Title Details

Jorge Bravo is professor in the department of inorganic chemistry at the University of Vigo. His research interests encompass organometallic chemistry of group 7 - 9 metals, the development of water-soluble complexes, and their structure elucidation. He joined the University of Vigo in 1978.

Preface XV

List of Contributors XVII

1 Interaction of Radiation with Matter 1
Ignacio Pérez-Juste and Olalla Nieto Faza

1.1 Introduction 1

1.2 Spectroscopy: A Definition 1

1.3 Electromagnetic Radiation 2

1.4 Electromagnetic Spectrum 4

1.5 Interaction of Radiation with Matter 6

1.6 Magnetic Spectroscopies 12

1.7 Pulse Techniques in NMR Spectroscopy 14

1.8 Line Widths 15

1.9 Selection Rules 17

1.10 Summary of Spectroscopic Techniques 18

1.10.1 Absorption-Based Methods 19

1.10.2 Emission-Based Methods 20

1.10.3 Scattering and Diffraction Methods 21

References 23

2 Computational Spectroscopy Tools for Molecular Structure Analysis 27
Cristina Puzzarini and Malgorzata Biczysko

2.1 Introduction 27

2.2 Potential Energy Surface and Molecular Structure 29

2.2.1 Minima and Conformational Analysis 29

2.2.2 Spectroscopic Tools for Structure Determination 31

2.3 Computational Aspects for Spectroscopic Techniques 32

2.3.1 DFT and Hybrid Approaches for Spectroscopic Applications 32

2.3.2 Rotational Spectroscopy 33

2.3.3 Vibrational Spectroscopy: Infrared (IR), Vibrational Circular Dichroism (VCD), Raman 34

2.3.4 Electronic Spectroscopy: One-Photon Absorption (OPA) and Electronic Circular Dichroism (ECD) 36

2.3.5 Magnetic Resonance Spectroscopy: Electronic Spin Resonance (ESR) 38

2.4 Application and Case Studies 40

2.4.1 Semi-Experimental Equilibrium Structure 40

2.4.2 Identification of Conformers/Tautomers 42

2.4.3 3D Structure: Molecular Complexes and Flexible Macromolecules 50

Acknowledgments 55

References 55

3 Absolute Configuration and Conformational Analysis of Chiral Compounds via Experimental and Theoretical Prediction of Chiroptical Properties: ORD, ECD, and VCD 65
Ana G. Petrovic, Nina Berova, and José Lorenzo Alonso-Gómez

3.1 Introduction 65

3.2 Chirality 65

3.3 What is a Chiroptical Method? 66

3.4 Quantum Mechanical (Ab Initio) Methods for Predicting Chiroptical Properties 71

3.5 Electronic Circular Dichroism (ECD) 73

3.5.1 Advantages of ECD 73

3.5.2 Limitations of ECD 73

3.5.3 Applications of ECD 74

3.5.4 Challenge due to Vibronic Coupling 82

3.6 Vibrational Circular Dichroism (VCD) 82

3.6.1 Advantages of VCD 85

3.6.2 Limitations of VCD 86

3.6.3 Application of VCD 86

3.7 Optical Rotatory Dispersion (ORD) 95

3.7.1 Advantages of ORD 96

3.7.2 Limitations of ORD 96

3.8 When More than One Method is Needed 97

3.8.1 Combination of ECD and VCD 97

3.8.2 Combination of ECD and ORD 97

3.8.3 Combination of VCD and ORD 99

3.9 Concluding Remarks 100

References 100

4 Mass Spectrometry Strategies in the Assignment of Molecular Structure: Breaking Chemical Bonds before Bringing the Pieces of the Puzzle Together 105
Wilfried M.A. Niessen and Maarten Honing

4.1 Introduction 105

4.2 Instrumentation and Technology 106

4.2.1 Ionization Techniques 107

4.2.2 Mass Analyzers 109

4.2.3 Tandem Mass Spectrometry Technologies 111

4.2.4 Data Acquisition Strategies in Tandem Mass Spectrometry 115

4.3 Breaking Chemical Bonds–Fragmentation Reactions 116

4.3.1 Fragmentation of Odd-Electron Ions 116

4.3.2 Fragmentation of Even-Electron Ions 118

4.3.3 Additional Strategies and Tools 123

4.4 Confirmation of Identity 125

4.4.1 Retrieving Compound Identity by Library Searching 126

4.4.2 Multiple SRM Transitions in Residue Screening 126

4.4.3 Confirming the Identity of Synthetic Products 127

4.5 Putting the Puzzle Together–Structure Elucidation of Unknowns 128

4.5.1 Strategies for Identification of Related Substances 128

4.5.2 Identification of Unknowns 131

4.6 Conclusions and Perspectives 136

Abbreviations 136

References 137

5 Basic Principles of IR/Raman: Applications in Small Molecules Structural Elucidation 145
Ricardo F. Aroca

5.1 Introduction 145

5.2 Characteristic Vibrational Modes: Diatomics and Chemical Bonds 148

5.2.1 The Diatomic Example 150

5.2.2 Equilibrium Properties: Dipole Moment and Polarizability 153

5.3 Fundamental Vibrational Modes and Molecular Structure 158

5.4 Selection Rules and Finding the Number of Normal Modes in Each Symmetry Species 159

5.5 The Vibrational Assignment of Raman and Infrared Spectra 163

5.6 Conclusions 169

References 169

6 Solid-State NMR Applications in the Structural Elucidation of Small Molecules 173
Mariana Sardo, João Rocha, and Luís Mafra

6.1 Introduction 173

6.2 Line-Narrowing and Sensitivity Enhancement Methods in ssNMR Spectroscopy 174

6.3 Probing Dynamics in Solids 175

6.4 Application of ssNMR Spectroscopy to Small Molecules 178

6.4.1 Hydrogen Bonding 178

6.4.2 Guest Molecules Adsorbed in Porous Materials 180

6.4.3 Energy-Related Compounds 194

6.4.4 Pharmaceuticals 197

6.4.5 Biomolecules 206

6.5 NMR of Molecules on Surfaces (DNP) 214

6.6 NMR Crystallography 217

Acronyms 228

References 229

7 Simplified NMR Procedures for the Assignment of the Absolute Configuration 241
José Manuel Seco, Emilio Quiñoá, and Ricardo Riguera

7.1 Introduction 241

7.2 Single Derivatization Methods for Mono- and Polyfunctional Compounds 243

7.2.1 Low Temperature 243

7.2.2 Selective Complexation 252

7.2.3 Esterification Shifts 254

7.3 Resin-Bound Chiral Derivatizing Agents (Mix and Shake Method) 257

7.4 Non-resin in Tube Assignment (BPG and BINOL Borates) 260

7.5 Tandem HPLC-NMR: Simultaneous Enantioresolution and Configurational Assignment 262

7.6 Assignment Based on the Chemical Shifts from the Auxiliaries 264

7.7 Scope and Conclusions 272

References 273

8 Structural Elucidation of Small Organic Molecules Assisted by NMR in Aligned Media 279
Roberto R. Gil, Christian Griesinger, Armando Navarro-Vázquez, and Han Sun

8.1 Introduction 279

8.2 Aligning Media 284

8.2.1 Magnetic Susceptibility 284

8.2.2 Paramagnetic Systems 288

8.2.3 Mechanically Strained Polymer Gels 290

8.3 Measurement of RDCs 291

8.3.1 Measurement of 1DCH RDCs 292

8.3.2 1H–1H Couplings E.COSY and P.E.HSQC Experiments 296

8.4 Computational Methodology 297

8.4.1 Determination of the Alignment Tensor 297

8.4.2 Symmetrical Rotors 299

8.5 Data Analysis: Use of RDCs as Structural Constraints in Small Molecules 300

8.5.1 Determination of Configuration for Rigid Molecules 300

8.5.2 Assignment of Diastereotopic Groups 303

8.5.3 RC Assignment in Molecules with Conformational Flexibility 305

8.6 RDCs and Determination of Absolute Configuration 311

8.6.1 Assignment of the Absolute Configuration: Combination of Residual Dipolar Couplings and Chiroptical Techniques 312

8.7 Conclusions and Perspectives 316

Acknowledgments 316

References 316

9 NMR Techniques for the Study of Transient Intermolecular Interactions 325
Jesús Angulo, Ana Ardá, Eurico J. Cabrita, Manuel Martín-Pastor, Jesús Jiménez-Barbero, and PedroM. Nieto

9.1 Introduction 325

9.2 Nuclear Overhauser Effect 326

9.2.1 Introduction to NOE-Based Methods 326

9.2.2 Transferred NOE 328

9.2.3 CORCEMA: Relaxation Matrix 331

9.2.4 Transfer-NOE Applications 332

9.2.5 Transfer-NOE: Quantitative Applications 334

9.3 Saturation Transfer Difference NMR 335

9.3.1 STD NMR Applications 337

9.4 Diffusion NMR 345

9.4.1 Diffusion and Molecular Structure 345

9.4.2 Measuring Diffusion with NMR 345

9.4.3 Diffusion Coefficient in the Presence of Chemical Exchange 348

9.4.4 Diffusion NMR Applications 349

9.5 Conclusions 354

References 354

10 Analysis of Molecular Interactions by Surface Plasmon Resonance Spectroscopy 361
Eva Muñoz and Daniel Ricklin

10.1 Introduction 361

10.2 General Aspects of the Surface Plasmon Resonance Principle 362

10.3 The SPR Experiment 363

10.3.1 Sensor Surface Design and Preparation 364

10.3.2 The Binding Experiment 367

10.4 The Information Contained in the SPR Experiment 369

10.4.1 Qualitative Information 369

10.4.2 Binding Affinity and Kinetics 370

10.4.3 Concentration Analysis 372

10.4.4 Thermodynamics 373

10.5 SPR Applications: From Large to Small Molecules 373

10.5.1 Working with SPR and Large Molecules 373

10.5.2 Working with SPR and Small Molecules 378

10.6 Beyond SPR–Orthogonal Interaction Biosensor Technologies 386

References 387

11 Determination of Absolute Configurations by Electronic CD Exciton Chirality, Vibrational CD, 1H NMR Anisotropy, and X-ray Crystallography Methods–Principles, Practices, and Reliability 393
Nobuyuki Harada

11.1 Introduction 393

11.2 Reliability in the AC Determination and Selection of Method 394

11.3 Non-empirical Method: AC Determination by the X-ray Bijvoet Method 395

11.4 Non-empirical Method: AC Determination by the ECD Exciton Chirality Method 396

11.4.1 Outline of the ECD Exciton Chirality Method 396

11.4.2 Molecular Exciton Theory of the CD Exciton Chirality Rule and Application to Steroidal Dibenzoate 398

11.4.3 The Most Ideal Exciton CD of (6R,15R)-(+)-6, 15-Dihydro-6,15-ethanonaphtho[2,3-c]pentaphene 400

11.4.4 Illustrative Cases: Application of the CD Exciton Chirality Rule 401

11.5 Non-empirical Method: AC Determination by VCD Spectroscopy and DFT MO Simulation 403

11.6 Empirical Method: AC Determination by 1H NMR Anisotropy Method Using MαNP Acid 408

11.6.1 Enantioresolution of Racemic Aliphatic Alcohols Using MαNP Acid and Simultaneous Determination of Their ACs 411

11.6.2 Application of the MαNP Acid Method to cis-2-Butyl-2-methyl-1-tetralol 411

11.6.3 Verification of the AC of cis-2-Butyl-2-methyl-1-tetralol by X-ray Crystallography 414

11.6.4 Verification of the AC of (S)-(−)-[VCD(+)984]-4-Ethyl-4-methyloctane by Chemical Correlation 415

11.7 Relative Method: X-ray Crystallography Using Camphorsultam Dichlorophthalic Acid (CSDP Acid) 416

11.7.1 Application of the CSDP Acid Method to Other Racemic Alcohols 418

11.7.2 Application of the CSDP Acid Method to Asymmetric Reaction Products 430

11.8 Relative Method: X-ray Crystallography Using of MαNP Group as Internal Reference 432

11.8.1 Alternative Preparation of Enantiopure MαNP Acid 432

11.8.2 AC Determination of Other MαNP Esters by X-ray Crystallography 433

11.9 Conclusion 438

Acknowledgments 439

References 439

12 An Integrated Approach to Structure Verification Using Automated Procedures 445
Juan Carlos Cobas Gómez,Michael Bernstein, and Stanislav Sýkora

12.1 Introduction 445

12.1.1 Setting the Scene:The Need for an Automatic Structure Verification,(ASV) Platform 445

12.1.2 Automatic Structure Verification:What It Is and What It Is Not 449

12.1.3 Background and Existing ASV System 451

12.2 Practical Aspects of NMR Automatic Verification 453

12.2.1 Digital Resolution 453

12.2.2 Window Functions 457

12.2.3 Linear Prediction 462

12.2.4 Relaxation Times and Delays 464

12.2.5 Alignment of 1H andHSQC Spectra 465

12.2.6 General Recommendations for the Choice of NMR Acquisition and Processing Parameters 466

12.3 The Architecture of the Automatic Verification Expert System 471

12.3.1 Introduction 471

12.3.2 The Scoring System 472

12.3.3 NMR Prediction and Spectral Synthesis 474

12.3.4 Automatic Importing and Processing of NMR Data Sets 476

12.3.5 Automatic Analysis: Spectral Deconvolution and Peaks Labeling 478

12.3.6 ASV Tests 483

12.4 Performance of the Automated Structure Verification Systems 485

12.4.1 Basic Definitions 485

12.4.2 Tests of Performance 488

12.5 Conclusions 490

Acknowledgments 490

References 490

13 On the Search for the Appropriate Techniques for Structural Elucidation of Small Molecules 493
María Magdalena Cid and Jorge Bravo

13.1 Introduction 493

13.2 The Challenge of Structural Determination 495

13.3 Tools: Mass Spectrometry (MS) 497

13.4 Tools: Solution NMR Spectroscopy 499

13.5 Tools: Solid-State NMR Spectroscopy 501

13.6 Chiroptical Spectroscopies 507

13.7 Theoretical Calculations: Ab initio Calculations of NMR Shifts 512

13.8 Theoretical Calculations: Computer-Assisted Structure Elucidation 514

13.9 Summary 515

Acknowledgments 516

References 516

Index 521