n‐Propyl Acetate

1‐Methoxyhexane

2‐Ethyl‐1‐Butanol

n‐Propyl Acetate: Mismatch of Nearly Equal J Values.

Acetaminophen (para‐acetaminophenol)

Methyl m‐Nitrobenzoate

Acetylsalicylic Acid (Aspirin)

ortho‐Chloroacetophenone (o‐Cl‐C₆H₄‐CO‐CH₃): Strong Coupling Effects

2,6‐Di‐(o‐anisyl)‐anisole, a meta‐terphenyl: the AB₂ System

Saturated Fatty Acids: Methyl Stearate

Methyl β‐D‐Riboside 2,3‐Acetonide

N‐(tert‐Butoxycarbonyl)‐L‐Glutamine

Anisole (methoxybenzene): ¹³C Substituent Effects

Acetaminophen (para‐acetamidophenol): ¹³C Substituent Effects

Methyl meta‐Nitrobenzoate (methyl 3‐nitrobenzate): ¹³C Substituent Effects

cis‐6a‐Hydroxymaackiain Analog: ¹³C Substituent Effects

Phlorizin

4‐Methoxy‐1‐Naphthaldehyde: ¹³C Spectrum

Indole‐2‐Carboxylic Acid

Cinchonidine

1,1,1‐Trifluoro‐2‐Propanol

Fluorobenzene

Triphenylphosphine Oxide

Adenosine Triphosphate (ATP): ³¹P Spectrum

4‐Fluorobenzonitrile (C₇H₄NF): ¹⁹F Spectrum

Perfluorooctanesulfonic acid (PFOS, C₈F₁₇SO₃H): ¹⁹F Spectrum

Cinnamic Acid

n‐Butyl Acrylate (CH₃‐CH₂‐CH₂‐CH₂‐O‐CO‐CH=CH₂)

1‐Octene (CH₃‐CH₂‐CH₂‐CH₂‐CH₂‐CH₂‐CH=CH₂)

Limonene (C₁₀H₁₆)

Linalool (C₁₀H₁₈O)

6α‐Methylprednisolone (C₂₂H₃₀O₅)

Elemol (C₁₅H₂₆O)

2‐Hydroxy‐2‐methylsuccinic acid: the AB System

2‐Hydroxysuccinic acid: the ABX System

Diethyl Ethyl(phenyl)malonate: ABX₃

2‐Butanol (sec‐butanol): ABXY₃

Cholesterol (A Ring)

3‐n‐Butylcyclohexanone

1‐n‐Butylcyclohex‐2‐en‐1‐ol

A Synthetic Pyrrolidine: Determining the Major and Minor Diastereomers

Menthol

Hydrocinnamic Acid: AA′BB′

3‐Phenyl‐1‐propanol: AA′BB′

trans,trans‐1,4‐diphenyl‐1,3‐butadiene: AA′BB′

cis,trans‐1,4‐diphenyl‐1,3‐butadiene: First Order

endo‐Borneol

Synthetic Bicyclo[2.2.1] Compounds

α‐Thujone and β‐Thujone

α‐Pinene (Unknown Monoterpene)

D‐Glucose in D₂O

Methyl α‐D‐Glucoside in CD₃OD

Methyl α‐D‐Glucoside in DMSO‐d₆

Methyl α‐D‐Glucoside (1D TOCSY): Selection of H1 Peak

Methyl α‐D‐Glucoside (1D TOCSY): Sequential Selection of All Peaks

β‐D‐Glucose in D₂O: Assignment of the ¹H Spectrum Using Selective TOCSY

α‐D‐Glucose in D₂O: Assignment of the ¹H Spectrum Using Selective TOCSY

5‐Ethyl‐2‐Methylpyridine: Regiochemistry of Alkyl Substituents by NOE

Thujone Isomers (α and β): Stereochemistry of CH₃ Group by NOE

Sucralose: Selective NOE Experiment

Aspartame (L‐Asp‐L‐Phe‐OCH₃)

Leucine Enkephalin Acetate (Tyr‐Gly‐Gly‐Phe‐Leu) in DMSO‐d₆

Adenosine Triphosphate (ATP): ¹H Spectrum

Methyl β‐D‐Glucopyranoside in D₂O: COSY Spectrum

D‐Glucose in D₂O: COSY Spectrum

2‐Naphthol (2‐hydroxynaphthalene) in CDCl₃: COSY Spectrum

Cholesterol in CDCl₃: COSY Spectrum

3‐Heptanone: 2D‐TOCSY Spectrum

Leucine Enkephalin Acetate (Tyr‐Gly‐Gly‐Phe‐Leu): 2D‐TOCSY Spectrum

β‐D‐Lactose Peracetate (β‐D‐Lactose Octaacetate): 2D‐TOCSY Spectrum

α‐Thujone in CDCl₃: 2D‐NOESY Spectrum

Leucine Enkephalin Acetate (Tyr‐Gly‐Gly‐Phe‐Leu): 2D‐NOESY Spectrum

D‐Glucose in D₂O. HSQC Spectrum

Cholesterol in CDCl₃: HSQC Spectrum

Ethyl Acetate in CDCl₃: ¹³C Spectrum without Decoupling

Ethyl Acetate in CDCl₃: HMBC Spectrum

Oxybenzone: HMBC Spectrum

Testosterone: HMBC Spectrum

β‐D‐Lactose Peracetate in CDCl₃: HMBC Spectrum

Telekin: Unknown A, a Sesquiterpene Natural Product

Ergosterol Analog: Unknown B, a Steroid Natural Product

Raffinose: Unknown C, a Trisaccharide

Monocrotaline: Unknown D, an Alkaloid Natural Product

Pristimerin Analog: Unknown E, a Triterpene Natural Product

Nuclear magnetic resonance (NMR) spectroscopy is a technique used to determine the structure of molecules at the level of individual atoms and covalent bonds. While it does not provide a direct picture or image of the molecule, the NMR data can be interpreted to determine which atoms in a molecule are connected to which atoms, and whether these bonds connecting them are single, double, or triple bonds. Further information can be obtained from this data about the distances between atoms that are not bonded, and the angles between bonds, leading to a complete three-dimensional model of the molecule.

The field of NMR can be divided into three categories: imaging (MRI), solid-state NMR, and solution-state (liquids) NMR. NMR imaging is familiar to anyone who has gone to a hospital or clinic for an MRI “scan,” which yields a picture of “slices” through the human body that is extremely useful in medical diagnosis. Solid-state NMR is the analysis of solid materials, usually ground into a powder; this is applied primarily to the analysis of materials such as polymers, but it can also be applied to biological membranes. Solution-state NMR looks at molecules dissolved in a solvent, which can be water or an organic solvent such as acetone or chloroform. This book is focused on solution-state NMR, the primary tool used by organic chemists and biochemists to determine molecular structure.

A further distinction is made between “small molecules” and “large molecules” in solution. In the context of solution-state NMR, a large molecule is a biological molecule such as a protein or nucleic acid, made up of many repeating units that all have similar structures. A small molecule has a molecular weight less than 1000 Da and is usually made up of diverse structural elements (carbon chains, rings, and functional groups) rather than a repeating pattern. Small molecules are the domain of the organic chemist: natural products, drugs, and the intermediates and products of organic synthesis. Also included in this category are the short chains of biological molecules: peptides, oligonucleotides, and oligosaccharides (sugars). This book will focus on the use of NMR data to determine the covalent structure (which atoms are connected to which atoms) and three-dimensional shape (stereochemistry and conformation) of these small molecules.

This book is different from most books on NMR because it is focused on examples and exercises. Each topic is introduced with one of more examples of NMR data with detailed explanations of the interpretation of that data. Examples are then followed by a number of exercises using detailed images of NMR data, and these are followed by solutions, again with detailed explanation of the step-by-step reasoning used to solve the exercise. The title, NMR Data Interpretation Explained, is an indication of this focus on example and explanation. Every detail and aspect of the NMR data is explained, not just the simple and beautiful spectra but also the complex and surprising spectra. A large number of additional exercises, almost all of them showing detailed graphics of NMR data, have been provided at www.wiley.com/go/jacobsen/nmrdata. Solutions with detailed explanations are provided for half of the exercises, with the remaining solutions provided to instructors on the same website in a forum accessible by instructors only. All of the commonly used techniques of small-molecule solution-state NMR are covered: simple one-dimensional (H1 and C13), edited (DEPT) C13, selective one-dimensional H1 (NOE, ROE, and TOCSY), and two-dimensional (COSY, TOCSY, NOESY, ROESY, HSQC, and HMBC). The final chapter puts all of these techniques together to solve the structures of a number of complex natural products: sesquiterpenes, steroids, alkaloids, sugars, and triterpenes. Many exercises are provided for each of these molecule types.

Another unique aspect of this book is that it does not attempt to explain the theory of NMR. Other books, including my own book (NMR Spectroscopy Explained, Wiley-Interscience, 2007), do an excellent job of explaining the theoretical basis of NMR and how the experiments actually work to give the NMR data. In my experience, the actual users of NMR spectrometers are more interested in solving a chemical problem using NMR data, and have little interest in how the spectrometer works or how the nuclei respond to magnetic fields and radio frequency pulses. It is for these NMR users, industry researchers as well as undergraduates, graduate students, and postdoctoral researchers in chemistry, biochemistry, medicinal chemistry, and pharmacy, that this book was written.

The NMR data used in this book came primarily from the NMR facility in the Department of Chemistry and Biochemistry at the University of Arizona. The instruments used include a Bruker Avance-III (400.13 MHz), a Bruker DRX-500 (499.28 MHz), a Bruker DRX-600 (600.13 MHz), and a Varian Inova-600 (599.7 MHz) with cryogenic probe. Every attempt was made to obtain the highest-quality NMR data from pure samples. Data was processed using the Felix software package (Felix NMR, Inc., San Diego, CA) and the MestReNova software package (MestReLab Research, Santiago de Compostela, Spain). Literature data was also used, downloaded from the Japanese database SDBS (Spectral Database for Organic Compounds, National Institute of Advanced Industrial Science and Technology, AIST). In a few cases, NMR spectra were simulated using parameters (chemical shifts and J values) obtained from the literature.

NMR spectrometers are expensive (around $800,000 for a 600 MHz instrument), and require specialized expertise and expensive cryogens (liquid nitrogen and liquid helium) to operate, so many teaching institutions are unable to obtain a high-field NMR instrument. It was also with these colleges and universities in mind, all over the world, that this book was written, so that students can learn the technique using high-quality data from a wide variety of samples.

The idea for this book came from a Chemistry course created by Professor Eugene Mash at the University of Arizona. The course, Chemistry 447, is a laboratory course in the identification of organic compounds, and over the years the technique used by students has become almost exclusively NMR. Prof. Mash gathered together an amazing collection of unknown samples, including a large number of simple aromatics and monoterpenes, and more than 50 different steroids. I began giving a series of lectures on two-dimensional NMR in this course in 2006, and gradually acquired complete 1D and 2D data sets at 600 MHz for all of the steroid unknowns. Prof. Mash encouraged me to write a book that would include this data as well as data on a large number of organic compounds, so that students all over the world, especially in small colleges and in developing countries, would have access to high-quality 600 MHz NMR data.

In 2012, a new graduate course was created by Professor Hamish Christie at the University of Arizona, aimed at preparing new graduate students in Organic Chemistry for their research work. The course, Chemistry 545, teaches all of the latest laboratory techniques in organic synthesis while using the synthetic intermediates and products to teach students to use our NMR instruments and to interpret the NMR data. In this course I developed a deeper look at one-dimensional proton NMR data, beyond the simple spectra found in most undergraduate courses. Two of these laboratory experiments—isolation of the α- and β-isomers of the monoterpene thujone from cedar leaf oil, and preparation of a Shi oxidation catalyst from fructose—adapted well to teaching selective NOE and 2D NMR experiments, forming the core of the more advanced portions of this book.

I would like to thank Prof. Mash and Prof. Christie for these unique opportunities to develop an NMR curriculum and to gain years of experience in explaining and discussing NMR data with undergraduate and graduate students.

I also thank Prof. Robert Bates and Prof. Leslie Gunatilaka, both experts in natural product isolation and structure elucidation, for many exciting collaborations that ignited my fascination with using NMR to solve these complex structures. In the course of these studies, I developed the systematic method outlined in this book for solving structure problems using NMR data.

Dr. Jixun Dai, Assistant Director of the NMR Facility at the University of Arizona, prepared a large number of samples and ran the NMR experiments for those samples. He optimized many of the experiments on the Bruker DRX-500 and DRX-600 instruments, doing especially difficult work of implementing the most modern versions of the selective TOCSY and selective NOE experiments. His programming and data handling skills also saved me more than once from challenging issues in using old NMR data from obsolete platforms, and in simulation of NMR data. I thank him for the significant contribution he made to this book.

A large number of 1D H1 and C13 exercises in this book came from literature data provided by the National Institute of Advanced Industrial Science and Technology (AIST, Japan). Their website (SDBSWeb: http://sdbs.riodb.aist.go.jp) is a goldmine of NMR data for a wide variety of organic compounds. Their line lists (lists of NMR line frequencies) were used to reconstruct the literature spectra used in these exercises (e.g., 300 and 399.65 MHz H1 spectra). I am grateful for being able to use this data for educational purposes.

Finally, I would like to thank my wife, Dr. Linda Breci, for her unwavering support and patience, especially in the last year, as I completed this enormously time-consuming project. She also taught me what little I know about mass spectrometry (MS) and helped me with the section on MS, and she compiled the index of this book.

This book is accompanied by a companion website:

www.wiley.com/go/jacobsen/nmrdata

The Student's website includes:

• Additional Chapter Exercises
  • A large number of exercises are provided, many showing detailed graphics of NMR data
• Solutions to Exercises
  • With detailed explanations are provided for half of the exercises

The Instructor's website includes:

• Instructor's Solutions Manual
  • Provides remaining solutions to exercises