Structure Elucidation in Organic Chemistry: The Search for the Right Tools

Intended for advanced readers, this is a review of all relevant techniques for structure analysis in one handy volume. As such, it provides the latest knowledge on spectroscopic and related techniques for chemical structure analysis, such as NMR, optical spectroscopy, mass spectrometry and X-ray crystallography, including the scope and limitation of each method. As a result, readers not only become acquainted with the techniques, but also the advantages of the synergy between them. This enables them to choose the correct analytical method for each problem, saving both time and resources. Special emphasis is placed on NMR and its application to absolute configuration determination and the analysis of molecular interactions. Adopting a practical point of view, the author team from academia and industry guarantees both solid methodology and applications essential for structure determination, equipping experts as well as newcomers with the tools to solve any structural problem.

Table of Contents:
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

About the Author :
Magdalena Cid received her PhD from the Universidade of Santiago de Compostela in 1990 and did postdoctoral stages in Sandoz Pharma, now Novartis (Basel, Switzerland) and The Scripps Research Institute (La Jolla, CA, USA) mainly dealing with synthesis of nitrogen-containing compounds. In 1996 she joined the Universidade de Vigo where she has become an associate professor. She is interested in the design, synthesis and characterization of chiral (macro)molecules and the usage of chiroptical properties and NMR (scalar and dipolar coupling constants) for total elucidation of their structures. 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.