High-Resolution NMR Techniques in Organic Chemistry

Timothy D.W. Claridge

• Publisher: Elsevier Science
• Year: 2008
• ISBN:
  9780080915036
• Edition: 2
• Topic: Mathematics
• Subtopic: Mathematical Analysis
• Index: Mathematics

High-Resolution NMR Techniques in Organic Chemistry describes the most important high-resolution NMR techniques that find use in the structure elucidation of organic molecules and the investigation of their behavior in solution.

The techniques are presented and explained using pictorial formats wherever possible, limiting the number of mathematical descriptions. The emphasis is on the more recently developed methods of solution-state NMR spectroscopy with a considerable amount of information on implementation and on the setting of critical parameters for anyone wishing to exploit these methods.

• Presents a large number of examples to demonstrate the utility of the methods covered
• Serves the needs of students and professionals in every chemistry laboratory
• Describes the most important methods available, with guidance on execution of experiments

Chapter 1

Introduction

Timothy D.W. Claridge Chemistry Research Laboratory, Department of Chemistry, University of Oxford

Publisher Summary

This chapter introduces the book to present the most important nuclear magnetic resonance (NMR) methods used for organic structure elucidation, to explain the information they provide, how they operate and to provide some guidance on their practical implementation. The choice of experiments is naturally a subjective one, partially based on personal experience, but also taking into account those methods most commonly encountered in the chemical literature and those recognized within the NMR community as being most informative and of widest applicability. The sheer number of available NMR methods may make this seem an overwhelming task, but in reality, most experiments are composed of a smaller number of comprehensible building blocks pieced together, and once these have been mastered, an appreciation of more complex sequences becomes a far less daunting task. For those readers wishing to pursue a particular topic in greater detail, the original references are given but otherwise all descriptions are self-contained.

From the initial observation of proton magnetic resonance in water [1] and in paraffin [2], the discipline of nuclear magnetic resonance (NMR) has seen unparalleled growth as an analytical method and now, in numerous different guises, finds application in chemistry, biology, medicine, materials science and geology. The founding pioneers of the subject, Felix Bloch and Edward Purcell, were recognised with a Nobel Prize in 1952 ‘for their development of new methods for nuclear magnetic precision measurements and discoveries in connection therewith’. The maturity of the discipline has since been recognised through the awarding of Nobel prizes to two of the pioneers of modern NMR methods and their application, Richard Ernst (1991, ‘for his contributions to the development of the methodology of high-resolution NMR spectroscopy’) and Kurt Wüthrich (2002, ‘for his development of NMR spectroscopy for determining the three-dimensional structure of biological macromolecules in solution’). Despite its inception in the laboratories of physicists, it is in the chemical and biochemical laboratories that NMR spectroscopy has found greatest use. To put into context the range of techniques now available in the modern organic laboratory, including those described in this book, we begin with a short overview of the evolution of high-resolution (solution-state) NMR spectroscopy and some of the landmark developments that have shaped the subject.

1.1 THE DEVELOPMENT OF HIGH-RESOLUTION NMR

It is now over 16 years since the first observations of NMR were made in both solid and liquid samples, from which the subject has evolved to become the principal structural technique of the research chemist, alongside mass spectrometry. During this time, there have been a number of key advances in high-resolution NMR that have guided the development of the subject [3–5] (Table 1.1) and consequently the work of organic chemists and their approaches to structure elucidation. The seminal step occurred during the early 1950s when it was realised that the resonant frequency of a nucleus is influenced by its chemical environment and that one nucleus could further influence the resonance of another through intervening chemical bonds. Although these observations were seen as unwelcome chemical complications by the investigating physicists, a few pioneering chemists immediately realised the significance of these chemical shifts and spin–spin couplings within the context of structural chemistry. The first high-resolution proton NMR spectrum (Fig. 1.1) clearly demonstrated how the features of an NMR spectrum, in this case chemical shifts, could be directly related to chemical structure, and it is from this that NMR has evolved to attain the significance it holds today.

Table 1.1

A summary of some key developments that have had a major influence on the practice and application of high-resolution NMR spectroscopy in chemical research

Decade	Notable advances
1940s	First observation of NMR in solids and liquids (1945)
1950s	Development of chemical shifts and spin–spin coupling constants as structural tools
1960s	Use of signal averaging for improving sensitivity Application of the pulse-FT approach The NOE employed in structural investigations
1970s	Use of superconducting magnets and their combination with the FT approach Computer controlled instrumentation
1980s	Development of multipulse and two-dimensional NMR techniques Automated spectroscopy
1990s	Routine application of pulsed field gradients for signal selection Development of coupled analytical methods, e.g. LC-NMR
2000−	Use of high-sensitivity cryogenic probes Routine availability of actively shielded magnets for reduced stray fields Development of microscale tube and flow probes
2010+	Adoption of fast and parallel data acquisition methods…?

FT, Fourier transformation; LC-NMR, liquid chromatography and nuclear magnetic resonance.

Figure 1.1 The first ‘high-resolution’ proton NMR spectrum, recorded at 30 MHz, displaying the proton chemical shifts in ethanol. (reprinted with permission from [6], Copyright 1951, American Institute of Physics)

The 1950s also saw a variety of instrumental developments that were to provide the chemist with even greater chemical insight. These included the use of sample spinning for averaging to zero field inhomogeneities, which provided a substantial increase in resolution, so revealing fine splittings from spin–spin coupling. Later, spin decoupling was able to provide more specific information by helping the chemists understand these interactions. With these improvements, sophisticated relationships could be developed between chemical structure and measurable parameters, leading to realisations such as the dependence of vicinal coupling constants on dihedral angles (the now well-known Karplus relationship). The inclusion of computers during the 1960s was also to play a major role in enhancing the influence of NMR on the chemical community. The practice of collecting the same continuous wave spectrum repeatedly and combining them with a CAT (computer of average transients) led to significant gains in sensitivity and made the observation of smaller sample quantities a practical realisation. When the idea of stimulating all spins simultaneously with a single pulse of radio frequency, collecting the time-domain response and converting this to the required frequency-domain spectrum by a process known as Fourier transformation (FT), was introduced, more rapid signal averaging became possible. This approach provided an enormous increase in signal-to-noise ratio and was to change completely the development of NMR spectroscopy. The mid-1960s also saw the application of the nuclear Overhauser effect (NOE) to conformational studies. Although described during the 1950s as a means of enhancing the sensitivity of nuclei through the simultaneous irradiation of electrons, the Overhauser effect has since found widest application in sensitivity enhancement between nuclei, or in the study of the spatial proximity of nuclei, and remains one of the most important tools of modern NMR. By the end of the 1960s, the first commercial FT spectrometer was available, operating at 90 MHz for protons. The next great advance in field strengths was provided by the introduction of superconducting magnets during the 1970s, which were able to provide significantly higher fields than the electromagnets previously employed. These, combined with the FT approach, made the observation of carbon-13 routine and provided the organic chemists with another probe of molecular structure. This also paved the way for the routine observation of a whole variety of previously inaccessible nuclei of low natural abundance and low magnetic moment. It was also in the early 1970s that the concept of spreading the information contained within the NMR spectrum into two separate frequency dimensions was proposed in a lecture. However, because of instrumental limitations, the quality of the first two-dimensional (2D) spectra was considered too poor to be published, and not until the mid-1970s, when instrument stability had improved and developments in computers made the necessary complex calculations feasible, did the development of 2D methods begin in earnest. These methods, together with the various multipulse one-dimensional (1D) methods that also became possible with the FT approach, did not have significant impact on the wider chemical community until the 1980s, from which point their development was nothing less than explosive. This period saw an enormous number of new pulse techniques presented that were capable of performing a variety of ‘spin gymnastics’, thus providing the chemist with ever more structural data, on smaller sample quantities and in less time. No longer was it necessary to rely on empirical correlations of chemical shifts and coupling constants with structural features to identify molecules, but instead a collection of spin interactions (through-bond, through-space and chemical exchange) could be ma...