Pioneers of High-Resolution NMR
[Ray Freeman, Concepts in Magnetic Resonance, V. 11(20 61-70 (1999)]
Arnold, Dharmatti, Packard, and Anderson
The chemical shift
At first, magnetic resonance seemed to be the fief of physicists as they carefully measured the magnetic moments of all the magnetic nuclei with extremely high precision. However, these physicists soon lost interest when it was discovered that these fundamental constants were not constants at all, but varied from one compound to another. In this way, the ?chemical shift”? was born. It was Shrinivas Dharmatti, a young chemist working in a physics laboratory, who pointed out that any simple organic compound (such as ethanol) should show a proton spectrum of several distinct resonances, a separate response for each different chemical site. Arnold et al. then demonstrated the famous three-line spectrum of ethanol, and the philosophy of structural chemistry was changed forever. Martin Packard (a physicist) claimed that he never believed the structural formulas that chemists used until he saw the ethanol spectrum for the first time.
The chemical shifts of protons are, of course, very small and are expressed in parts per million. At this time (1951), a chemistry laboratory seldom boasted a magnet of any kind, and existing magnetic fields were not very uniform in space or stable in time. What appeared to be required was a magnet with spatial uniformity of about one part in 100,000,000 over the sample volume, with a stability to match. Undeterred by the fact that this had never been attempted before, Jim Arnold set out to build a permanent magnet for proton resonance at 30 MHz with this incredible specifications, perhaps not realizing the enormity of his task. He was helped to some extent by Felix Bloch’s idea that spinning the sample tube would average out some of the residual gradients of the field. In two classic papers taken from their doctoral research, Jim Arnold and Wes Anderson demonstrated the amazing complexity of proton high-resolution spectra when recorded with a resolution of 0.5 Hz. Even quite simple organic molecules then revealed a wealth of detail, showing chemical shifts, spin-spin splitting, higher-order effects, and the influence of chemical exchange.
Two-dimensional NMR spectroscopy
Jeener and Ernst
Probably the most exciting and influential example of lateral thinking is due to Jean Jeener. A spectrum is a graph of absorption against frequency; no one at that time imagined NMR spectroscopy in more than one frequency dimension. An excessively modest scientist, Jeener first mentioned his ideas at a NATO summer school that was not widely attended by the leading NMR spectroscopist, and it was not until 23 years later that this work was properly published. He demonstrated that a multiplepulse experiment that included a second time variable (the evolution interval) could be subject to two stages of Fourier transformation, generating a spectrum that showed absorption as a function of two frequency dimensions-a two-dimensional spectrum. Unfortunately, the high-resolution NMR equipment available in Brussels was not well suited to the task, and the resulting two-dimensional spectra were degraded by the effects of spectrometer instabilities (now known as t1 noise) and were never published.
The revolutionary idea was taken up and generalized by Richard Ernst, and this set the stage for a veritable explosion of two-dimensional Fourier transform experiments. One reason for the popularity of two-dimensional spectra is that they offer such a simple pictorial representation of the correlations that exist between different chemical sites. A widely used example is the heteronuclear single-quantum correlation experiment (HSQC), where two successive INEPT sequences execute a round-trip transfer of polarization from protons to carbon-13 (or nitrogen-15) and then back to protons for detection. Sensitivity is high, being determined by the initial proton spin populations and the high inherent detection efficiency for protons. The technique has proved to be invaluable for the study of isotopically labeled proteins.
Two-dimensional spectroscopy also provides a convenient access to multiple quantum effects, which are not directly observable by standard NMR methods. It also proved to be a powerful catalyst for imagining new spin manipulation tricks. The instrumental challenges thrown up by two-dimensional spectroscopy have been the inspiration for several important developments: polarization transfer, phase cycling, pulsed-field gradients, and broad band decoupling with composite pulses or with adiabatic passage.
