Research projects are often started in a wild burst of enthusiasm, but later, in the cold light of day, the initial confidence may wane. Here is Ray’s choice of those topics that appear to have stood the test of time. Full papers have been selected in preference to initial communications. The numbering scheme and titles match those of the main publication list.
2) Cobalt Nuclear Resonance Spectra. In general, Ramsey’s theory of chemical shielding involves a summation over all excited electronic wavefunctions, but in the special case of cobalt-III complexes there is a very low-lying excited state (which determines the colour of these complexes). This term dominates all other contributions to the cobalt-59 chemical shifts, which therefore show a very good linear relationship with respect to the UV-visible wavelength, thus corroborating Ramsey’s theory.
5) Frequency Control of an Oscillator by Nuclear Magnetic Resonance. Robert Pound employed a super-regenerative oscillator to detect radar responses from aircraft. This pulse-modulated oscillator normally runs incoherently with the phase of each new oscillation determined by circuit noise. But when the device detects a radar echo, this triggers subsequent oscillations in a coherent mode. This simple (double-triode) circuit can also detect NMR signals because the oscillator locks onto the NMR free precession frequency, faithfully following any variations of the applied magnetic field.
15) The Relative Signs of Geminal and Vicinal Proton Spin Coupling Constants. In a coupled three-spin (AMX) proton system, the A and X regions both consist of J(AX) doublets split again by the coupling to M, but the assignment of these doublets remains ambiguous. The relative signs of J(AM) and J(MX) are determined by selectively irradiating the low-field A doublet and observing which of the two X doublets is decoupled. This experiment demonstrated that geminal and vicinal couplings have opposite signs, whereas Karplus predicted that both should be positive.
18) Use of Weak Perturbing Magnetic Fields in Nuclear Magnetic Double Resonance. An early indication that NMR spectra might be manipulated in new and useful ways. Weak irradiation of a single line of a high-resolution spectrum generates new splittings on lines that share a common energy level (connected transitions). How well these splittings are resolved depends on the relative configuration of the irradiated and observed transitions – either progressive (poorly resolved) or regressive (well resolved). Jeener has asserted that this paper prompted him to think about the possibilities of two-dimensional NMR.
23) Assignment of NMR Spectra with the Aid of Double Quantum Transitions. First practical application of double-quantum (DQ) transitions in NMR. The first step in computer analysis of strongly-coupled proton spectra requires assignment of the observed transitions to an energy-level diagram, accomplished by detecting the DQ transitions. Then the iterative fitting the experimental spectrum converges rapidly, even with arbitrary starting parameters. Sample: trivinylphosphine.
38) Selective Determination of Relaxation Times in High Resolution NMR. Application of a ‘soft’ frequency-selective pulse in the form of a weak audiofrequency modulation sideband, controlled by a simple mechanical gating system. Pulse durations of the order of hundreds of milliseconds. NMR signals can be observed during the pulses. Studies of spin-lattice and spin-spin relaxation times in proton spectra, one line at a time.
43) Spin-Lattice Relaxation of High Resolution NMR Spectra of Carbon-13. The advent of Fourier transform NMR allowed new ‘hard-pulse’ methods to supersede the ‘soft-pulse’ technique. This note describes the first Fourier transform measurements of carbon-13 spin-lattice relaxation of six sites monitored simultaneously. Triggered a flurry of investigations of relaxation of carbon-13 in natural abundance samples.
45) High Resolution Study of NMR Spin Echoes: 'J-Spectra'. Fourier transformation of spin echo modulation generates a ‘J-spectrum’ where the scalar couplings can be measured with high precision. A proton resonance of 0.028 Hz (full width) is recorded in the J-spectrum 3-bromothiophene-2-aldehyde. Hints at the possibility of two-dimensional spectroscopy, where the indirect dimension maps spin-spin multiplet structure.
46) Fourier Transform Study of NMR Spin-Lattice Relaxation by 'Progressive Saturation'. Describes a simple scheme for determining spin-lattice relaxation with a pulse scheme that operates in a steady-state regime. Variation of the pulse rates affects the observed NMR intensities by changing the balance between pulse excitation and spin-lattice relaxation. No modification of the spectrometer is required.
47) Phase and Intensity Anomalies in Fourier Transform NMR. Fourier transform spectrometers often operate with interpulse intervals comparable with the spin-spin relaxation times. This sets up a steady-state regime that causes anomalies in the amplitude and phase of the detected signals. Short pseudo-random delays between pulses suppresses these effects. Recently applied to problems in fast magnetic resonance imaging.
71) Double Fourier Transformation in High Resolution NMR. Nuts and bolts of the methodology of two-dimensional NMR. The ‘phase twist’ line-shape (combining absorption and dispersion contributions) is described for the first time. The ‘phantom’ and ‘ghost’ artifacts are analyzed, and the shapes of two-dimensional Lorentzian and Gaussian responses are illustrated.
73) Suppression of Artifacts in Two-Dimensional J-Spectroscopy. Describes a phase cycle to suppress artifacts (phantoms and ghosts) generated by imperfections of radiofrequency pulse sequences used in two-dimensional NMR. Phase cycling has later been extended to most complex NMR sequences, only superseded when pulsed field gradient methods became available.
79) Selective Excitation in Fourier Transform Nuclear Magnetic Resonance. First comprehensive description of the DANTE experiment, where selective irradiation is achieved by a repetitive sequence of hard pulses of small flip angle. Excitation is at the transmitter frequency and at sidebands separated by multiples of the pulse repetition rate.
86) Enhancement of NMR Signals by Polarization Transfer. The INEPT pulse sequence, where the signals from nuclear species of low intrinsic sensitivity (carbon-13 or nitrogen-15) are enhanced by transfer of polarization from protons. Now an integral part of many complex pulse sequences.
87) NMR Population Inversion using a Composite Pulse. First description of a composite radiofrequency pulse [90º(X) 180º(Y) 90º(X)] designed to compensate the imperfections of a single 180º pulse. Later became an important element in broadband composite decoupling sequences.
106) An NMR Technique for Tracing out the Carbon Skeleton of an Organic Molecule. The two-dimensional INADEQUATE experiment for samples with carbon-13 in natural abundance. Signals from coupled pairs of carbon-13 spins are separated from the much stronger signals from isolated arbon-13 spins by momentary creation of double-quantum coherence. The evolution dimension is used to separate the individual coupled subspectra as a function of the double quantum frequencies.
110) Composite Pulse Decoupling. Broadband heteronuclear decoupling employing composite spin inversion pulses. The protons follow cyclic trajectories at a rate fast compared with the coupling constant. Composite inversion elements R are arranged in a magic cycle R R R’ R’, where R’ is the phase-inverted counterpart of R. Fore-runner of a host of broadband decoupling schemes.
112) Investigation of Complex Networks of Spin-Spin Coupling by Two-Dimensional NMR. Comprehensive analysis of Jeener’s COSY experiment. Shows how to employ time-domain weighting functions to emphasize correlation peaks at the expense of diagonal peaks, and how to determine relative signs of coupling constants by inspection. Demonstrates the utility of intensity contour plots. Can be used to generate proton spectra without proton-proton splittings.
118) Echoes and Antiechoes in Coherence Transfer NMR: Determining the Signs of Double-Quantum Frequencies. A theoretical treatment of the INADEQUATE pulse sequence indicates that if the final ‘read’ pulse differs from 90º the observed signal contains components derived from both the real and imaginary parts of the double-quantum coherence. This introduces phase modulation during evolution, permitting the sign of the double-quantum frequency to be determined.
126) Simplification of NMR Spectra by Filtration through Multiple-Quantum Coherence. The sensitivity of a N-quantum coherence to the relative phases of the radiofrequency pulses allows separation of signals derived from different orders N. A two-dimensional proton spectrum of a mixture of two-spin, three-spin and four-spin systems is filtered to show only the four-spin spectrum.
130) Evaluation of a New Broadband Decoupling Sequence: WALTZ-16. A new spin inversion pulse 90º(X) 180º(–X) 270º(X) proves to be remarkably insensitive to imperfections in the phase or amplitude of the radiofrequency pulses. Employed in a supercycle (WALTZ-16) it achieves a decoupling bandwidth equal to twice the intensity of the decoupling field (γB2/2π).
138) Gaussian Pulses. Selective radiofrequency irradiation with pulses having a rectangular envelope suffers from undesirable sinc-function wiggles. Shaping with a Gaussian function greatly improves the excitation envelope in the frequency domain.
151) Pulsed Field Gradients in NMR. An Alternative to Phase Cycling. Scheme to replace the ubiquitous phase cycle with suitably matched pairs of pulsed field gradients, thus saving time and complication. An extension is employed to filter signals that pass through triple-quantum coherence.
152) Computer Optimized Decoupling Scheme for Wideband Applications and Low-Level Operation (CODSWALLOP). A remarkable improvement in decoupling bandwidth of WALTZ-16 is achieved by relaxing the usual settings of the pulse-length parameters, and by accepting slightly larger residual splittings in the decoupled spectrum. Non-linear numerical optimization employed. Decoupling efficiency is more than doubled.
189) Band-Selective Radiofrequency Pulses. Simulated annealing used to design soft radiofrequency ‘BURP’ pulses that excite uniformly in pure absorption over a predefined frequency band with negligible excitation outside that band. There are versions for excitation (E-BURP), spin inversion (I-BURP), refocusing (RE-BURP) and universal rotation (U-BURP).
195) Accurate Measurement of Coupling Constants by J-Doubling. A free induction decay containing a modulation term cos(πJt) is multiplied by a function sin(πJ*t) where J* is varied. When J* = J, the transformed spectrum shows a splitting of 2J, and the integral of the absolute magnitude of the spectral intensities reaches a minimum, allowing J to be determined with high accuracy.
200) User-Friendly Selective Pulses. This ‘spin pinging’ experiment acts on magnetization prepared along the Y axis of the rotating frame, alternatively rotating it about the X and Y axis by means of a soft 180° pulse. Pure absorption-mode signals are excited. Can be extended to two-dimensional spectroscopy where the detection bands are restricted in both dimensions.
240) Adiabatic Pulses for Wideband Inversion and Broadband Decoupling. First description of sausage-shaped ‘WURST’ stretched adiabatic pulses. Supersedes previous schemes for broadband heteronuclear decoupling, achieving very broad decoupling bandwidths at low radiofrequency intensity.
264) An Implementation of the Deutsch-Josza Algorithm on a Three-Qubit NMR Quantum Computer. First practical example of the use of a high-resolution NMR spectrum for quantum computation. Two or more line-selective radiofrequency inversion pulses are applied simultaneously to a three-spin proton system. The experiment distinguishes between constant and balanced functions.
281) Hadamard NMR Spectroscopy. Review of Hadamard encoding for speeding up multidimensional NMR, using prior knowledge of the chemical shifts. Permits fast recording of multidimensional spectra of selected sites in globally enriched proteins, as if specific isotopic enrichment had been used.
285) The Projection-Reconstruction Technique for Speeding up Multidimensional NMR Spectroscopy. Faster multidimensional NMR by restricting acquisition to a limited set of plane projections at different inclinations, relying on Bracewell’s slice/projection theorem. Several schemes for the reconstruction stage are described.
293) Hyperdimensional NMR Spectroscopy. Describes a method for deriving any of the N(N–1)/2 two-dimensional correlation spectra from a coupled N-dimensional spin system (Agitoxin, N = 10). Low-dimensional spectra are combined on a hypothetical N-dimensional scaffold.
301) SPEED: Single-point evaluation of the evolution dimension. Contrary to common belief, the evolution domain of a two-dimensional experiment need not be explored comprehensively point-by-point, provided there is prior knowledge of the chemical shifts. Measurement at a single time-point in the evolution dimension is then sufficient to derive the complete two-dimensional spectrum.
308) Molecular structure from a single NMR sequence (fast PANACEA). Three standard sequences (INADEQUATE, HSQC, HMBC) are combined into a single measurement by exploiting new multiple receiver technology. Hadamard encoding is used to speed up the INADEQUATE feature. Establishes the molecular structure of menthol in less than a minute.

Ray Freeman; 7 December 2012.
Ray Freeman FRS
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