Table of Contents. Chapter 1 lntroduction and Practical Considerations of Two-Dimensional. Chapter 2 Establishing Proton-Proton Connectivities

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1 Table of Contents Chapter 1 lntroduction and Practical Considerations of Two-Dimensional NMR Spectroscopy lntroduction Fundamental Segments of Two-Dimensional NMR Experiments Preparation Evolution Mixing Detection NMR Data in Two Time Domains: How lnformation Gets There Evolution Times Encoding Spin-Lattice (T,) Relaxation lnformation via an Evolution Period Encoding Spin Coupling lnformation via Evolution Periods Dwell Times: Control of Spectral Width in the Second Dimension Data Processing Beyond the First Fourier Transformation Transposition The Second Fourier Transformation Data Presentation Whitewashed Stack Plots Contour Plots Projections Two-Dimensional J-Resolved NMR Spectroscopy Heteronuclear Two-Dimensional J-Resolved Spectroscopy Homonuclear Two-Dimensional J-Resolved Spectroscopy Pulse Width Calibration and Specialized Pulses Pulse Width Calibration Pulse Width versus Spectral Width Relaxation Times and Pulse Calibration Observation (Transmitter) Pulses Calibration of Decoupler Pulses for Heteronuclear Experiments Calibration of X-Band Decoupler Pulses Composite Pulses and Specialized Pulse Clusters Composite Pulses Pulse Operators: BIRD and TANGO Pulses References Chapter 2 Establishing Proton-Proton Connectivities Classical Proton Homonuclear Decoupling Autocorrelated Homonuclear Proton COSY Experiments lntroduction The Basic COSY Experiment Data Processing and Presentation Interpretation of COSY Spectra Variants of the Basic COSY Experiment

2 xii Contents Phase Sensitive COSY Long Range COSY (LRCOSY) Broadband Proton Decoupled COSY (HDCOSY) Super COSY Edited COSY Spectra Incorporating BIRD Pulses Spin-Echo Correlated Spectroscopy (SECSY) Multiple Quantum Filtered COSY Experiments Multiple Quantum Filtration Phase Sensitive Double Quantum Filtered COSY Higher Order Multiple Quantum Filtered COSY Applications of Multiple Quantum Filtered COSY Other Quantum Methods for Establishing Proton-Proton Connectivities Proton Double Quantum Coherence Location of Response in Proton Double Quantum 2D NMR Spectra The Proton Double Quantum Pulse Sequence and and Experiment Execution Proton Double Quantum Data Processing Presentation of Proton Double Quantum Spectra Quadrature Data Acquisition in the Second Frequency Domain Interpretation of Proton Double Quantum Spectra Strategy in Recording Proton Double Quantum Spectra Alternative Proton Double Quantum Pulse Sequences A Brief Survey of Proton Double Quantum Applications Proton Zero Quantum Coherence The Proton Zero Quantum Pulse Sequence and Location of Responses in Proton Zero Quantum 2D-NMR Spectra and Experiment Execution Proton Zero Quantum Data Processing Interpretation of Proton Zero Quantum Spectra Presentation of Proton Zero Quantum Spectra Alternative Zero Quantum Pulse Sequences A Brief Survey of Proton Zero Quantum Applications References Chapter 3 Heteronuclear Chemical Shift Correlation Classical Methods for Establishing Heteronuclear Correlation Spin Population Inversion/Transfer (SPI/SPT) Experiments Nonselective Polarization Transfer Proton Carbon Heteronuclear Chemical Shift Correlation Heteronuclear Chemical Shift Corelation: The Basic Experiment; Heteronuclear Coupling on Both Frequency Axes Heteronuclear Chemical Shift Correlation: Heteronuclear Decoupling in the F, Frequency Domain Heteronuclear Chemical Shift Correlation: Broadband Heteronuclear Decoupling in the F1 Frequency Domain Pulse Widths Dwell Time Selection Digitization in the Fl Frequency Domain

3 Contents xiii Digitization in the F, Frequency Domain Optimal Fixed Delay (A1 and 4) Durations Selection of an Interpulse Delay Data Processing The First Fourier Transformation Transposition The Second Fourier Transformation Other Processing Considerations Artifacts and Spurious Responses "Virtual Coupling" in Heteronuclear Chemical Shift Correlation Spectra Doublets in F, Rather than Singlets as a Result of lsotopomeric Breaking of Proton Chemical Shift Degeneracy DEPT Based Heteronuclear Chemical Shift Correlation Sequences Leading to DEPT Based Heteronuclear Chemical Shift Correlation Heteronuclear Chemical Shift Correlation Using the DEPT Sequence Reorganization of the DEPT Based Heteronuclear Chemical Shift Correlation Sequence Spectral Editing Using the DEPT Based Heteronuclear Chemical Shift Correlation Experiment Other DEPT Based Hetronuclear Chemical Shift Correlaion Variants and Applications Heteronuclear Chemical Shift Correlation with Broadband Homonuclear Proton Decoupling via Bilinear Rotational Decoupling INEPT Based Polarization Transfer Data Processing Examples of the Application of Broadband Homonuclear Proton Decoupling in Heteronuclear Chemical Shift Correlation Norharmane 9-Methylphenanthro[4,3-aldibenzothiophene Strychnine DEPT Based Polarization Transfer Variations Heteronuclear Chemical Shift Correlation with Broadband Proton Homonuclear Decoupling via a Constant Evolution Time Proton Detected (Inverse) Heteronuclear Proton-Carbon Chemical Shift Correlation Introduction Suppression of the Signal for Protons not Directly Bonded to 13C Chemical Shift Correlation via Heteronuclear Multiple Quantum Coherence: "Small" Molecules Application to the Cyclic Depsipeptide Didemnim-B Chemical Shift Correlation via Heteronuclear Multiple Quantum

4 xiv Contents Coherence: Larger Molecules A Brief Survey of Applications of Chemical Shift Correlation via Heteronuclear Multiple Quantum Coherence Long Range Heteronuclear Chemical Shift Correlation Long Range Optimization of the Conventional Heteronuclear Chemical Shift Correlation Experiment General Considerations of Long Range Heteornuclear Coupling Constants Long Range Optimization of the Heteronuclear Chemical Shift Correlation Sequence of Freeman and Morris Long Range Optimized DEPT Long Range Heteronuclear Correlation Using the Fully Coupled (FUCOUP) Technique Data Processing A Brief Survey of Applications of the FUCOUP Experiment A Modification of the FUCOUP Experiment: lntroduction of F, Decoupling Modifications Intended to Suppress Direct Responses Replacing Proton 90" Pulses by TANGO Pulses: The CSCMLR Experiment Using Low Pass J-Filters to Remove Direct Responses Decoupling One Bond Modulations in Long Range Heteronuclear Shift Correlation Experiments Suppression of One Bond Modulations in the CSCMLR Sequence by lncorpporation of a BlRD Pulse Suppression of One Bond Modulation in the Freeman-Morris Sequence by Insertion of a BlRD Pulse Constant Evolution Time Long Range Heteronuclear Correlation The Bauer, Freeman and Wimperis Constant Evolution Time Long Range Heteronuclear Correlation Experiment The Kessler-Griesinger Correlation by Long Range Coupling (COLOC) Constant Evolution Time Pulse Sequence COLOC-S: A Modified COLOC Experiment Incorporating TANGO and BlRD Pulses The XCORFE Constant Evolution Time Experiment Devised by Reynolds and Coworkers Heteronuclear Multiple Quantum Coherence Long Range Chemical Shift Correlation Experiments The Bax and Summers Long Range Heteornuclear Multiple Quantum Coherence Experiment (HMBC) A Brief Survey of Applications of the Proton Detected Long Range Heteronuclear Multiple Quantum Correlation Experiment References Chapter 4 Relayed Coherence Transfer and Related 2D-NMR Experiments 280 Introduction 280 Homonuclear Relayed Coherence Transfer via Scalar Coupling Pathways 281 Why Is Relayed Coherence Transfer Useful or Desirable? 281

5 Contents The Single Relay Experiment: RCOSY Data Processing and Presentation Interpretation of RCOSY Spectra A Brief Survey of RCOSY Applications Long Range (Four Bond) Relayed Coherence Transfer Multiple Quantum Filtered Relay: MQF-RELAY The Double Relay Experiment: 2RCOSY Data Processing and Presentation A Comparison of the COSY, RCOSY and 2RCOSY Spectra of Strychnine Multiple Quantum Relayed Coherence Transfer Proton Double Quantum Relayed Coherence Transfer Data Processing and Presentation Application of the Proton Double Quantum Relayed Coherence Transfer Experiment to Strychnine Homonuclear Relayed Coherence: Transfer via Scalar Coupling Pathways or by lsotropic Mixing Homonuclear Relayed Coherence Transfer via lsotropic Mixing Total Correlation Spectroscopy: TOCSY Homonuclear Hartmann-Hahn Spectroscopy: HOHAHA Data Processing Applications of HOHAHA A Brief Survey of Applications of the HOHAHA Experiment lsotropic Mixing Using Other Sequences TOCSY with 2-Filters Heteronuclear Relayed Coherence Transfer Conventional Heteronuclear Relayed Coherence Transfer Efficiency of the Relay Step Data Acquisition, Processing and Presentation lnterpretation of Heteronuclear Relayed Coherence Transfer Spectra Applications of HC-RELAY A Brief Survey of Applications of the HC-RELAY Experiment Techniques to Eliminate Direct Responses from Heteronuclear Relayed Coherence Transfer Spectra Low Pass J-Filtered Heteronuclear Relayed Coherence Transfer HC-RELAY With Semiselective Refocusing Heteronuclear Relayed Hartmann-Hahn Spectroscopy Applications of Heteronuclear Relayed Hartmann-Hahn Spectroscopy Proton Detected (Reverse) Heteronuclear Relayed Coherence Transfer The Bolton Sequence for Proton Detected Heteronuclear Relay The Bax Sequences for Proton Detected Heteronuclear Relay The Bruhwiler-Wagner Proton Detected Heteronuclear Relay Experiment

6 xvi Contents Comparative Evaluation of the Various Proton Detected Heteronuclear Relay Experiments 341 Multiple Quantum Heteronuclear Relayed Coherence Transfer Spectroscopy 341 Proton Double Quantum Heteronuclear Relayed Coherence Transfer 341 Proton Zero Quantum Heteronuclear Relayed Coherence Transfer 343 References 344 Chapter 5 13C-13C Double Quantum Coherence 2D-NMR The INADEQUATE Experiment 348 Introduction 348 The One-Dimensional INADEQUATE Experiment Double Quantum Coherence and the Density Matrix 351 The Two-Dimensional INADEQUATE Experiment 352 Quadrature Detection in the F1 Dimension Using Composite Z-Pulses 353 Autocorrelated Two-Dimensional INADEQUATE 355 Obtaining Quadrature Detection in Fl Using a 135" Read Pulse 356 Excitation of Double Quantum Coherence Using 'Double Selection" 356 Practical Aspects of Double Quantum NMR Spectroscopy 357 Sample Preparation and Solubility Data Processing 360 Double Quantum NMR Spectra of Menthol 360 The Conventional INADEQUATE Spectrum of Menthol 360 The Autocorrelated INADEQUATE Spectrum of Menthol Recorded Using the Turner Pulse Sequnence 363 Intentionally Folded INADEQUATE Spectra 363 Assembling the Carbon Skeleton of Cedrol Using INADEQUATE Data 365 The INADEQUATE Spectrum of Benzo[3,4]phenanthro[l,2-blthiophene 371 for Two-Dimensional INADEQUATE 374 A Brief Survey of Applications of the INADEQUATE Experiment 375 Using Proton Detection to Increase the Sensitivity of the INADEQUATE Technique 377 Assignments of Quaternary Carbons Using Carbon Relayed Proton-Carbon Spectroscopy 377 References 379 Chapter 6 Applications Problems 38 1 Introduction 381 Homonuclear Correlation Problems Assignment of the Proton NMR Resonances of a Simple Dinaphthothiophene Derivative Assignemnt of the Proton NMR Spectrum of the Sesquiterpene Annulatol-A 382 Simultaneous Use of Homo- and Heteronuclear Correlation Assignment of the Proton NMR Spectrum of the Alkaloid a-yohimbine with Simultaneous Verification of 13C-NMR Assignments 384

7 Contents xvii 6.4 ldentifying Heteronuclear Spin Systems of a Polynuclear Aromatic Using a Combination of Heteronuclear Chemical Shift Correlation and Relayed Coherence Transfer Assigning the Proton and Carbon-NMR Spectra of the Complex Helicene Phenanthro[3,4:3',4']phenanthro[2,1-blthiophene Using Long Range Heteronuclear Chemical Shift Correlation 393 Molecular Structure Determination Elucidation of the Structure of a Marine Sesquiterpene Elucidation of the Structure of a Complex Alkaloid Using INADEQUATE Establishing the Structure of a Complex Alkaloid Using Proton-Proton, Proton-Carbon and Long Range Proton-Carbon Connectivity Data Determination of the Structure of a Dinaphthothiophene Isomer of the Compound Consdiered in Problem References 41 7 Chapter 7 Solutions to Problems Introduction Solution to Problem 6.1 Assignment of the Proton NMR Resonances of a Simple Dinaphthothiophene Identification of Resonances in Individual Spin Systems Orienting Spin Systems Relative to One Another Solution to Problem 6.2 Assigning the Ring A Protons of Annulatol-A Using the COSY Data Using the Zero Quantum Data Assigning the Ring B Protons of Annulatol-A Solution to Problem 6.3 Assignment of the Proton NMR Spectrum of the Alkaloid a-yohimbine with Simultaneous Verification of the 13C-NMR Assignments Locating a Starting Point Establishing a Heteronuclear Connectivity Network Solution to Problem 6.4 ldentifying Heteronuclear Spin Systems of a Polynuclear Aromatic Using a Combination of Heteronuclear Chemical Shift Correlation and Heteronuclear Relayed Coherence Transfer Locating a Starting Point Assigning the Two Proton Four Spin Systems and Their Heteronuclear Partners Assigning the Two Proton Two Spin Systems and Their Heteronuclear Partners Conclusions Solution to Problem 6.5 Total Assignment of the Proton and Carbon NMR Spectra of the Complex Helicene Phenanthro[3,4:3',4']phenanthro[2,1-bjthiophene Where to Start? Establishing a Heteronuclear Connectivity Network from the Proton Resonating at 8.40 ppm Expanding the Connectivity Network Outward Assigning H14-HI7 Assigning the Remainder of the Spectrum Solution to Problem 6.6

8 xviii Contents Elucidation of the Structure of a Marine Sesquiterpene 453 Finding a Place to Start 453 Assembly of a Structural Fragment Beginning from the Hydroxyl Metine 453 Assembly of a Structural Fragment Beginning from the Bromo Methine 456 What Pieces Are Left? 459 Linking the Structural Fragments With Long Range Heteronuclear Connectivity Information from the HMBC Experiment 459 Solution to Problem Assignment of the Structure of a Complex Alkaloid Using Carbon-Carbon INADEQUATE Data 464 Where to Start? 464 Expanding the Connectivity Network Outward from Our Starting Point 464 Connectivities from "dm 465 Connectivities from "en 465 Connectivities from "h" 467 Connectivities from "I" 468 Linking the Structural Fragment into a Single Unified Structure 469 Solution to Problem Establishing the Structure of a Complex Alkaloid Using Proton-Proton, Proton-Carbon and Long Range Proton-Carbon Connectivity Information 471 Where to Begin? 471 Solution to Problem Determining the Structure of an Isomeric Dinaphthothiophene 482 Preliminary Structural Considerations 482 Interpreting the COSY Data 482 Connectivity Information Provided by the ZQCOSY Experiment 485 Heteronuclear Correlation Data 485 Using the HC-RELAY Data 488 Assigning the Quaternary Carbons 488 Conclusions 489 References 491