organoaluminum Compounds 41 2.3. Beryllium and Magnesium Compounds 50 2.4. Organolithium Compounds 53 2.5. Organocopper, Silver, and Gold Compounds 58 2.6. Scandium, Yttrium, and Lanthanide Compounds 62 2.7. Titanium, Zirconium, and Hafnium Compounds 64 2.8. Manganese Compounds 66 2.9. Other Metal Compounds with Bridging Alkyl Groups 68 2.10. Agostic Systems Containing Carbon–Hydrogen–Metal 3c–2e Bonds 70 2.11. Conclusions 76 References 77 3. Carboranes and Metallacarboranes 85 3.1. Introduction 85 3.2. Carborane Structures and Skeletal Electron Numbers 87 3.4. MO Treatments of Closo Boranes and Carboranes 104 3.5. The Bonding in Nido and Arachno Carboranes 107 3.6. Methods of Synthesis and Interconversion Reactions 111 3.7. Some Carbon-Derivatized Carboranes 114 3.8. Boron-Derivatized Carboranes: Weakly Basic Anions [CB11H6X6]− 122 3.9. Metallacarboranes 123 3.10. Supraicosahedral Carborane Systems 133 3.11. Conclusions 137 References 137 4. Mixed Metal–Carbon Clusters and Metal Carbides 149 4.1. Introduction 149 4.2. Complexes of CnHn Ring Systems with a Metal Atom: Nido-Shaped MCn Clusters 150 4.3. Metal Complexes of Acyclic Unsaturated Ligands, CnHn+2 157 4.4. Complexes of Unsaturated Organic Ligands with Two or More Metal Atoms: Mixed Metal–Carbon Clusters 160 4.5. Metal Clusters Incorporating Core Hypercarbon Atoms 162 4.6. Bulk Metal Carbides 173 4.7. Metallated Carbocations 176 4.8. Conclusions 176 References 177 5. Hypercoordinate Carbocations and Their Borane Analogs 185 5.1. General Concept of Carbocations: Carbenium Versus Carbonium Ions 185 5.2. Methods of Generating Hypercoordinate Carbocations 188 5.3. Methods Used to Study Hypercoordinate Carbocations 189 5.4. Methonium Ion (CH5 +) and Its Analogs 195 5.5. Homoaromatic Cations 247 5.6. Hypercoordinate (Nonclassical) Pyramidal Carbocations 260 5.7. Hypercoordinate Heterocations 266 5.8. Carbocation–Borane Analogs 268 5.9. Conclusions 276 References 277 6. Reactions Involving Hypercarbon Intermediates 295 6.1. Introduction 295 6.2. Reactions of Electrophiles with C–H and C–C Single Bonds 298 6.3. Electrophilic Reactions of π-Donor Systems 383 6.4. Bridging Hypercoordinate Species with Donor Atom Participation 388 6.5. Conclusions 394 References 394 Conclusions and Outlook 417 Index 419

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Book SynopsisThe definitive guide to mass spectrometry techniques in biology and biophysics The use of mass spectrometry (MS) to study the architecture and dynamics of proteins is increasingly common within the biophysical community, and Mass Spectrometry in Structural Biology and Biophysics: Architecture, Dynamics, and Interaction of Biomolecules, Second Edition provides readers with detailed, systematic coverage of the current state of the art. Offering an unrivalled overview of modern MS-based armamentarium that can be used to solve the most challenging problems in biophysics, structural biology, and biopharmaceuticals, the book is a practical guide to understanding the role of MS techniques in biophysical research. Designed to meet the needs of both academic and industrial researchers, it makes mass spectrometry accessible to professionals in a range of fields, including biopharmaceuticals. This new edition has been significantly expanded and updated to include the most Table of ContentsPreface to the Second Edition xi Preface to the First Edition xiii 1 General Overview of Basic Concepts in Molecular Biophysics 1 1.1 Covalent Structure of Biopolymers, 1 1.2 Noncovalent Interactions and Higher Order Structure, 3 1.2.1 Electrostatic Interaction, 3 1.2.2 Hydrogen Bonding, 6 1.2.3 Steric Clashes and Allowed Conformations of the Peptide Backbone: Secondary Structure, 6 1.2.4 Solvent--Solute Interactions, Hydrophobic Effect, Side-Chain Packing, and Tertiary Structure, 7 1.2.5 Intermolecular Interactions and Association: Quaternary Structure, 9 1.3 The Protein Folding Problem, 9 1.3.1 What Is Protein Folding?, 9 1.3.2 Why Is Protein Folding So Important?, 10 1.3.3 What Is the Natively Folded Protein and How Do We Define a Protein Conformation?, 11 1.3.4 What Are Non-Native Protein Conformations?: Random Coils, Molten Globules, and Folding Intermediates, 12 1.3.5 Protein Folding Pathways, 13 1.4 Protein Energy Landscapes and the Folding Problem, 14 1.4.1 Protein Conformational Ensembles and Energy Landscapes: Enthalpic and Entropic Considerations, 14 1.4.2 Equilibrium and Kinetic Intermediates on the Energy Landscape, 16 1.5 Protein Dynamics and Function, 17 1.5.1 Limitations of the Structure--Function Paradigm, 17 1.5.2 Protein Dynamics under Native Conditions, 17 1.5.3 Is Well-Defined Structure Required for Functional Competence?, 18 1.5.4 Biomolecular Dynamics and Binding from The Energy Landscape Perspective, 19 1.5.5 Energy Landscapes Within a Broader Context of Nonlinear Dynamics: Information Flow and Fitness Landscapes, 21 1.6 Protein Higher Order Structure and Dynamics from A Biotechnology Perspective, 22 References, 22 2 Overview of Traditional Experimental Arsenal to Study Biomolecular Structure and Dynamics 26 2.1 X-Ray Crystallography, 26 2.1.1 Fundamentals, 26 2.1.2 Crystal Structures at Atomic and Ultrahigh Resolution, 27 2.1.3 Crystal Structures of Membrane Proteins, 27 2.1.4 Protein Dynamics and X-Ray Diffraction, 28 2.2 Solution Scattering Techniques, 28 2.2.1 Static and Dynamic Light Scattering, 28 2.2.2 Small-Angle X-Ray Scattering, 29 2.2.3 Cryo-Electron Microscopy, 29 2.2.4 Neutron Scattering, 30 2.3 NMR Spectroscopy, 30 2.3.1 Heteronuclear NMR, 32 2.3.2 Hydrogen Exchange by NMR, 33 2.4 Other Spectroscopic Techniques, 34 2.4.1 Cumulative Measurements of Higher Order Structure: Circular Dichroism, 34 2.4.2 Vibrational Spectroscopy, 37 2.4.3 Fluorescence: Monitoring Specific Dynamic Events, 39 2.5 Other Biophysical Methods to Study Macromolecular Interactions and Dynamics, 41 2.5.1 Calorimetric Methods, 41 2.5.2 Analytical Ultracentrifugation, 43 2.5.3 Surface Plasmon Resonance, 45 2.5.4 Size Exclusion Chromatography (Gel Filtration), 46 2.5.5 Electrophoresis, 47 2.5.6 Affinity Chromatography, 48 References, 48 3 Overview of Biological Mass Spectrometry 52 3.1 Basic Principles of Mass Spectrometry, 52 3.1.1 Stable Isotopes and Isotopic Distributions, 53 3.1.2 Macromolecular Mass: Terms and Definitions, 57 3.2 Methods of Producing Biomolecular Ions, 57 3.2.1 Macromolecular Ion Desorption Techniques: General Considerations, 57 3.2.2 Electrospray Ionization, 58 3.2.3 Matrix Assisted Laser Desorption Ionization (MALDI), 60 3.3 Mass Analysis, 63 3.3.1 General Considerations: m/z Range and Mass Discrimination, Mass Resolution, Duty Cycle, and Data Acquisition Rate, 63 3.3.2 Mass Spectrometry Combined with Separation Methods, 64 3.4 Tandem Mass Spectrometry, 65 3.4.1 Basic Principles of Tandem Mass Spectrometry, 65 3.4.2 Collision-Induced Dissociation: Collision Energy, Ion Activation Rate, and Dissociation of Large Biomolecular Ions, 66 3.4.3 Surface- and Photoradiation-Induced Dissociation, 68 3.4.4 Electron-Based Ion Fragmentation Techniques: Electron Capture Dissociation and Electron Transfer Dissociation, 71 3.4.5 Ion-Molecule Reactions in the Gas Phase: Internal Rearrangement and Charge Transfer, 71 3.5 Brief Overview of Common Mass Analyzers, 72 3.5.1 Mass Analyzer As an Ion Dispersion Device: Magnetic Sector Mass Spectrometry, 72 3.5.2 Temporal Ion Dispersion: Time-of-Flight Mass Spectrometer, 73 3.5.3 Mass Analyzer As an Ion Filter, 75 3.5.4 Mass Analyzer As an Ion-Storing Device: The Quadrupole (Paul) Ion Trap and Linear Ion Trap, 76 3.5.5 Mass Analyzer As an Ion Storing Device: FT ICR MS, 78 3.5.6 Mass Analyzer as An Ion Storing Device: Orbitrap MS, 80 3.5.7 Ion Mobility Analyzers, 81 3.5.8 Hybrid Mass Spectrometers, 82 References, 82 4 Mass Spectrometry Based Approaches to Study Biomolecular Higher Order Structure 89 4.1 Direct Methods of Structure Characterization: Native Electrospray Ionization Mass Spectrometry, 89 4.1.1 Preservation of Noncovalent Complexes in the Gas Phase: Stoichiometry of Biomolecular Assemblies, 89 4.1.2 Utilization of Ion Chemistry in the Gas Phase to Aid Interpretation of ESI MS Data, 91 4.1.3 Dissociation of Noncovalent Complexes in the Gas Phase: Can It Lead to Wrong Conclusions?, 93 4.1.4 Evaluation of Macromolecular Shape in Solution: The Extent of Multiple Charging in ESI MS, 94 4.1.5 Macromolecular Shape in the Gas Phase: Ion Mobility--Mass Spectrometry, 97 4.1.6 How Relevant Are Native ESI MS Measurements? Restrictions on Solvent Composition in ESI, 98 4.1.7 Noncovalent Complexes by MALDI MS, 98 4.2 Chemical Cross-Linking for Characterization of Biomolecular Topography, 99 4.2.1 Mono- and Bifunctional Cross-Linking Reagents, 99 4.2.2 Chemical Cross-Linkers with Fixed Arm-Length: Molecular Rulers or Tape Measures?, 100 4.2.3 Mass Spectrometry Analysis of Chemical Cross-Linking Reaction Products, 102 4.2.4 Intrinsic Cross-Linkers: Methods to Determine Disulfide Connectivity Patterns in Proteins, 108 4.2.5 Other Intrinsic Cross-Linkers: Oxidative Cross-Linking of Tyrosine Side Chains, 109 4.3 Mapping Solvent-Accessible Areas with Chemical Labeling and Footprinting Methods, 110 4.3.1 Selective Chemical Labeling, 110 4.3.2 Nonspecific Chemical Labeling, 115 4.4 Hydrogen Exchange, 116 4.4.1 Hydrogen Exchange in Peptides and Proteins: General Considerations, 116 4.4.2 Probing Exchange Patterns with HDX MS at the Local Level, 116 References, 119 5 Mass Spectrometry Based Approaches to Study Biomolecular Dynamics: Equilibrium Intermediates 127 5.1 Direct Methods of Monitoring Equilibrium Intermediates: Protein Ion Charge-State Distributions in ESI MS, 127 5.1.1 Protein Conformation as a Determinant of the Extent of Multiple Charging in ESI MS, 127 5.1.2 Detection and Characterization of Large-Scale Conformational Transitions by Monitoring Protein Ion Charge-State Distributions in ESI MS, 128 5.1.3 Detection of Small-Scale Conformational Transitions by Monitoring Protein Ion Charge-State Distributions, 130 5.1.4 Pitfalls and Limitations of Protein Ion Charge-State Distribution Analysis, 133 5.2 Chemical Labeling and Trapping Equilibrium States in Unfolding Experiments, 135 5.2.1 Characterization of the Solvent-Exposed Surfaces with Chemical Labeling, 135 5.2.2 Exploiting Intrinsic Protein Reactivity: Disulfide Scrambling and Protein Misfolding, 136 5.3 Structure and Dynamics of Intermediate Equilibrium States by Hydrogen Exchange, 137 5.3.1 Protein Dynamics and Hydrogen Exchange, 137 5.3.2 Global Exchange Kinetics in the Presence of Non-Native States: EX1, EX2, and EXX Exchange Regimes in a Simplified Two-State Model System, 138 5.3.3 A More Realistic Two-State Model System: Effect of Local Fluctuations on the Global Exchange Pattern Under EX2 Conditions, 141 5.3.4 Effects of Local Fluctuations on the Global Exchange Pattern Under EX1 and Mixed (EXX) Conditions, 143 5.3.5 Exchange in Multistate Protein Systems: Superposition of EX1 and EX2 Processes and Mixed-Exchange Kinetics, 144 5.4 Measurements of Local Patterns of Hydrogen Exchange in the Presence of Non-Native States, 146 5.4.1 Bottom-Up Approaches to Probing the Local Structure of Intermediate States, 146 5.4.2 Top-Down Approaches to Probing the Local Structure of Intermediate States, 150 5.4.3 Further Modifications and Improvements of HDX MS in Conformationally Heterogeneous Systems, 153 References, 153 6 Kinetic Studies By Mass Spectrometry 160 6.1 Kinetics of Protein Folding, 160 6.1.1 Stopped-Flow Measurement of Kinetics, 160 6.1.2 Kinetic Measurements with Hydrogen Exchange, 162 6.2 Kinetics by Mass Spectrometry, 163 6.2.1 Pulse Labeling Mass Spectrometry, 163 6.2.2 Continuous-Flow Mass Spectrometry, 168 6.2.3 Stopped-Flow Mass Spectrometry, 169 6.2.4 Kinetics of Disulfide Formation During Folding, 171 6.2.5 Irreversible Covalent Labeling As a Probe of Protein Kinetics, 172 6.3 Kinetics of Protein Assembly, 174 6.4 Kinetics of Enzyme Catalysis, 178 References, 181 7 Protein Interactions: A Closer Look at the Structure--Dynamics--Function Triad 186 7.1 Direct Methods of Monitoring Protein Interactions with Their Physiological Partners in Solution by ESI MS: From Small Ligands to Other Biopolymers, 186 7.2 Assessment of Binding Affinity with Direct ESI MS Approaches, 189 7.3 Indirect Characterization of Non-covalent Interactions Under Physiological and Near-Physiological Conditions, 190 7.3.1 Assessment of Ligand Binding by Monitoring Dynamics of “Native” Proteins with Hydrogen--Deuterium Exchange (HDX MS), 190 7.3.2 PLIMSTEX and Related Techniques: Binding Assessment by Monitoring Conformational Changes with HDX MS in Titration Experiments, 192 7.3.3 Binding Revealed by Changes in Ligand Mobility, 194 7.4 Indirect Characterization of Noncovalent Interactions Under Partially Denaturing Conditions, 194 7.4.1 Ligand-Induced Protein Stabilization Under Mildly Denaturing Conditions: Effect of Ligand Binding on Charge-State Distributions of Protein Ions, 195 7.4.2 SUPREX: Utilizing HDX Under Denaturing Conditions to Discern Protein--Ligand Binding Parameters, 196 7.5 Understanding Protein Action: Mechanistic Insights from the Analysis of Structure and Dynamics under Native Conditions, 198 7.5.1 Dynamics at the Catalytic Site and Beyond: Understanding Enzyme Mechanism, 198 7.5.2 Allosteric Effects Probed by HDX MS, 201 7.6 Going Full Circle with MS: Native ESI MS Reveals Structural Changes Predicted by HDX MS Measurements, 201 7.7 Understanding Protein Action: Mechanistic Insights from the Analysis of Structure and Dynamics under Non-Native (Partially Denaturing) Conditions, 203 References, 206 8 Other Biopolymers and Synthetic Polymers of Biological Interest 212 8.1 Nucleic Acids, 212 8.1.1 Characterization of the Covalent Structure of Nucleic Acids, 212 8.1.2 DNA Higher Order Structure and Interactions with Physiological Partners and Therapeutics, 215 8.1.3 Higher Order Structure and Dynamics of RNA, 219 8.2 Oligosaccharides, 223 8.2.1 Covalent Structure of Oligosaccharides, 225 8.2.2 Higher Order Structure of Oligosaccharides and Interactions with their Physiological Partners, 226 8.3 Synthetic Polymers and their Conjugates with Biomolecules, 226 8.3.1 Covalent Structure of Polymers and Polymer--Protein Conjugates, 229 8.3.2 Higher Order Structure of Polymers and Polymer--Protein Conjugates, 232 References, 233 9 Mass Spectrometry on the Frontiers of Molecular Biophysics and Structural Biology: Perspectives and Challenges 239 9.1 Mass Spectrometry and the Unique Challenges of Membrane Proteins, 239 9.1.1 Analysis of Membrane Proteins in Organic Solvents, 240 9.1.2 Analysis of Membrane Proteins Using Detergents, 241 9.1.3 Analysis of Membrane Proteins Utilizing Other Membrane Mimics, 244 9.1.4 Analysis of Membrane Proteins in Their Native Environment, 249 9.2 The Protein Aggregation Problem, 249 9.2.1 The Importance and Challenges of Protein Aggregation, 249 9.2.2 Direct Monitoring of Protein Aggregation and Amyloidosis with Mass Spectrometry, 250 9.2.3 Structure of Protein Aggregates, Amyloids, and Pre-Amyloid States, 253 9.3 The Many Faces of Complexity: Mass Spectrometry and the Problem of Structural Heterogeneity, 258 9.4 How Large Is “Too Large”? Mass Spectrometry in Characterization of Ordered Macromolecular Assemblies, 263 9.4.1 Proteasomes, 264 9.4.2 Ribosomes, 264 9.4.3 Molecular Chaperones, 267 9.5 Complexity of Macromolecular Interactions In Vivo and Emerging Mass Spectrometry Based Methods to Probe Structure and Dynamics of Biomolecules in Their Native Environment, 269 9.5.1 Macromolecular Crowding Effect, 269 9.5.2 Macromolecular Properties In Vitro and In Vivo, 270 9.5.3 “Live” Macromolecules: Equilibrium Systems or Dissipative Structures?, 271 References, 272 Appendix: Physics of Electrospray 279 Index 285

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Book SynopsisWith a focus on practical applications of biophysical techniques, this book links fundamental biophysics to the process of biopharmaceutical development. Helps formulation and analytical scientists in pharma and biotech better understand and use biophysical methods Chapters organized according to the sequential nature of the drug development process Helps formulation, analytical, and bioanalytical scientists in pharma and biotech better understand and usestrengths and limitations of biophysical methods Explains how to use biophysical methods, the information obtained, and what needs to be presented in a regulatory filing, assess impact on quality and immunogenicity With a focus on practical applications of biophysical techniques, this book links fundamental biophysics to the process of biopharmaceutical development.Table of ContentsPreface vii About the Editor ix Contributors xi Section 1 Early Discovery Stages and Biotherapeutic Candidate Selection 1 Biophysical Methods Applied in Early Discovery of a Biotherapeutic: Case Study of an EGFR-IGF1R Bispecific Adnectin 3Michael L. Doyle, James W. Bryson, Virginie Lafont, Zheng Lin, Paul E. Morin, Lumelle A. Schneeweis, Aaron P. Yamniuk, and Joseph Yanchunas Jr. 2 X-Ray Crystallography for Biotherapeutics 25Glen Spraggon 3 Solubility and Early Assessment of Stability for Protein Therapeutics 65Sheng-Jiun Wu, Gary L. Gilliland, and Yiqing Feng Section 2 First-in-Human and up to Proof-of-Concept Clinical Trials 4 Biophysical and Structural Characterization Needed Prior to Proof of Concept 95Angela W. Blake-Haskins, Yen-Huei Lin, Zhuchun Wu, Melissa D. Perkins, and Thomas M. Spitznagel 5 Nucleation, Aggregation, and Conformational Distortion 125Christopher J. Roberts 6 Utilization of Chemical Labeling and Mass Spectrometry for the Biophysical Characterization of Biopharmaceuticals 151Justin B. Sperry and Lisa M. Jones 7 Application of Biophysical and High-Throughput Methods in the Preformulation of Therapeutic Proteins—Facts and Fictions 173Ahmad M. Abdul-Fattah and Hanns-Christian Mahler 8 Bioanalytical Methods and Immunogenicity Assays 207Bonita Rup, Corinna Krinos-Fiorotti, Boris Gorovits, and Hendrik Neubert 9 Structures and Dynamics of Proteins Probed by UV Resonance Raman Spectroscopy 243Brian S. Leigh, Diana E. Schlamadinger, and Judy E. Kim 10 Freezing- and Drying-Induced Micro- and Nano-Heterogeneity in Biological Solutions 269Alptekin Aksan, Vishard Ragoonanan, and Carol Hirschmugl Section 3 Phase III and Commercial Development 11 Late-Stage Product Characterization: Applications in Formulation, Process, and Manufacturing Development 287Christine P. Chan and Li Shi 12 Biophysical Analyses Suitable for Chemistry, Manufacturing, and Control Sections of the Biologic License Application (BLA) 317Zahra Shahrokh, Nazila Salamat-Miller, and John J. Thomas Index 355

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Book SynopsisThe 9th edition of Malone''s Basic Concepts of Chemistry provides many new and advanced features that continue to address general chemistry topics with an emphasis on outcomes assessment. New and advanced features include an objectives grid at the end of each chapter which ties the objectives to examples within the sections, assessment exercises at the end each section, and relevant chapter problems at the end of each chapter. Every concept in the text is clearly illustrated with one or more step by step examples. Making it Real essays have been updated to present timely and engaging real-world applications, emphasizing the relevance of the material they are learning. This edition continues the end of chapter Student Workshop activities to cater to the many different learning styles and to engage users in the practical aspect of the material discussed in the chapter. WileyPLUS sold separately from text.Table of ContentsPrologue. CHAPTER 1 Chemistry and Measurements. CHAPTER 2 Elements and Compounds. CHAPTER 3 The Properties of Matter and Energy. CHAPTER 4 The Periodic Table and Chemical Nomenclature. CHAPTER 5 Quantities in Chemistry. CHAPTER 6 Chemical Reactions. CHAPTER 7 Quantitative Relationships in Chemical Reactions. CHAPTER 8 Modern Atomic Theory. CHAPTER 9 The Chemical Bond. CHAPTER 10 The Gaseous State. CHAPTER 11 The Solid and Liquid States. CHAPTER 12 Aqueous Solutions. CHAPTER 13 Acids, Bases, and Salts. CHAPTER 14 Oxidation–Reduction Reactions. CHAPTER 15 Reaction Rates and Equilibrium. CHAPTER 16 Nuclear Chemistry.

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Book SynopsisSets forth the history, state of the science, and future directions of drug discovery Edited by Jie Jack Li and Nobel laureate E. J. Corey, two leading pioneers in drug discovery and medicinal chemistry, this book synthesizes great moments in history, the current state of the science, and future directions of drug discovery into one expertly written and organized work. Exploring all major therapeutic areas, the book introduces readers to all facets and phases of drug discovery, including target selection, biological testing, drug metabolism, and computer-assisted drug design. Drug Discovery features chapters written by an international team of pharmaceutical and medicinal chemists. Contributions are based on a thorough review of the current literature as well as the authors'' firsthand laboratory experience in drug discovery. The book begins with the history of drug discovery, describing groundbreaking moments in the field. Next, it covers such topics as:Trade Review“Taken together, the book is an excellent introduction into drug discovery and an eminent summary of the very important milestones of drug discovery in the most critical indication areas. This book is a valuable addition to the library of all different kinds of scientists working in the field of drug discovery.” (ChemMedChem, 1 October 2013)Table of ContentsChapter 1. History of Drug Discovery 1 1. Introduction 1 2. Antibacterials 1 3. Cancer Drugs 6 4. Cardiovascular Drugs 10 5. Cholesterol Drugs 16 6. CNS Drugs 21 7. Anti-inflammatory Drugs 26 8. Anti-ulcer Drugs 30 9. Antiviral Drugs 33 10. References 38 Chapter 2. Target Identification and Validation 43 1. History 43 2. Definition of Drug Targets 43 3. Classification of Currently Utilized Drug Targets 45 4. Receptors as Drug Targets 46 5. Enzymes as Drug Targets 48 6. Transporter Proteins as Drug Targets 49 7. Modern Technologies Employed in Target Identification and Validation 49 8. Impact of Therapeutic Modalities on the Selection Drug Targets 62 9. Future Directions 63 10. References 3. In vitro and in vivo Assays 67 1. Introduction 67 2. The Testing Funnel 67 3. In vitro assays 70 4. In vivo Assays 89 5. Outlook 92 6. References 93 Chapter 4. Drug Metabolism and Pharmacokinetics in Drug Discovery 95 1. Introduction 95 2. Drug Metabolism 97 3. Pharmacokinetic Fundamentals 106 4. Drug Metabolism and Pharmacokinetics in Drug Discovery 95 1. Introduction 95 2. Drug Metabolism 97 3. Pharmacokinetic Fundamentals 106 4. Pharmacokinetics Studies in Support of Drug Optimization 112 5. Absorption and Permeability 114 6. Drug Transporters 117 7. Protein Binding 119 8. Pharmacokinetics and Pharmacodynamics 123 9. Predicting Human Pharmacokinetics 130 10. Summary 133 11. References 133 Chapter 5. Cardiovascular Drugs 137 1. Introduction 137 2. Early History of Coronary Heart Disease (CHD) 138 3. Lipid Lowering Agents 139 4. Antihypertensive Agents 153 5. Antithrombotic Drugs 177 6. Thrombolytic Agents 190 7. Anti-anginal Agents 191 8. Heart Failure Drugs 191 9. The Future 193 10. References 193 Chapter 6. Diabetes Drugs 201 1. Introduction 201 2. Current therapies for Type 2 Diabetes 204 3. Other Treatments for T2DM 215 4. Novel Mechanisms of Action: Future Treatments for Type 2 Diabetes 217 5. Current Therapies for Type 1 Diabetes 221 6. Future Treatments for Type 1 Diabetes 227 7. Future Prospects for New Diabetes Drugs 231 8. References 231 Chapter 7. CNS Drugs 241 1. Introduction 241 2. Antipsychotic Drugs 241 3. Antidepressant drugs 246 4. Drugs for Epilepsy and Bipolar Disorder 255 5. Anxiolytic Drugs 259 6. Centrally Acting Analgesic Drugs 262 7. Drugs for treating Substance Abuse and ADHD 265 8. Drugs for Neurodegenerative Diseases 267 9. Future Prospects for New CNS Drugs 273 10. References 276 Chapter 8. Cancer Drugs 283 1. Introduction 283 2. Historical Perspective of Cancer Drugs 285 3. Antimetabolites 286 4. Alkylating Agents 291 5. Platinum Complexes 294 6. Plant and Marine Based Natural Products 295 7. Toposiomerase Inhibitors 300 8. Antitumor Antibiotics 305 9. Tyrosine Kinase Inhibitors (TKI) 306 10. Hormones 314 11. Histone Deacylase (HDAC) Inhibitors 321 12. Miscellaneous Cancer Drugs 323 13. Conclusion 325 14. References 326 Chapter 9. Antiinflammatory and Immunomodulatory Drugs 333 1. Introduction 333 2. Arachidonic Acid Cascade 334 3. Leukotriene Pathway Inhibitors 347 4. Anti-histamines 351 5. Corticosteroids 353 6. Rheumatoid Arthritis 356 7. Osteoarthritis 363 8. Chronic Inflammatory Arthritis and Gout 364 9. Multiple Sclerosis 366 10. Transplantation 368 11. Biological Agents That Suppress Cytokine Production or Signaling 372 12. B Cell Therapy 374 13. Cytotoxic T-lymphocyte Antigen 4 (CTLA4) 374 14. Interleukins 375 15. Safety 377 16. Summary 377 17. References 378 Chapter 10. Anti-bacterial Drugs 385 1. Introduction 385 2. The Rise and Decline of Antibiotics 386 3. The Unique Challenges of Anti-bacterial Drug Discovery 387 4. Antibiotic Classes 390 5. Emerging Strategies to Discover New Anti-bacterial Drugs 420 6. Conclusions 425 7. References 425 Chapter 11. Antiviral Drug Discovery 437 1. Introduction 437 2. Human Immunodeficiency Virus-1 Inhibitors 442 3. Hepatitis B Virus Inhibitors 459 4. Hepatitis C Virus Inhibitors 463 5. Inhibitors of Respiratory Viruses-Influenza and Respiratory Syncytial Virus 476 6. Herpesviridae Inhibitors 487 7. Epilogue 490 8. References 490 Index 517

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Book SynopsisFacilitates the discovery and development of new, effective therapeutics With coverage of the latest mass spectrometry technology, this book explains how mass spectrometry can be used to enhance almost all phases of drug discovery and drug development, including new and emerging applications. The book''s fifteen chapters have been written by leading pharmaceutical and analytical scientists. Their contributions are based on a thorough review of the current literature as well as their own experience developing new mass spectrometry techniques to improve the ability to discover and develop new and effective therapeutics. Mass Spectrometry for Drug Discovery and Drug Development begins with an overview of the types of mass spectrometers that facilitate drug discovery and development. Next it covers: HPLC?high-resolution mass spectrometry for quantitative assays Mass spectrometry for siRNA Quantitative analysis of peptides <Table of ContentsContributors ix Preface xi 1 Overview of the Various Types of Mass Spectrometers that are Used in Drug Discovery and Drug Development 1 Gérard Hopfgartner 2 Utility of High-Resolution Mass Spectrometry for New Drug Discovery Applications 37 William Bart Emary and Nanyan Rena Zhang 3 Quantitative Mass Spectrometry Considerations in a Regulated Environment 55 Mohammed Jemal and Yuan-Qing Xia 4 Mass Spectrometry for Quantitative In Vitro ADME Assays 97 Jun Zhang and Wilson Z. Shou 5 Metabolite Identifi cation Using Mass Spectrometry in Drug Development 115 Natalia Penner, Joanna Zgoda-Pols, and Chandra Prakash 6 MS Analysis of Biological Drugs, Proteins, and Peptides 149 Yi Du, John Mehl, and Pavlo Pristatsky 7 Characterization of Impurities and Degradation Products in Small Molecule Pharmaceuticals and Biologics 191 Hui Wei, Guodong Chen, and Adrienne A. Tymiak 8 Liquid Extraction Surface Analysis (LESA): A New Mass Spectrometry-Based Technique for Ambient Surface Profiling 221 Daniel Eikel and Jack D. Henion 9 MS Applications in Support of Medicinal Chemistry Sciences 239 Maarten Honing, Benno Ingelse, and Birendra N. Pramanik 10 Imaging Mass Spectrometry of Proteins and Peptides 277 Michelle L. Reyzer and Richard M. Caprioli 11 Imaging Mass Spectrometry for Drugs and Metabolites 303 Stacey R. Oppenheimer 12 Screening Reactive Metabolites: Role of Liquid Chromatography–High-Resolution Mass Spectrometry in Combination with “Intelligent” Data Mining Tools 339 Shuguang Ma and Swapan K. Chowdhury 13 Mass Spectrometry of siRNA 357 Mark T. Cancilla and W. Michael Flanagan 14 Mass Spectrometry for Metabolomics 387 Petia Shipkova and Michael D. Reily 15 Quantitative Analysis of Peptides with Mass Spectrometry: Selected Reaction Monitoring or High-Resolution Full Scan? 403 Lieve Dillen and Filip Cuyckens Index 427

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Book Synopsis* The volume gives insight into many topics related to green chemistry and clean environment providing solutions to many of the existing pollution problems. * It highlights with examples the need to avoid the usage of toxic solvents to get a better product with higher yield without compromising on its economic ease.Table of ContentsList of Contributors xvii Foreword xix Part 1. Green Chemistry and Societal Sustainability 1 1. Environment and the Role of Green Chemistry 3 2. The Greening of the Chemical Industry: Past, Present and Challenges Ahead 35 3. Designing Sustainable Chemical Synthesis: The Influence of Chemistry on Process Design 79 4. Green Chemical Processing in the Teaching Laboratory: Microwave Extraction of Natural Products 107 5. Ensuring Sustainability through Microscale Chemistry 119 6. Capability Development and Technology Transfer Essential for Economic Transformation 137 Part 2. Green Lab Technologies 153 7. Ultrasound Cavitation as a Green Processing Technique in the Design and Manufacture of Pharmaceutical Nanoemulsions in Drug Delivery System 155 8. Microwave-Enhanced Methods for Biodiesel Production and Other Environmental Applications 209 9. Emergence of Base Catalysts for Synthesis of Biodiesel 251 10. Hydrothermal Technologies for the Production of Fuels and Chemicals from Biomass 291 11. Ionic Liquids in Green Chemistry Prediction of Ionic Liquids Toxicity Using Cell Models 343 12. Nano-catalyst: A Second Generation Tool for Green Chemistry 357 13. Green Polymer Synthesis: An Overview on Use of Microwave-Irradiation 379 Part 3. Green Bio-energy Sources 425 14. Bioenergy as a Green Technology Frontier 427 15. Biofuels as Suitable Replacement for Fossil Fuels 451 16. Biocatalysts-Greener Solutions 479 17. Lignocellulosics as a Renewable Feedstock for Chemical Industry. Chemical Hydrolysis and Pretreatment Processes 505 18. Lignocellulosics as a Renewable Feedstock for Chemical Industry Chemicals from Lignin 561 19. Genome Enabled Technologies in Green Chemistry 611 Part 4. Green Solutions for Remediation 627 20. Green Biotechnology for Municipal and Industrial Wastewater 629 21. Phytoremediation of Cadmium: A Green Approach 659 22. A Closer Look at “Green” Glass: Remediation with Organosilica Sol-Gels Through the Application of Green Chemistry 697 23. Modification and Applications of Guar Gum in the Field of Green Chemistry 727

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Book SynopsisThe application of plant chemical biology is currently limited to specialized subfields of plant research.Table of ContentsPreface vii Contributors ix part one Introduction 1 1.1 From Herbal Remedies to Cutting-Edge Science: A Historical Perspective of Plant Chemical Biology 3 Michelle Q. Brown, Abel Rosado, and Natasha V. Raikhel part Two Sources of small molecules 19 2.1 Compound Collections 21 Reg Richardson 2.2 Combinatorial Chemistry Library Design 40 Robert Klein and Stephen D. Lindell 2.3 Natural Product-Based Libraries 64 Alan L. Harvey part three Identification of new chemical tools by High-Throughput Screening 73 3.1 Assay Design for High-Throughput Screening 75 Frank W. An and Jose R. Perez part four Use of chemical biology to study plant physiology 93 4.1 Use of Chemical Biology to Understand Auxin Metabolism, Signaling, and Polar Transport 95 Ken-ichiro Hayashi and Paul Overvoorde 4.2 Brassinosteroids Signaling and Biosynthesis 128 Takeshi Nakano and Tadao Asami 4.3 Chemical Genetic Approaches on ABA Signal Transduction 145 Eunjoo Park and Tae-Houn Kim 4.4 Jasmonic Acid 160 Christian Meesters and Erich Kombrink 4.5 Chemical Genetics as a Tool to Study Ethylene Biology in Plants 184 Yuming Hu, Filip Vandenbussche, and Dominique Van Der Straeten part five Use of chemical biology to study plant cellular processes 203 5.1 The Use of Small Molecules to Dissect Cell Wall Biosynthesis and Manipulate the Cortical Cytoskeleton 205 Darby Harris and Seth DeBolt 5.2 The Use of Chemical Biology to Study Plant Cellular Processes: Subcellular Trafficking 218 Ash Haeger, Malgorzata £angowska, and Stéphanie Robert part six Target identification 233 6.1 Target Identification of Biologically Active Small Molecules 235 Paul Overvoorde and Dominique Audenaert part seven Translation of plant chemical biology from the lab to the field 247 7.1 Prospects and Challenges for Translating Emerging Insights in Plant Chemical Biology into New Agrochemicals 249 Terence A. Walsh 7.2 In Vitro Propagation 263 Hans Motte, Stefaan Werbrouck, and Danny Geelen Index 289

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Book SynopsisThis book presents both the fundamentals concepts and latest achievements of a field that is growing in importance since it represents a possible solution for global energy problems. It focuses on an atomic-level understanding of heterogeneous catalysis involved in important energy conversion processes.Table of ContentsContributors xiii 1 Introduction 1Franklin (Feng) Tao, William F. Schneider, and Prashant V. Kamat 2 Chemical Synthesis of Nanoscale Heterogeneous Catalysts 9Jianbo Wu and Hong Yang 2.1 Introduction 9 2.2 Brief Overview of Heterogeneous Catalysts 10 2.3 Chemical Synthetic Approaches 11 2.3.1 Colloidal Synthesis 11 2.3.2 Shape Control of Catalysts in Colloidal Synthesis 12 2.3.3 Control of Crystalline Phase of Intermetallic Nanostructures 14 2.3.4 Other Modes of Formation for Complex Nanostructures 17 2.4 Core–Shell Nanoparticles and Controls of Surface Compositions and Surface Atomic Arrangements 21 2.4.1 New Development on the Preparation of Colloidal Core–Shell Nanoparticles 21 2.4.2 Electrochemical Methods to Core–Shell Nanostructures 22 2.4.3 Control of Surface Composition via Surface Segregation 24 2.5 Summary 25 3 Physical Fabrication of Nanostructured Heterogeneous Catalysts 31Chunrong Yin, Eric C. Tyo, and Stefan Vajda 3.1 Introduction 31 3.2 Cluster Sources 34 3.2.1 T hermal Vaporization Source 34 3.2.2 Laser Ablation Source 36 3.2.3 Magnetron Cluster Source 37 3.2.4 Arc Cluster Ion Source 38 3.3 Mass Analyzers 39 3.3.1 Neutral Cluster Beams 40 3.3.2 Quadrupole Mass Analyzer 41 3.3.3 Lateral TOF Mass Filter 42 3.3.4 Magnetic Sector Mass Selector 43 3.3.5 Quadrupole Deflector (Bender) 44 3.4 Survey of Cluster Deposition Apparatuses in Catalysis Studies 44 3.4.1 Laser Ablation Source with a Quadrupole Mass Analyzer at Argonne National Lab 44 3.4.2 ACIS with a Quadrupole Deflector at the Universität Rostock 46 3.4.3 Magnetron Cluster Source with a Lateral TOF Mass Filter at the University of Birmingham 47 3.4.4 Laser Ablation Cluster Source with a Quadrupole Mass Selector at the Technische Universität München 48 3.4.5 Laser Ablation Cluster Source with a Quadrupole Mass Analyzer at the University of Utah 49 3.4.6 Laser Ablation Cluster Source with a Magnetic Sector Mass Selector at the University of California, Santa Barbara 49 3.4.7 Magnetron Cluster Source with a Quadrupole Mass Filter at the Toyota Technological Institute 51 3.4.8 PACIS with a Magnetic Sector Mass Selector at Universität Konstanz 52 3.4.9 Magnetron Cluster Source with a Magnetic Sector at Johns Hopkins University 53 3.4.10 Magnetron Cluster Source with a Magnetic Sector at HZB 53 3.4.11 Magnetron Sputtering Source with a Quadrupole Mass Filter at the Technical University of Denmark 54 3.4.12 CORDIS with a Quadrupole Mass Filter at the Lausanne Group 56 3.4.13 Electron Impact Source with a Quadrupole Mass Selector at the Universität Karlsruhe 56 3.4.14 CORDIS with a Quadrupole Mass Analyzer at the Universität Ulm 58 3.4.15 Magnetron Cluster Source with a Lateral TOF Mass Filter at the Universität Dortmund 59 3.4.16 Z-Spray Source with a Quadrupole Mass Filter for Gas-Phase Investigations at FELIX 60 3.4.17 Laser Ablation Source with an Ion Cyclotron Resonance Mass Spectrometer for Gas-Phase Investigations at the Technische Universität Berlin 61 4 Ex Situ Characterization 69Minghua Qiao, Songhai Xie, Yan Pei, and Kangnian Fan 4.1 Introduction 69 4.2 Ex Situ Characterization Techniques 70 4.2.1 X-Ray Absorption Spectroscopy 71 4.2.2 Electron Spectroscopy 72 4.2.3 Electron Microscopy 74 4.2.4 Scanning Probe Microscopy 75 4.2.5 Mössbauer Spectroscopy 76 4.3 Some Examples on Ex Situ Characterization of Nanocatalysts for Energy Applications 77 4.3.1 Illustrating Structural and Electronic Properties of Complex Nanocatalysts 77 4.3.2 Elucidating Structural Characteristics of Catalysts at the Nanometer or Atomic Level 81 4.3.3 Pinpointing the Nature of the Active Sites on Nanocatalysts 85 4.4 Conclusions 88 5 Applications of Soft X-Ray Absorption Spectroscopy for In Situ Studies of Catalysts at Nanoscale 93Xingyi Deng, Xiaoli Gu, and Franklin (Feng) Tao 5.1 Introduction 93 5.2 In Situ SXAS under Reaction Conditions 96 5.3 Examples of In Situ SXAS Studies under Reaction Conditions Using Reaction Cells 99 5.3.1 Atmospheric Corrosion of Metal Films 99 5.3.2 Cobalt Nanoparticles under Reaction Conditions 101 5.3.3 Electrochemical Corrosion of Cu in Aqueous NaHCO3 Solution 108 5.4 Summary 112 6 First-Principles Approaches to Understanding Heterogeneous Catalysis 115Dorrell C. McCalman and William F. Schneider 6.1 Introduction 115 6.2 Computational Models 116 6.2.1 Electronic Structure Methods 116 6.2.2 System Models 117 6.3 NOx Reduction 118 6.4 Adsorption at Metal Surfaces 119 6.4.1 Neutral Adsorbates 119 6.4.2 Charged Adsorbates 122 6.5 Elementary Surface Reactions Between Adsorbates 125 6.5.1 Reaction Thermodynamics 125 6.5.2 Reaction Kinetics 129 6.6 Coverage Effects on Reaction and Activation Energies at Metal Surfaces 131 6.7 Summary 135 7 Computational Screening for Improved Heterogeneous Catalysts and Electrocatalysts 139Jeffrey Greeley 7.1 Introduction 139 7.2 T rends-Based Studies in Computational Catalysis 140 7.2.1 Early Groundwork for Computational Catalyst Screening 140 7.2.2 Volcano Plots and Rate Theory Models 141 7.2.3 Scaling Relations, BEP Relations, and Descriptor Determination 144 7.3 Computational Screening of Heterogeneous Catalysts and Electrocatalysts 148 7.3.1 Computational Catalyst Screening Strategies 149 7.4 Challenges and New Frontiers in Computational Catalyst Screening 153 7.5 Conclusions 155 8 Catalytic Kinetics and Dynamics 161Rafael C. Catapan, Matthew A. Christiansen, Amir A. M. Oliveira, and Dionisios G. Vlachos 8.1 Introduction 161 8.2 Basics of Catalyst Functionality, Mechanisms, and Elementary Reactions on Surfaces 163 8.3 T ransition State Theory, Collision Theory, and Rate Constants 166 8.4 Density Functional Theory Calculations 168 8.4.1 Calculation of Energetics and Coverage Effects 169 8.4.2 Calculation of Vibrational Frequencies 172 8.5 T hermodynamic Consistency of the DFT-Predicted Energetics 172 8.6 State Properties from Statistical Thermodynamics 176 8.6.1 Strongly Bound Adsorbates 177 8.6.2 Weakly Bound Adsorbates 177 8.7 Semiempirical Methods for Predicting Thermodynamic Properties and Kinetic Parameters 178 8.7.1 Linear Scaling Relationships 178 8.7.2 Heat Capacity and Surface Entropy Estimation 179 8.7.3 Brønsted-Evans-Polanyi Relationships 180 8.8 Analysis Tools for Microkinetic Modeling 181 8.8.1 Rates in Microkinetic Modeling 181 8.8.2 Reaction Path Analysis and Partial Equilibrium Analysis 181 8.8.3 Rate-Determining Steps, Most Important Surface Intermediates, and Most Abundant Surface Intermediates 184 8.8.4 Calculation of the Overall Reaction Order and Apparent Activation Energy 186 8.9 Concluding Remarks 187 9 Catalysts for Biofuels 191Gregory T. Neumann, Danielle Garcia, and Jason C. Hicks 9.1 Introduction 191 9.2 Lignocellulosic Biomass 192 9.2.1 Cellulose 192 9.2.2 Hemicellulose 194 9.2.3 Lignin 195 9.3 Carbohydrate Upgrading 195 9.3.1 Zeolitic Upgrading of Cellulosic Feedstocks 196 9.3.2 Levulinic Acid Upgrading 199 9.3.3 GVL Upgrading 201 9.3.4 Aqueous-Phase Processing 202 9.4 Lignin Conversion 205 9.4.1 Zeolite Upgrading of Lignin Feedstocks 206 9.4.2 Catalysts for Hydrodeoxygenation of Lignin 208 9.4.3 Selective Unsupported Catalyst for Lignin Depolymerization 211 9.5 Continued Efforts for the Development of Robust Catalysts 212 10 Development of New Gold Catalysts for Removing CO from H2 217Zhen Ma, Franklin (Feng) Tao, and Xiaoli Gu 10.1 Introduction 217 10.2 General Description of Catalyst Development 218 10.3 Development of WGS catalysts 220 10.3.1 Initially Developed Catalysts 220 10.3.2 Fe2O3-Based Gold Catalysts 221 10.3.3 CeO2-Based Gold Catalysts 221 10.3.4 TiO2- or ZrO2-Based Gold Catalysts 223 10.3.5 Mixed-Oxide Supports with 1:1 Composition 223 10.3.6 Bimetallic Catalysts 224 10.4 Development of New Gold Catalysts for PROX 225 10.4.1 General Considerations 225 10.4.2 CeO2-Based Gold Catalysts 226 10.4.3 TiO2-Based Gold Catalysts 227 10.4.4 Al2O3-Based Gold Catalysts 228 10.4.5 Mixed Oxide Supports with 1:1 Composition 228 10.4.6 Other Oxide-Based Gold Catalysts 229 10.4.7 Supported Bimetallic catalysts 229 10.5 Perspectives 229 11 Photocatalysis in Generation of Hydrogen from Water 239Kazuhiro Takanabe and Kazunari Domen 11.1 Solar Energy Conversion 239 11.1.1 Solar Energy Conversion Technology for Producing Fuels and Chemicals 239 11.1.2 Solar Spectrum and STH Efficiency 242 11.2 Semiconductor Particles: Optical and Electronic Nature 244 11.2.1 Reaction Sequence and Principles of Overall Water Splitting and Reaction Step Timescales 244 11.2.2 Number of Photons Striking a Single Particle 245 11.2.3 Absorption Depth of Light Incident on Powder Photocatalyst 247 11.2.4 Degree of Band Bending in Semiconductor Powder 248 11.2.5 Band Gap and Flat-Band Potential of Semiconductor 250 11.3 Photocatalyst Materials for Overall Water Splitting: UV to Visible Light Response 251 11.3.1 UV Photocatalysts: Oxides 251 11.3.2 Visible-Light Photocatalysts: Band Engineering of Semiconductor Materials Containing Transition Metals 253 11.3.3 Visible-Light Photocatalysts: Organic Semiconductors as Water-Splitting Photocatalysts 255 11.3.4 Z-Scheme Approach: Two-Photon Process 257 11.3.5 Defects and Recombination in Semiconductor Bulk 257 11.4 Cocatalysts for Photocatalytic Overall Water Splitting 259 11.4.1 Metal Nanoparticles as Hydrogen Evolution Cocatalysts: Novel Core/Shell Structure 259 11.4.2 Reaction Rate Expression on Active Catalytic Centers for Redox Reaction in Solution 261 11.4.3 Measurement of Potentials at Semiconductor and Metal Particles Under Irradiation 264 11.4.4 Metal Oxides as Oxygen Evolution Cocatalyst 266 11.5 Concluding Remarks 268 12 Photocatalysis in Conversion of Greenhouse Gases 271Kentaro Teramura and Tsunehiro Tanaka 12.1 Introduction 271 12.2 Outline of Photocatalytic Conversion of CO2 273 12.3 Reaction Mechanism for the Photocatalytic Conversion of CO2 276 12.3.1 Adsorption of CO2 and H2 276 12.3.2 Assignment of Adsorbed Species by FT-IR Spectroscopy 279 12.3.3 Observation of Photoactive Species by Photoluminescence (PL) and Electron Paramagnetic Resonance (EPR) Spectroscopies 281 12.4 Summary 283 13 Electrocatalyst Design in Proton Exchange Membrane Fuel Cells for Automotive Application 285Anusorn Kongkanand, Wenbin Gu, and Frederick T. Wagner 13.1 Introduction 285 13.2 Advanced Electrocatalysts 288 13.2.1 Pt-Alloy and Dealloyed Catalysts 288 13.2.2 Pt Monolayer Catalysts 290 13.2.3 Continuous-Layer Catalysts 293 13.2.4 Controlled Crystal Face Catalysts 296 13.2.5 Hollow Pt Catalysts 298 13.3 Electrode Designs 299 13.3.1 Dispersed-Catalyst Electrodes 299 13.3.2 NSTF Electrodes 302 13.4 Concluding Remarks 307 Index 315

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Book SynopsisThis expanded second edition provides a concise overview of the main principles and reactions of heterocyclic chemistry for undergraduate students studying chemistry and related courses. Using a successful and student-friendly at a glance approach, this book helps the student grasp the essence of heterocyclic chemistry, ensuring that they can confidently use that knowledge when required. The chapters are thoroughly revised and updated with references to books and reviews; extra examples and student exercises with answers online; and color diagrams that emphasize exactly what is happening in the reaction chemistry depicted.Trade Review"Joule and Mills have succeeded here in condensing the essence of introductory undergraduate heterocyclic chemistry into a slim volume, presented (as is the way in this series) in an A4 page format and in a very easy-to-grasp style with many structures and reactions. All of the key areas are covered. ...the price and the concise nature of the text make it a feasible purchase and easy read for all those working in the area. I shall certainly be recommending it to my own classes." Chemistry World, June 2007 "The book delivers on its stated purpose to present the key concepts of heterocyclic chemistry to the nonspecialist and will likely find good application in the hands of molecular modelers, pharmacologists and undergraduates." Journal of Medicinal Chemistry, 2007, Vol.50, No.4, p6289Table of ContentsBiography v Abbreviations xii Introduction to Second Edition xiv 1. Heterocyclic Nomenclature 1 Six-membered aromatic heterocycles 2 Five-membered aromatic heterocycles 2 Non-aromatic heterocycles 3 Small-ring heterocycles 3 2. Structures of Heteroaromatic Compounds 4 Structures of benzene and naphthalene 4 Structures of pyridines and pyridiniums 5 Structures of quinolines and isoquinolines 6 Structures of diazines (illustrated using pyrimidine) 6 Structures of pyrroles, thiophenes and furans 6 Structure of indoles 8 Structures of azoles (illustrated using imidazole) 8 3. Common Reaction Types in Heterocyclic Chemistry 9 Introduction 9 Acidity and basicity 9 Electrophilic substitution of aromatic molecules 10 Nucleophilic substitution of aromatic molecules 13 Radical substitution of heterocycles 14 C-Metallated heterocycles as nucleophiles 15 Generation of C-metallated heterocycles 16 Dimethylformamide dimethyl acetal (DMFDMA) 17 Formation and hydrolysis of imine/enamine 18 Common synthetic equivalents of carbonyl compounds in ring synthesis 19 Cycloaddition reactions 19 4. Palladium in Heterocyclic Chemistry 21 Palladium(0)-catalysed (and related) reactions 21 Addition to alkenes: the Heck reaction 26 Carbonylation reactions 26 Cross-coupling reactions between heteroatom nucleophiles and halides – making carbon–heteroatom bonds 27 Triflates as substrates for palladium-catalysed reactions 27 Mechanisms of palladium(0)-catalysed processes 28 Reactions involving electrophilic palladation 29 Copper-catalysed amination 30 Selectivity 31 5. Pyridines 33 Electrophilic addition to nitrogen 33 Electrophilic substitution at carbon 34 Nucleophilic substitution 35 Nucleophilic addition to pyridinium salts 36 C-metallated pyridines 37 Palladium(0)-catalysed reactions 39 Oxidation and reduction 39 Pericyclic reactions 40 Alkyl and carboxylic acid substituents 40 Oxygen substituents 41 N-Oxides 42 Amine substituents 43 Ring synthesis – disconnections 43 Synthesis of pyridines from 1,5-dicarbonyl compounds 44 Synthesis of pyridines from an aldehyde, two equivalents of a 1,3-dicarbonyl compound and ammonia 45 Synthesis of pyridines from 1,3-dicarbonyl compounds and a C2N unit 45 Exercises 47 6. Diazines 48 Electrophilic addition to nitrogen 49 Electrophilic substitution at carbon 49 Nucleophilic substitution 50 Radical substitution 52 C-Metallated diazines 52 Palladium(0)-catalysed reactions 53 Pericyclic reactions 54 Oxygen substituents 55 N-Oxides 57 Amine substituents 57 Ring synthesis – disconnections 58 Synthesis of pyridazines from 1,4-dicarbonyl compounds 58 Synthesis of pyrimidines from 1,3-dicarbonyl compounds 58 Synthesis of pyrazines from 1,2-dicarbonyl compounds 59 Synthesis of pyrazines from -amino-carbonyl compounds 60 Benzodiazines 60 Exercises 61 7. Quinolines and Isoquinolines 62 Electrophilic addition to nitrogen 62 Electrophilic substitution at carbon 62 Nucleophilic substitution 63 Nucleophilic addition to quinolinium/isoquinolinium salts 64 C-Metallated quinolines and isoquinolines 65 Palladium(0)-catalysed reactions 65 Oxidation and reduction 66 Alkyl substituents 66 Oxygen substituents 67 N-Oxides 67 Ring synthesis – disconnections 67 Synthesis of quinolines from anilines 67 Synthesis of quinolines from ortho-aminoaryl ketones or aldehydes 68 Synthesis of isoquinolines from 2-arylethamines 69 Synthesis of isoquinolines from aryl-aldehydes and an aminoacetaldehyde acetal 69 Synthesis of isoquinolines from ortho-alkynyl aryl-aldehydes or corresponding imines 70 Exercises 70 8. Pyryliums, Benzopyryliums, Pyrones and Benzopyrones 71 Pyrylium salts 71 Electrophiles 71 Nucleophilic addition 71 Ring-opening reactions of 2H-pyrans 71 Oxygen substituents – pyrones and benzopyrones 73 Ring synthesis of pyryliums from 1,5-diketones 74 Ring synthesis of 4-pyrones from 1,3,5-triketones 75 Ring synthesis of 2-pyrones from 1,3-keto-aldehydes 75 Ring synthesis of 1-benzopyryliums, coumarins and chromones 76 Exercises 77 9. Pyrroles 78 Electrophilic substitution at carbon 78 N-Deprotonation and N-metallated pyrroles 80 C-Metallated pyrroles 80 Palladium(0)-catalysed reactions 81 Oxidation and reduction 81 Pericyclic reactions 82 Reactivity of side-chain substituents 82 The ‘pigments of life’ 82 Ring synthesis – disconnections 83 Synthesis of pyrroles from 1,4-dicarbonyl compounds 83 Synthesis of pyrroles from -amino-ketones 83 Synthesis of pyrroles using isocyanides 84 Exercises 85 10. Indoles 86 Electrophilic substitution at carbon 86 N-Deprotonation and N-metallated indoles 89 C-Metallated indoles 90 Palladium(0)-catalysed reactions 91 Oxidation and reduction 92 Pericyclic reactions 92 Reactivity of side-chain substituents 93 Oxygen substituents 94 Ring synthesis – disconnections 94 Synthesis of indoles from arylhydrazones 94 Synthesis of indoles from ortho-nitrotoluenes 95 Synthesis of indoles from ortho-aminoaryl alkynes 96 Synthesis of indoles from ortho-alkylaryl isocyanides 96 Synthesis of indoles from ortho-acyl anilides 96 Synthesis of isatins from anilines 97 Synthesis of oxindoles from anilines 97 Synthesis of indoxyls from anthranilic acids 97 Azaindoles 97 Exercises 98 11. Furans and Thiophenes 99 Electrophilic substitution at carbon 99 C-Metallated thiophenes and furans 101 Palladium(0)-catalysed reactions 102 Oxidation and reduction 102 Pericyclic reactions 103 Oxygen substituents 104 Ring synthesis – disconnections 105 Synthesis of furans and thiophenes from 1,4-dicarbonyl compounds 105 Exercises 106 12. 1,2-Azoles and 1,3-Azoles 107 Introduction 107 Electrophilic addition to N 107 Electrophilic substitution at C 109 Nucleophilic substitution of halogen 110 N-Deprotonation and N-metallated imidazoles and pyrazoles 110 C-Metallated N-substituted imidazoles and pyrazoles, and C-metallated thiazoles and isothiazoles 111 C-Deprotonation of oxazoles and isoxazoles 112 Palladium(0)-catalysed reactions 113 1,3-Azolium ylides 113 Reductions 114 Pericyclic reactions 114 Oxygen and amine substituents 115 1,3-Azoles ring synthesis – disconnections 116 Synthesis of thiazoles and imidazoles from -halo-ketones 116 Synthesis of 1,3-azoles from 1,4-dicarbonyl compounds 117 Synthesis of 1,3-azoles using tosylmethyl isocyanide 118 Synthesis of 1,3-azoles via dehydrogenation 118 1,2-Azoles ring synthesis – disconnections 119 Synthesis of pyrazoles and isoxazoles from 1,3-dicarbonyl compounds 119 Synthesis of isoxazoles and pyrazoles from alkynes 120 Synthesis of isothiazoles from -amino , -unsaturated carbonyl compounds 121 Exercises 121 13. Purines 122 Electrophilic addition to nitrogen 124 Electrophilic substitution at carbon 125 N-Deprotonation and N-metallated purines 125 Oxidation 126 Nucleophilic substitution 126 C-Metallated purines by direct deprotonation or halogen–metal exchange 128 Palladium(0)-catalysed reactions 128 Purines with oxygen and amine substituents 128 Ring synthesis – disconnections 130 Synthesis of purines from 4,5-diaminopyrimidines 130 Synthesis of purines from 5-aminoimidazole-4-carboxamide 131 ‘One-step syntheses’ 131 Exercises 131 14. Heterocycles with More than Two Heteroatoms: Higher Azoles (5-Membered) and Higher Azines (6-Membered) 132 Higher Azoles 132 Introduction 132 Higher azoles containing nitrogen as the only ring heteroatom: triazoles, tetrazole and pentazole 132 Benzotriazole 136 Higher azoles also containing ring sulfur or oxygen: oxa- and thiadiazoles 137 Higher azines 139 Exercises 142 15. Heterocycles with Ring-Junction Nitrogen (Bridgehead Nitrogen) 143 Introduction 143 Indolizine 144 Azaindolizines 144 Synthesis of indolizines and azaindolizines 146 Quinoliziniums and quinolizinones 147 Heteropyrrolizines (pyrrolizines containing additional heteroatoms) 148 Cyclazines 148 Exercises 149 16. Non-Aromatic Heterocycles 150 Introduction 150 Three-membered rings 150 Four-membered rings 153 Five- and six-membered rings 153 Ring synthesis 155 17. Heterocycles in Nature 158 Heterocyclic -amino acids and related substances 158 Heterocyclic vitamins – co-enzymes 159 Porphobilinogen and the ‘Pigments of Life’ 162 Deoxyribonucleic acid (DNA), the store of genetic information, and ribonucleic acid (RNA), its deliverer 163 Heterocyclic secondary metabolites 165 18. Heterocycles in Medicine 167 Medicinal chemistry – how drugs function 167 Drug discovery 168 Drug development 169 The neurotransmitters 169 Histamine 170 Acetylcholine (ACh) 171 Anticholinesterase agents 172 5-Hydroxytryptamine (5-HT) (serotonin) 172 Adrenaline and noradrenaline 173 Other significant cardiovascular drugs 173 Drugs acting specifically on the CNS 173 Other enzyme inhibitors 174 Anti-infective agents 175 Antiparasitic drugs 175 Antibacterial drugs 176 Antiviral drugs 177 Anticancer drugs 177 Photochemotherapy 178 19. Applications and Occurrences of Heterocycles in Everyday Life 180 Introduction 180 Dyes and pigments 180 Polymers 181 Pesticides 182 Explosives 184 Food and drink 186 Heterocyclic chemistry of cooking 187 Natural and synthetic food colours 190 Flavours and fragrances (F&F) 190 Toxins 192 Electrical and electronic 193 Index 195

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Book SynopsisThe successful implementation of greener chemical processes relies not only on the development of more efficient catalysts for synthetic chemistry but also, and as importantly, on the development of reactor and separation technologies which can deliver enhanced processing performance in a safe, cost-effective and energy efficient manner. Process intensification has emerged as a promising field which can effectively tackle the challenges of significant process enhancement, whilst also offering the potential to diminish the environmental impact presented by the chemical industry. Following an introduction to process intensification and the principles of green chemistry, this book presents a number of intensified technologies which have been researched and developed, including case studies to illustrate their application to green chemical processes. Topics covered include: Intensified reactor technologies: spinning disc reactors, microreactors, monolith reactTable of ContentsList of Contributors xiii Preface xv 1 Process Intensification: An Overview of Principles and Practice 1 Kamelia Boodhoo and Adam Harvey 1.1 Introduction 1 1.2 Process Intensification: Definition and Concept 2 1.3 Fundamentals of Chemical Engineering Operations 3 1.3.1 Reaction Engineering 3 1.3.2 Mixing Principles 5 1.3.3 Transport Processes 8 1.4 Intensification Techniques 11 1.4.1 Enhanced Transport Processes 11 1.4.2 Integrating Process Steps 19 1.4.3 Moving from Batch to Continuous Processing 20 1.5 Merits of PI Technologies 21 1.5.1 Business 22 1.5.2 Process 22 1.5.3 Environment 23 1.6 Challenges to Implementation of PI 24 1.7 Conclusion 25 Nomenclature 26 Greek Letters 26 References 27 2 Green Chemistry Principles 33 James Clark, Duncan Macquarrie, Mark Gronnow and Vitaly Budarin 2.1 Introduction 33 2.1.1 Sustainable Development and Green Chemistry 35 2.2 The Twelve Principles of Green Chemistry 35 2.2.1 Ideals of Green Chemistry 36 2.3 Metrics for Chemistry 37 2.3.1 Effective Mass Yield 38 2.3.2 Carbon Efficiency 38 2.3.3 Atom Economy 38 2.3.4 Reaction Mass Efficiency 39 2.3.5 Environmental (E) Factor 39 2.3.6 Comparison of Metrics 40 2.4 Catalysis and Green Chemistry 41 2.4.1 Case Study: Silica as a Catalyst for Amide Formation 43 2.4.2 Case Study: Mesoporous Carbonaceous Material as a Catalyst Support 45 2.5 Renewable Feedstocks and Biocatalysis 46 2.5.1 Case Study: Wheat Straw Biorefinery 48 2.6 An Overview of Green Chemical Processing Technologies 50 2.6.1 Alternative Reaction Solvents for Green Processing 50 2.6.2 Alternative Energy Reactors for Green Chemistry 52 2.7 Conclusion 55 References 55 3 Spinning Disc Reactor: Continuous Thin-film Flow Processing for Green Chemistry Applications 59 Kamelia Boodhoo 3.1 Introduction 59 3.2 Design and Operating Features of SDRs 60 3.2.1 Hydrodynamics 63 3.2.2 SDR Scale-up Strategies 64 3.3 Characteristics of SDRs 66 3.3.1 Thin-film Flow and Surface Waves 66 3.3.2 Heat and Mass Transfer 68 3.3.3 Mixing Characteristics 71 3.3.4 Residence Time and Residence Time Distribution 72 3.3.5 SDR Applications 75 3.4 Case Studies: SDR Application for Green Chemical Processing and Synthesis 76 3.4.1 Cationic Polymerization using Heterogeneous Lewis Acid Catalysts 76 3.4.2 Solvent-free Photopolymerization Processing 78 3.4.3 Heterogeneous Catalytic Organic Reaction in the SDR: An Example of Application to the Pharmaceutical/Fine Chemicals Industry 80 3.4.4 Green Synthesis of Nanoparticles 83 3.5 Hurdles to Industry Implementation 84 3.5.1 Control, Monitoring and Modelling of SDR Processes 84 3.5.2 Limited Process Throughputs 86 3.5.3 Cost and Availability of Equipment 86 3.5.4 Lack of Awareness of SDR Technology 86 3.6 Conclusion 86 Nomenclature 87 Greek Letters 87 Subscripts 87 References 87 4 Micro Process Technology and Novel Process Windows – Three Intensification Fields 91 Svetlana Borukhova and Volker Hessel 4.1 Introduction 91 4.2 Transport Intensification 93 4.2.1 Fundamentals 93 4.2.2 Mixing Principles 94 4.2.3 Micromixers 96 4.2.4 Micro Heat Exchangers 102 4.2.5 Exothermic Reactions as Major Application Examples 106 4.3 Chemical Intensification 108 4.3.1 Fundamentals 108 4.3.2 New Chemical Transformations 108 4.3.3 High Temperature 118 4.3.4 High Pressure 122 4.3.5 Alternative Reaction Media 124 4.4 Process Design Intensification 128 4.4.1 Fundamentals 128 4.4.2 Large-scale Manufacture of Adipic Acid – A Full Process Design Vision in Flow 130 4.4.3 Process Integration – From Single Operation towards Full Process Design 131 4.4.4 Process Simplification 135 4.5 Industrial Microreactor Process Development 137 4.5.1 Industrial Demonstration of Specialty/Pharma Chemistry Flow Processing 138 4.5.2 Industrial Demonstration of Fine Chemistry Flow Processing 138 4.5.3 Industrial Demonstration of Bulk Chemistry Flow Processing 139 4.6 Conclusion 140 Acknowledgement 141 References 141 5 Green Chemistry in Oscillatory Baffled Reactors 157 Adam Harvey 5.1 Introduction 157 5.1.1 Continuous versus Batch Operation 157 5.1.2 The Oscillatory Baffled Reactor’s ‘Niche’ 157 5.2 Case Studies: OBR Green Chemistry 164 5.2.1 A Saponification Reaction 164 5.2.2 A Three-phase Reaction with Photoactivation for Oxidation of Waste Water Contaminants 166 5.2.3 ‘Mesoscale’ OBRs 168 5.3 Conclusion 170 References 172 6 Monolith Reactors for Intensified Processing in Green Chemistry 175 Joseph Wood 6.1 Introduction 175 6.2 Design of Monolith Reactors 176 6.2.1 Monolith and Washcoat Design 176 6.2.2 Reactor and Distributor Design 178 6.3 Hydrodynamics of Monolith Reactors 179 6.3.1 Flow Regimes 179 6.3.2 Mixing and Mass Transfer 180 6.4 Advantages of Monolith Reactors 182 6.4.1 Scale-out, Not Scale-up? 182 6.4.2 PI for Green Chemistry 183 6.5 Applications in Green Chemistry 185 6.5.1 Chemical and Fine Chemical Industry 185 6.5.2 Cleaner Production of Fuels 187 6.5.3 Removal of Toxic Emissions 188 6.6 Conclusion 192 Acknowledgement 193 Nomenclature 193 Greek Letters 193 Subscripts and Superscripts 193 References 193 7 Process Intensification and Green Processing Using Cavitational Reactors 199 Vijayanand Moholkar, Parag Gogate and Aniruddha Pandit 7.1 Introduction 199 7.2 Mechanism of Cavitation-based PI of Chemical Processing 200 7.3 Reactor Configurations 201 7.3.1 Sonochemical Reactors 201 7.3.2 Hydrodynamic Cavitation Reactors 205 7.4 Mathematical Modelling 207 7.5 Optimization of Operating Parameters in Cavitational Reactors 209 7.5.1 Sonochemical Reactors 209 7.5.2 Hydrodynamic Cavitation Reactors 210 7.6 Intensification of Cavitational Activity 211 7.6.1 Use of PI Parameters 212 7.6.2 Use of a Combination of Cavitation and Other Processes 213 7.7 Case Studies: Intensification of Chemical Synthesis using Cavitation 214 7.7.1 Transesterification of Vegetable Oils Using Alcohol 214 7.7.2 Selective Synthesis of Sulfoxides from Sulfides Using Sonochemical Reactors 217 7.8 Overview of Intensification and Green Processing Using Cavitational Reactors 218 7.9 The Future 221 7.10 Conclusion 222 References 222 8 Membrane Bioreactors for Green Processing in a Sustainable Production System 227 Rosalinda Mazzei, Emma Piacentini, Enrico Drioli and Lidietta Giorno 8.1 Introduction 227 8.2 Membrane Bioreactors 228 8.2.1 Membrane Bioreactors with Biocatalyst Recycled in the Retentate Stream 228 8.2.2 Membrane Bioreactors with Biocatalyst Segregated in the Membrane Module Space 230 8.3 Biocatalytic Membrane Reactors 230 8.3.1 Entrapment 230 8.3.2 Gelification 231 8.3.3 Chemical Attachment 231 8.4 Case Studies: Membrane Bioreactors 232 8.4.1 Biofuel Production Using Enzymatic Transesterification 233 8.4.2 Waste Water Treatment and Reuse 237 8.4.3 Waste Valorization to Produce High-added-value Compounds 239 8.5 Green Processing Impact of Membrane Bioreactors 245 8.6 Conclusion 247 References 247 9 Reactive Distillation 251 Anton Kiss 9.1 Introduction 251 9.2 Principles of RD 252 9.3 Design, Control and Applications 253 9.4 Modelling RD 256 9.5 Economical and Technical Evaluation 257 9.5.1 Economical Evaluation 257 9.5.2 Technical Evaluation 260 9.6 Case Studies: RD 261 9.6.1 Biodiesel Production by Heat-Integrated RD 261 9.6.2 Fatty Ester Synthesis by Dual RD 267 9.7 Green Processing Impact of RD 270 9.8 Conclusion 271 References 271 10 Reactive Extraction Technology 275 Keat T. Lee and Steven Lim 10.1 Introduction 275 10.1.1 Definition and Description 275 10.1.2 Literature Review 276 10.2 Case Studies: Reactive Extraction Technology 277 10.2.1 Reactive Extraction for the Synthesis of FAME from Jatropha curcas L. Seeds 277 10.2.2 Supercritical Reactive Extraction for FAME Synthesis from Jatropha curcas L. Seeds 281 10.3 Impact on Green Processing and Process Intensification 284 10.4 Conclusion 286 References 286 11 Reactive Absorption 289 Anton A. Kiss 11.1 Introduction 289 11.2 Theory and Models 290 11.2.1 Equilibrium Stage Model 290 11.2.2 HTU/NTU Concepts and Enhancement Factors 291 11.2.3 Rate-based Stage Model 291 11.3 Equipment, Operation and Control 291 11.4 Applications in Gas Purification 293 11.4.1 Carbon Dioxide Capture 293 11.4.2 Sour Gas Treatment 296 11.4.3 Removal of Nitrogen Oxides 296 11.4.4 Desulfurization 297 11.4.5 Sulfuric Acid Production 299 11.4.6 Nitric Acid Production 299 11.4.7 Biodiesel and Fatty Esters Synthesis 302 11.5 Green Processing Impact of RA 307 11.6 Challenges and Future Prospects 307 References 307 12 Membrane Separations for Green Chemistry 311 Rosalinda Mazzei, Emma Piacentini, Enrico Drioli and Lidietta Giorno 12.1 Introduction 311 12.2 Membranes and Membrane Processes 312 12.3 Case Studies: Membrane Operations in Green Processes 318 12.3.1 Membrane Technology in Metal Ion Removal from Waste Water 318 12.3.2 Membrane Operations in Acid Separation from Waste Water 330 12.3.3 Membrane Operation for Hydrocarbon Separation from Waste Water 333 12.3.4 Membrane Operations for the Production of Optically Pure Enantiomers 336 12.4 Integrated Membrane Processes 342 12.4.1 Integrated Membrane Processes for Water Desalination 342 12.4.2 Integrated Membrane Processes for the Fruit Juice Industry 343 12.5 Green Processing Impact of Membrane Processes 344 12.6 Conclusion 347 References 347 13 Process Intensification in a Business Context: General Considerations 355 Dag Eimer and Nils Eldrup 13.1 Introduction 355 13.2 The Industrial Setting 356 13.3 Process Case Study 358 13.3.1 Essential Lessons 364 13.4 Business Risk and Ideas 366 13.5 Conclusion 367 References 367 14 Process Economics and Environmental Impacts of Process Intensification in the Petrochemicals, Fine Chemicals and Pharmaceuticals Industries 369 Jan Harmsen 14.1 Introduction 369 14.2 Petrochemicals Industry 370 14.2.1 Drivers for Innovation 370 14.2.2 Conventional Technologies Used 372 14.2.3 Commercially Applied PI Technologies 372 14.3 Fine Chemicals and Pharmaceuticals Industries 376 14.3.1 Drivers for Innovation 376 14.3.2 Conventional Technologies Used 377 14.3.3 Commercially Applied PI Technologies 377 References 377 15 Opportunities for Energy Saving from Intensified Process Technologies in the Chemical and Processing Industries 379 Dena Ghiasy and Kamelia Boodhoo 15.1 Introduction 379 15.2 Energy-Intensive Processes in UK Chemical and Processing Industries 380 15.2.1 What Can PI Offer? 380 15.3 Case Study: Assessment of the Energy Saving Potential of SDR Technology 383 15.3.1 Basis for Comparison 384 15.3.2 Batch Process Energy Usage 384 15.3.3 Batch/SDR Combined Energy Usage 386 15.3.4 Energy Savings 389 15.4 Conclusion 389 Nomenclature 390 Greek Letters 390 Subscripts 390 Appendix: Physical Properties of Styrene, Toluene and Cooling/Heating Fluids 391 References 391 16 Implementation of Process Intensification in Industry 393 Jan Harmsen 16.1 Introduction 393 16.2 Practical Considerations for Commercial Implementation 393 16.2.1 Reactive Distillation 394 16.2.2 Dividing Wall Column Distillation 396 16.2.3 Reverse Flow Reactors 396 16.2.4 Microreactors 397 16.2.5 Rotating Packed Bed Reactors 397 16.3 Scope for Implementation in Various Process Industries 397 16.3.1 Oil Refining and Bulk Chemicals 397 16.3.2 Fine Chemicals and Pharmaceuticals Industries 398 16.3.3 Biomass Conversion 399 16.4 Future Prospects 399 References 399 Index 401

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