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LC-NMR: Expanding the Limits of Structure ElucidationSuurem pilt
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"A practical guide to addressing problems in natural products chemistry, synthetic reaction impurities, degradants, and metabolite investigations. This edition includes implementation and application of qNMR and automated and practical use of computational chemistry combined with QM and DFT to predict highly accurate NMR chemical shifts"--

The isolation and structural characterization of substances present at very low concentrations, as is necessary to satisfy regulatory requirements for pharmaceutical drug degradants and impurities, can present scientific challenges. The coupling of HPLC with NMR spectroscopy has been at the forefront of cutting-edge technologies to address these issues. LC-NMR: Expanding the Limits of Structure Elucidation presents a comprehensive overview of key concepts in HPLC and NMR that are required to achieve definitive structure elucidation with very low levels of analytes. Because skill sets from both of these highly established disciplines are involved in LC-NMR, the author provides introductory background to facilitate readers’ proficiency in both areas, including an entire chapter on NMR theory.

The much-anticipated second edition provides guidance in setting up LC-NMR systems, discussion of LC methods that are compatible with NMR, and an update on recent hardware and software advances for system performance, such as improvements in magnet design, probe technology, and solvent suppression techniques that enable unprecedented mass sensitivity in NMR. This edition features methods to quantify concentration and assess purity of isolated metabolites on the micro scale and incorporates computational approaches to accelerate the structure elucidation process. The author also includes implementation and application of qNMR and automated and practical use of computational chemistry combined with QM and DFT to predict highly accurate NMR chemical shifts. The text focuses on current developments in chromatographic-NMR integration, with particular emphasis on utility in the pharmaceutical industry. Applications include trace analysis, analysis of mixtures, and structural characterization of degradation products, impurities, metabolites, peptides, and more. The text discusses novel uses and emerging technologies that challenge detection limits as well future directions for this important technique. This book is a practical primary resource for NMR structure determination—including theory and application—that guides the reader through the steps required for isolation and NMR structure elucidation on the micro scale.

Foreword xi
Preface xiii
Author xv
Chapter 1 Introduction to LC-NMR
1(28)
1.1 Historical Review
1(7)
1.2 Flow and NMR
8(2)
1.3 Setting up the LC-NMR System
10(6)
1.3.1 Continuous-Flow Mode
10(1)
1.3.2 Direct Stopped-Flow Mode
11(1)
1.3.3 Storage Mode
11(1)
1.3.4 Calibrating the System
11(3)
1.3.5 Preparation of a Solid-Phase Extraction System
14(1)
1.3.6 Adding More Sample to a Cartridge
15(1)
1.4 Solvent Requirements in LC-NMR
16(1)
1.5 Solvent Suppression and Referencing
17(2)
1.6 The Deuterium Lock
19(1)
1.7 The Solvent-Gradient Ramp
19(1)
1.8 Diffusion
20(1)
1.9 Shimming
20(1)
1.10 Acquisition Parameters
20(1)
1.11 Chemical-shift Tracking
21(1)
1.12 Other Considerations
22(1)
1.13 Sources of Error
23(1)
1.14 Summary
24(5)
Chapter 2 NMR Theory
29(30)
2.1 Magnetic Properties of Nuclei
29(3)
2.2 Data Acquisition
32(3)
2.3 Relaxation of Nuclei
35(6)
2.3.1 Spin-Lattice Relaxation Time Tx (Longitudinal)
35(1)
2.3.1.1 Relaxation and Molecular Motion
36(1)
2.3.1.2 Dipole-Dipole Interaction "Through Space"
36(2)
2.3.1.3 Paramagnetic Relaxation
38(1)
2.3.1.4 Chemical Shift Anisotropy Relaxation
39(1)
2.3.1.5 Scalar Coupling Relaxation
39(1)
2.3.1.6 Electric Quadrupolar Relaxation
39(1)
2.3.1.7 Spin Rotation
40(1)
2.3.2 Spin-Spin Relaxation Time T2 (Transverse)
40(1)
2.4 The Chemical Shift
41(1)
2.5 Spin Coupling
42(4)
2.6 Nuclear Overhauser Effect (NOE)
46(6)
2.6.1 Molecular Weight and Maximum NOE
48(2)
2.6.2 Time Dependence of NOE -- Mixing Times
50(2)
2.7 Coupling of HPLC with NMR
52(7)
Chapter 3 Separation Methods
59(18)
3.1 Modes of Separation
59(4)
3.2 General Method Development Strategies
63(3)
3.3 Column Packing Types
66(1)
3.4 Detector Selection
67(4)
3.5 RPC Method Development and Compatibility with NMR
71(1)
3.6 Integration of CE and NMR
72(1)
3.7 Transitioning from Analytical to Preparative Chromatography
73(1)
3.8 General Considerations
74(3)
Chapter 4 NMR Instrumentation and Probe Technologies
77(20)
4.1 Instrumentation Configuration
77(2)
4.2 The Magnet
79(2)
4.3 Room Temperature Flow Probe
81(1)
4.4 Microcapillary Probes (Room Temperature)
82(4)
4.4.1 Microcoil Capillary Flow Probes (Room Temperature)
82(3)
4.4.2 Microcoil Tube Probes (Room Temperature)
85(1)
4.5 Cryogenically Cooled Probes
86(4)
4.5.1 Cryo-flow Probe
88(1)
4.5.2 Cryo-capillary Tube Probe
88(1)
4.5.3 Affordable Cryogenically Cooled Probes
89(1)
4.6 Probe Coil Geometries
90(1)
4.7 Probe Sensitivity Comparison
91(6)
Chapter 5 NMR-Associated Isolation Technologies
97(22)
5.1 Stop Flow
97(1)
5.2 Loop Collector
98(1)
5.3 Solid-Phase Extraction (SPE)
99(2)
5.4 Non-chromatographic Flow NMR
101(3)
5.5 Direct Injection NMR (DI-NMR)
104(4)
5.5.1 Applications of DI-NMR
105(3)
5.5.2 Comparisons
108(1)
5.6 Capillary Electrophoresis and NMR
108(11)
5.6.1 Modes of Electrophoresis-NMR and Effects on NMR Spectral Properties
108(2)
5.6.2 NMR Observe Volume
110(1)
5.6.3 Capillary Electrochromatography (CEC)-NMR
111(1)
5.6.4 CE-NMR in Practice
112(7)
Chapter 6 NMR Experiments
119(20)
6.1 Solvent Suppression
119(1)
6.2 Structure Elucidation Experiments
120(7)
6.2.1 Heteronuclear Correlation Experiments (HSQC, HMQC, and HMBC)
122(2)
6.2.2 Wet Solvent Suppression and 2D NMR
124(1)
6.2.3 Decoupling and Power Levels in 2D NMR
125(2)
6.3 NOE Experiments
127(12)
6.3.1 Sample Considerations
129(2)
6.3.2 Processing (NOESY and ROESY) 2D Spectra
131(1)
6.3.3 Chemical/Conformational Exchange
132(1)
6.3.4 Spin Diffusion (Problematic for Large Molecules)
133(1)
6.3.5 NOE, Conformational Analysis, and Distance Determination
134(2)
6.3.6 ROESY -- Quantitative Distance Determination
136(3)
Chapter 7 Applications
139(58)
7.1 Degradation Products
139(7)
7.2 Impurities
146(6)
7.3 Trace Analysis
152(3)
7.4 Analysis of Mixtures
155(2)
7.5 Formulation Adduct
157(5)
7.6 Tautomer Kinetics
162(1)
7.7 Unstable Products
163(2)
7.8 Metabolites
165(6)
7.9 cITP Isolates
171(5)
7.10 Natural Products
176(8)
7.11 Proteins/Peptides
184(13)
Chapter 8 Other Specialized Flow NMR
197(30)
8.1 NMR and Parallel Detection
197(1)
8.2 Data Processing and Deconvolution of Parallel Data
197(2)
8.3 Parallel Probe Construction
199(4)
8.3.1 Multiplex Four-Coil Probe
199(3)
8.3.2 Multiplex Dual Probe
202(1)
8.4 Microprobes
203(1)
8.5 Advancements in Multiple-Coil Probe Design
203(3)
8.6 Biological Screening and Flow NMR
206(7)
8.7 NMR and Microreactors
213(1)
8.8 Signal-to-Noise Ratio (Microcoils)
214(4)
8.9 Microprobe Design (Microcoil/Microslot/Microstrip)
218(3)
8.10 Future Directions
221(6)
8.10.1 Portable NMR and Sensitivity
221(1)
8.10.2 DNP and NMR Sensitivity
222(5)
Chapter 9 Quantitation of Isolated Compounds
227(32)
9.1 Background of Quantitative NMR (qNMR)
227(2)
9.2 Comparison of qNMR with HPLC Methods
229(1)
9.3 Selecting a qNMR Reference Standard
230(7)
9.3.1 External versus Internal qNMR Reference
231(4)
9.3.2 Calibration Procedure
235(2)
9.4 Instrument Settings, Solvent Selection, Rapid Spectral Analysis
237(3)
9.5 Types of qNMR Calculations
240(1)
9.5.1 Concentration (ERETIC2)
240(1)
9.5.2 Mass of Compound (Internal Standard and ERETIC)
240(1)
9.5.3 Purity
241(1)
9.6 Applications
241(18)
Chapter 10 QM/DFT Chemical Shift Prediction
259(34)
10.1 Computational Methods
259(7)
10.1.1 Method Evaluation
260(2)
10.1.2 Systematic Errors
262(4)
10.2 Statistical Distribution of Chemical Shift Differences (1H, 13C, and 15N NMR)
266(3)
10.3 NMR Referencing
269(3)
10.3.1 TMS
269(1)
10.3.2 Nitromethane/LNH3
269(1)
10.3.3 Linear Scaling
270(2)
10.4 Automated Program Development
272(4)
10.4.1 H/PAS Holistic In-silico Prediction Application Software
272(1)
10.4.2 DP4, DP4+, and DiCE Diasteromeric In-silico Chiral Elucidation
272(4)
10.5 Applications
276(11)
10.5.1 Regioisomers
276(3)
10.5.2 Tautomers
279(1)
10.5.3 Natural Products
279(3)
10.5.4 Assignment Ambiguities
282(1)
10.5.5 Decomposition Products
282(3)
10.5.6 Diastereomers
285(2)
10.6 Summary
287(6)
Glossary 293(18)
Index 311
Nina C. Gonnella, Ph.D. is a Senior Associate Director at Boehringer Ingelheim (BI) where she heads a molecular structure and solid form informatics group, encompassing NMR Spectroscopy, Mass Spectrometry, Single Crystal X-ray and Computational Chemistry. She has extensive experience leading Pharmaceutical Research and Development groups spanning structural characterization /ligand screening and in-vitro and in-vivo biological studies.

Nina received her Ph.D. in Synthetic Organic Chemistry from the University of Pennsylvania and subsequently held postdoctoral positions at California Institute of Technology and Columbia University. Prior to joining BI, Nina was group leader / manager at Novartis where she established and led an NMR group in areas that included, small molecule characterization, protein-ligand structure elucidation and in-vivo drug metabolism. She has advanced discovery research through application of structure based drug design and ligand based screening technologies to identify and optimize new lead series in both kinase and protease programs. Nina also held a position as adjunct professor at the University of Medicine & Dentistry of NJ (UMDNJ) (Graduate Program). She subsequently joined AbbVie as Group Leader of an NMR-LC-MS group with focus on protein-ligand binding studies. At BI, Nina has advanced BI projects through the development of innovative solutions. She championed solid state NMR as a company-wide Center of Expertise and initiated the acquisition of small molecule single crystal X-ray for global R&D. She introduced "state of the art" performance in integrating LC-NMR and micro-cryo probe NMR technology to enable elucidation of micro-scale degradation products and impurities. Nina initiated and led an international team in the development of powerful commercial ready in-silico structure elucidation programs that use quantum chemistry, density functional theory and probability theory to solve challenging chemical structures. Nina co-founded, organized and chaired a new Gordon Research Conference in "Molecular Structure Elucidation." She has served on scientific review boards, published over 95 peer review journal articles, authored book chapters, taught courses and presented numerous national and international lectures.
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