Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful and widely used techniques in chemical research for investigating structures and dynamics of molecules. Advanced methods can even be utilized for structure determinations of biopolymers, for example proteins or nucleic acids. NMR is also used in medicine for magnetic resonance imaging (MRI). The method is based on spectral lines of different atomic nuclei that are excited when a strong magnetic field and a radiofrequency transmitter are applied. The method is very sensitive to the features of molecular structure because also the neighboring atoms influence the signals from individual nuclei and this is
important for determining the 3D-structure of molecules.

This new edition of the popular classic has a clear style and a highly practical, mostly non-mathematical approach. Many examples are taken from organic and organometallic chemistry, making this book an invaluable guide to undergraduate and graduate students of organic chemistry, biochemistry, spectroscopy or physical chemistry, and to researchers using this well-established and extremely important technique. Problems and solutions are included.

Preface XV

1 Introduction 1

1.1 Literature 8

1.2 Units and Constants 9

References 10

Part I Basic Principles and Applications 11

2 The Physical Basis of the Nuclear Magnetic Resonance Experiment.

Part I 13

2.1 The Quantum Mechanical Model for the Isolated Proton 13

2.2 Classical Description of the NMR Experiment 16

2.3 Experimental Verification of Quantized Angular Momentum and of the Resonance Equation 17

2.4 The NMR Experiment on Compact Matter and the Principle of the NMR Spectrometer 19

2.4.1 How to Measure an NMR Spectrum 19

2.5 Magnetic Properties of Nuclei beyond the Proton 25

References 27

3 The Proton Magnetic Resonance Spectra of Organic Molecules – Chemical Shift and Spin–Spin Coupling 29

3.1 The Chemical Shift 29

3.1.1 Chemical Shift Measurements 32

3.1.2 Integration of the Spectrum 35

3.1.3 Structural Dependence of the Resonance Frequency – A General Survey 37

3.2 Spin–Spin Coupling 41

3.2.1 Simple Rules for the Interpretation of Multiplet Structures 46

3.2.2 Spin–Spin Coupling with Other Nuclei 49

3.2.2.1 Nuclei of Spin I = 12 49

3.2.2.2 Nuclei of Spin I > 12 51

3.2.3 Limits of the Simple Splitting Rules 52

3.2.3.1 The Notion of Magnetic Equivalence 52

3.2.3.2 Significance of the Ratio J/ν0δ 56

3.2.4 Spin–Spin Decoupling 58

3.2.5 Two-Dimensional NMR – the COSY Experiment 60

3.2.6 Structural Dependence of Spin–Spin Coupling – A General Survey 62

References 66

4 General Experimental Aspects of Nuclear Magnetic Resonance Spectroscopy 67

4.1 Sample Preparation and Sample Tubes 67

4.2 Internal and External Standards; Solvent Effects 70

4.3 Tuning the Spectrometer 74

4.4 Increasing the Sensitivity 78

4.5 Measurement of Spectra at Different Temperatures 81

References 83

Textbooks 83

Review Articles 83

5 Proton Chemical Shifts and Spin–Spin Coupling Constants as Functions of Structure 85

5.1 Origin of Proton Chemical Shifts 86

5.1.1 Influence of the Electron Density at the Proton 87

5.1.2 Influence of the Electron Density at Neighboring Carbon Atoms 87

5.1.3 The Influence of Induced Magnetic Moments of Neighboring Atoms and Bonds 94

5.1.4 Ring Current Effect in Cyclic Conjugated π-Systems 101

5.1.5 Alternative Methods to Measure Diatropicity 110

5.1.6 Diamagnetic Anisotropy of the Cyclopropane Ring 113

5.1.7 Electric Field Effect of Polar Groups and the van-derWaals Effect 114

5.1.8 Chemical Shifts through Hydrogen Bonding 117

5.1.9 Chemical Shifts of Protons in Organometallic Compounds 119

5.1.10 Solvent Effects 120

5.1.11 Empirical Substituent Constants 121

5.1.11.1 Tables of Proton Resonances in Organic Molecules 122

5.2 Proton–Proton Spin–Spin Coupling and Chemical Structure 122

5.2.1 The Geminal Coupling Constant (2J) 123

5.2.1.1 Dependence on the Hybridization of the Methylene Carbon 123

5.2.1.2 Effect of Substituents 124

5.2.1.3 A Molecular Orbital Model for the Interpretation of Substituent Effects on 2J 126

5.2.2 The Vicinal Coupling Constant (3J) 128

5.2.2.1 Dependence on the Dihedral Angle 129

5.2.2.2 Dependence upon the C–C Bond Length, Rμν 130

5.2.2.3 Dependence on HCC Valence Angles 132

5.2.2.4 Substituent Effects 133

5.2.3 Long-Range Coupling Constants (4J, 5J) 137

5.2.3.1 Saturated Systems 138

5.2.3.2 Unsaturated Systems 139

5.2.4 Through-Space and Dipolar Coupling 143

5.2.5 Tables of Spin–Spin Coupling Constants in Organic Molecules 144

References 147

Monograph 148

Review Articles 148

6 The Analysis of High-Resolution Nuclear Magnetic Resonance Spectra 149

6.1 Notation for Spin Systems 150

6.2 Quantum Mechanical Formalism 151

6.2.1 The Schr¨odinger Equation 151

6.3 The Hamilton Operator for High-Resolution Nuclear Magnetic Resonance Spectroscopy 153

6.4 Calculation of Individual Spin Systems 155

6.4.1 Stationary States of a Single Nucleus A 156

6.4.2 Two Nuclei without Spin–Spin Interaction (Jij = 0); Selection Rules 156

6.4.3 Two Nuclei with Spin–Spin Interaction (Jij = 0) 158

6.4.3.1 The A2 Case and the Variational Method 158

6.4.3.2 Calculation of the Relative Intensities 162

6.4.3.3 Symmetric and Antisymmetric Wave Functions 163

6.4.4 The AB System 164

6.4.5 The AX System and the First-Order Approximation 167

6.4.6 General Rules for the Treatment of More Complex Spin Systems 170

6.5 Calculation of the Parameters νi and Jij from the Experimental Spectrum 174

6.5.1 Direct Analysis of the AB System 175

6.5.2 Spin Systems with Three Nuclei 177

6.5.2.1 The AB2 (A2B) System 177

6.5.2.2 The Particle Spin 181

6.5.2.3 The ABX System 182

6.5.3 Spin Systems with Four Nuclei – The AAXX System 192

6.5.4 Computer Analysis 206

References 209

Textbooks 210

Review Articles 210

7 The Influence of Molecular Symmetry and Chirality on Proton Magnetic Resonance Spectra 211

7.1 Spectral Types and Structural Isomerism 211

7.2 Influence of Chirality on the NMR Spectrum 216

7.3 Analysis of Degenerate Spin Systems by Means of 13C Satellites and H/D Substitution 226

References 229

Review Articles 230

Part II Advanced Methods and Applications 231

8 The Physical Basis of the Nuclear Magnetic Resonance Experiment.

Part II: Pulse and Fourier-Transform NMR 233

8.1 The NMR Signal by Pulse Excitation 234

8.1.1 Resonance for the Isolated Nucleus 234

8.1.2 Pulse Excitation for a Macroscopic Sample 236

8.2 Relaxation Effects 239

8.2.1 Longitudinal or Spin–Lattice Relaxation 239

8.2.2 Transverse or Spin–Spin Relaxation 243

8.2.3 Experiments for Measuring Relaxation Times 247

8.2.3.1 T1 Measurements – the Inversion Recovery Experiment 247

8.2.3.2 The Spin Echo Experiment 248

8.3 Pulse Fourier-Transform (FT) NMR Spectroscopy 249

8.3.1 Pulse Excitation of Entire NMR Spectra 250

8.3.2 The Receiver Signal and its Analysis 252

8.4 Experimental Aspects of Pulse Fourier-Transform Spectroscopy 254

8.4.1 The FT NMR Spectrometer – Basic Principles and Operation 254

8.4.1.1 The Computer and the Analog–Digital Converter (ADC) 254

8.4.1.2 RF Sources of an FT NMR Spectrometer 258

8.4.1.3 Transmitter and Signal Phase 259

8.4.1.4 Selective Excitation and Shaped Pulses in FT NMR Spectroscopy 260

8.4.1.5 Pulse Calibration 263

8.4.1.6 Composite Pulses 264

8.4.1.7 Single and Quadrature Detection 264

8.4.1.8 Phase Cycles 266

8.4.2 Complications in FT NMR Spectroscopy 267

8.4.3 Data Improvement 269

8.5 Double Resonance Experiments 272

8.5.1 Homonuclear Double Resonance – Spin Decoupling 272

8.5.2 Heteronuclear Double Resonance 273

8.5.3 Broadband Decoupling 275

8.5.3.1 Broadband Decoupling by CW Modulation 275

8.5.3.2 Broadband Decoupling by Pulse Methods 276

8.5.4 Off-Resonance Decoupling 277

References 279

Textbooks 280

Review articles 280

9 Two-Dimensional Nuclear Magnetic Resonance Spectroscopy 281

9.1 Principles of Two-Dimensional NMR Spectroscopy 281

9.1.1 Graphical Presentation of Two-Dimensional NMR Spectra 284

9.2 The Spin Echo Experiment in Modern NMR Spectroscopy 285

9.2.1 Time-Dependence of Transverse Magnetization 285

9.2.2 Chemical Shifts and Spin–Spin Coupling Constants and the Spin Echo Experiment 286

9.3 Homonuclear Two-Dimensional Spin Echo Spectroscopy: Separation of the Parameters J and δ for Proton NMR Spectra 289

9.3.1 Applications of Homonuclear 1H J,δ-Spectroscopy 291

9.3.2 Practical Aspects of 1H J,δ-Spectroscopy 294

9.4 The COSY Experiment – Two-Dimensional 1H,1H Shift Correlations 296

9.4.1 Some Experimental Aspects of 2D-COSY Spectroscopy 300

9.4.2 Artifacts in COSY Spectra 302

9.4.3 Modifications of the Jeener Pulse Sequence 304

9.4.3.1 COSY-45 304

9.4.3.2 Long-Range COSY (COSY-LR) 305

9.4.3.3 COSY with Double Quantum Filter (COSY-DQF) 307

9.5 The Product Operator Formalism 309

9.5.1 Phenomenon of Coherence 309

9.5.2 Operator Basis for an AX System 311

9.5.3 Zero- and Multiple-Quantum Coherences 312

9.5.4 Evolution of Operators 313

9.5.5 The Observables 316

9.5.6 The COSY Experiment within the Product Operator Formalism 317

9.5.7 The COSY Experiment with Double-Quantum Filter (COSY-DQF) 320

9.6 Phase Cycles 322

9.6.1 COSY Experiment 324

9.7 Gradient Enhanced Spectroscopy 326

9.8 Universal Building Blocks for Pulse Sequences 329

9.8.1 Constant Time Experiments: ω1-Decoupled COSY 329

9.8.2 BIRD Pulses 329

9.8.3 Low-Pass Filter 330

9.8.4 z-Filter 331

9.9 Homonuclear Shift Correlation by Double Quantum Selection of AX Systems – the 2D-INADEQUATE Experiment 331

9.10 Single-Scan 2D NMR 336

References 337

Textbooks and Monographs 338

Methods Oriented 338

Application Oriented 338

Review articles 338

10 More 1D and 2D NMR Experiments: the Nuclear Overhauser Effect – Polarization Transfer – Spin Lock Experiments – 3D NMR 341

10.1 The Overhauser Effect 341

10.1.1 Original Overhauser Effect 341

10.1.2 Nuclear Overhauser Effect (NOE) 343

10.1.3 One-Dimensional Homonuclear NOE Experiments 345

10.1.3.1 NOE Measurements of Relative Distances between Protons 345

10.1.3.2 NOE Difference Spectroscopy 346

10.1.4 Complications during NOE Measurements 348

10.1.5 Two-Dimensional Homonuclear Overhauser Spectroscopy (NOESY) 350

10.1.6 Two-Dimensional Heteronuclear Overhauser Spectroscopy (HOESY) 355

10.2 Polarization Transfer Experiments 357

10.2.1 SPI Experiment 357

10.2.2 INEPT Pulse Sequence 360

10.3 Rotating Frame Experiments 364

10.3.1 Spin Lock and Hartmann–Hahn Condition 364

10.3.2 Spin Lock Experiments in Solution 366

10.3.2.1 Homonuclear Hartmann–Hahn or TOCSY Experiments 366

10.3.2.2 One-Dimensional Selective TOCSY Spectroscopy 368

10.3.2.3 ROESY Experiment 369

10.4 Multidimensional NMR Experiments 371

References 376

Textbooks 376

Review articles 376

11 Carbon-13 Nuclear Magnetic Resonance Spectroscopy 377

11.1 Historical Development and the Most Important Areas of Application 378

11.2 Experimental Aspects of Carbon-13 Nuclear Magnetic Resonance Spectroscopy 381

11.2.1 Gated Decoupling 382

11.2.2 Assignment Techniques 383

11.2.2.1 Multiplicity Selection with the Heteronuclear Spin Echo Experiment (SEFT, APT) 383

11.2.2.2 Polarization Transfer Experiments 387

11.2.2.3 Heteronuclear Two-Dimensional 1H,13C Chemical Shift Correlation 389

11.2.2.4 The 13C,13C INADEQUATE Experiment 398

11.2.2.5 Heteronuclear J, δ Spectroscopy 401

11.2.2.6 Assignment Techniques with Selective Excitation 403

11.2.2.7 Alternative Assignment Techniques 405

11.3 Carbon-13 Chemical Shifts 407

11.3.1 Theoretical Models 409

11.3.2 Empirical Correlations 418

11.4 Carbon-13 Spin–Spin Coupling Constants 420

11.4.1 Carbon-13 Coupling Constants and Chemical Structure 422

11.4.1.1 13C,13C Coupling Constants 422

11.4.1.2 13C,1H Coupling Constants 424

11.4.1.3 13C,X Coupling Constants 427

11.5 Carbon-13 Spin–Lattice Relaxation Rates 428

References 430

Textbooks and Monographs 430

Review articles 430

12 Selected Heteronuclei 431

12.1 Semimetals and Non-metals with the Exception of Hydrogen and Carbon 435

12.1.1 Boron-11 435

12.1.1.1 Referencing and Chemical Shifts 437

12.1.1.2 Polyhedral Boranes 438

12.1.2 Nitrogen-15 439

12.1.2.1 Referencing and Chemical Shifts 441

12.1.2.2 Spin-Spin Coupling 445

12.1.3 Oxygen-17 445

12.1.3.1 Referencing and Chemical Shifts 446

12.1.4 Fluorine-19 447

12.1.4.1 Referencing and Chemical Shifts 448

12.1.4.2 Spin-Spin Coupling 452

12.1.5 Silicon-29 454

12.1.5.1 Referencing and Chemical Shifts 454

12.1.5.2 Spin-Spin Coupling 457

12.1.6 Phosphorus-31 458

12.1.6.1 Referencing and Chemical Shifts 458

12.1.6.2 Spin-Spin Coupling 461

12.2 Main Group Metals 462

12.2.1 Lithium-6,7 462

12.2.1.1 Referencing and Chemical Shifts 463

12.2.1.2 Spin-Spin Coupling 463

12.2.2 Aluminum-27 468

12.2.2.1 Referencing and Chemical Shifts 469

12.2.3 Tin-119 471

12.2.3.1 Referencing and Chemical Shifts 472

12.2.3.2 Spin-Spin Coupling 473

12.3 Transition Metals 474

12.3.1 Vanadium-51 476

12.3.2 Platinum-195 480

12.3.2.1 Spin-Spin Coupling 482

12.3.3 Cobalt-59 482

12.3.4 Copper-63 484

12.3.5 Rhodium-103 485

12.3.6 Cadmium-113 488

12.3.7 Iron-57 489

12.3.8 Manganese-55 491

12.3.9 Molybdenum-95 492

12.3.10 Tungsten-183 492

12.3.11 Mercury-199 494

12.3.12 Osmium-187 496

References 496

Textbooks 498

Monographs 498

General Review Articles 498

Selected Review Articles dealing with Individual Nuclei not cited Above 498

13 Influence of Dynamic Effects on Nuclear Magnetic Resonance Spectra 501

13.1 Exchange of Protons between Positions with Different Larmor Frequencies 501

13.1.1 Quantitative Description of Dynamic Nuclear Magnetic Resonance 504

13.1.2 Relationships to Reaction Kinetics 505

13.1.3 Approximate Solutions and Sources of Error 509

13.1.4 More Complex Exchange Phenomena 512

13.1.5 Application of Inversion-Recovery Experiments to the Determination of Rate Constants 513

13.1.6 Two-Dimensional Exchange Spectroscopy (EXSY) 514

13.1.7 Measurements of First-Order Rate Constants by Integration 516

13.2 Internal Dynamics of Organic Molecules 517

13.2.1 Hindrance to Internal Rotation 518

13.2.1.1 Bonds with Partial Double Bond Character 518

13.2.1.2 Substituted Ethanes 521

13.2.2 Inversion of Configuration 523

13.2.3 Ring Inversion 526

13.2.4 Valence Tautomerism and Bond Shifts 532

13.2.5 Dynamic Processes in Organometallic Compounds and Carbocations 542

13.3 Intermolecular Exchange Processes 549

13.4 Line Broadening by Fast Relaxing Neighboring Nuclei 554

References 555

Textbooks 556

Review Articles 556

14 Nuclear Magnetic Resonance of Partially Oriented Molecules and Solid State NMR 557

14.1 Nuclear Magnetic Resonance of Partially Oriented Molecules 557

14.1.1 Nuclear Magnetic Resonance in Liquid Crystals 558

14.1.2 Other Alignment Methods – Residual Dipolar Couplings 565

14.2 High-Resolution Solid State Nuclear Magnetic Resonance Spectroscopy 568

14.2.1 Experimental Techniques of High-Resolution Solid State NMR Spectroscopy 570

14.2.1.1 Line Narrowing 570

14.2.1.2 Assignment Methods 576

14.2.1.3 Quadrupolar Nuclei 577

14.2.2 Applications of High-Resolution Solid State NMR Spectroscopy 580

14.2.2.1 Spin 12 Nuclei 580

14.2.2.2 Quadrupolar Nuclei 584

14.2.2.3 Dynamic Processes 588

References 589

Textbooks 590

Review Articles 590

15 Selected Topics of Nuclear Magnetic Resonance Spectroscopy 591

15.1 Isotope Effects in Nuclear Magnetic Resonance 591

15.1.1 Isotopic Perturbation of Equilibrium 595

15.2 Nuclear Magnetic Resonance Spectroscopy of Paramagnetic Materials 597

15.2.1 Contact Shifts 597

15.2.2 Pseudo-contact Shifts – Shift Reagents 599

15.3 Chemically Induced Dynamic Nuclear Polarization (CIDNP) 604

15.3.1 Energy Polarization (Net Effect) 605

15.3.2 Entropy Polarization (Multiplet Effect) 608

15.3.3 The Kaptein Rules 611

15.4 Diffusion-Controlled Nuclear Magnetic Resonance Spectroscopy – DOSY 612

15.4.1 Measurement of Diffusion Coefficients 612

15.4.2 Mixture Analysis by Diffusion-Ordered Spectroscopy (DOSY) 615

15.5 Unconventional Methods for Sensitivity Enhancement – Hyperpolarization 617

15.5.1 Hydrogenation Reactions and the Effect of para-Hydrogen 617

15.5.2 Optical Pumping – Xenon-129 NMR 621

15.5.3 Dynamic Nuclear Polarization 623

15.6 Nuclear Magnetic Resonance in Biochemistry and Medicine 625

15.6.1 Biomolecules 625

15.6.2 Peptides and Proteins 627

15.6.3 Nucleic Acids 634

15.6.4 Oligo- and Polysaccharides 636

15.6.5 Solvent Suppression 639

15.6.6 NMR of Body Fluids and In-vivo NMR Spectroscopy 640

15.6.7 NMR Imaging 642

References 647

Review Articles 648

Appendix 649

1 The ‘‘Ring Current Effect’’ of the Benzene Nucleus 649

2 Tables of Proton Resonance Frequencies and Substituent Effects S(δ) 650

2.1 Substituent Effects S(δ) or SCS 652

3 Tables of 1H,1H Coupling Constants 654

4 Chemical Shifts and Substuent Effects S(δ) of 13C Resonances in Organic Compounds 659

5 The Hamiltonian Operator in Polar Coordinates 664

6 Intensity Distribution in A-multiplets Caused by n Neighbouring X-Nuclei with Spin I = 1 or I = 32 664

7 Commutable Operators 665

8 The Fz Operator 665

9 Equations for the Direct Analysis of AABB Spectra 666

10 Bloch Equations 667

11 Bloch Equations Modified for Chemical Exchange 668

12 Phase Behavior of Cross Peaks in 2D Nuclear Overhauser Spectroscopy (NOESY), Rotating-Frame Overhauser Spectroscopy (ROESY), and Total Correlation Spectroscopy (TOCSY) and Chemical Exchange (EXSY) Experiments 671

13 The International System (SI) of Units (MKSA System) 672

References 673

Solutions for Exercises 675

Glossary 691

Index 695