

RAY'S PERSONAL CHOICE 

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 cobaltIII complexes there is a very lowlying excited state (which determines the colour of these complexes). This term dominates all other contributions to the cobalt59 chemical shifts, which therefore show a very good linear relationship with respect to the UVvisible wavelength, thus corroborating Ramsey’s theory.
5) Frequency Control of an Oscillator by Nuclear Magnetic Resonance. Robert Pound employed a superregenerative oscillator to detect radar responses from aircraft. This pulsemodulated 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 (doubletriode) 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 threespin (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 lowfield 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 highresolution 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 twodimensional NMR.
23) Assignment of NMR Spectra with the Aid of Double Quantum Transitions. First practical application of doublequantum (DQ) transitions in NMR. The first step in computer analysis of stronglycoupled proton spectra requires assignment of the observed transitions to an energylevel 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’ frequencyselective 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 spinlattice and spinspin relaxation times in proton spectra, one line at a time.
43) SpinLattice Relaxation of High Resolution NMR Spectra of Carbon13. The advent of Fourier transform NMR allowed new ‘hardpulse’ methods to supersede the ‘softpulse’ technique. This note describes the first Fourier transform measurements of carbon13 spinlattice relaxation of six sites monitored simultaneously. Triggered a flurry of investigations of relaxation of carbon13 in natural abundance samples.
45) High Resolution Study of NMR Spin Echoes: 'JSpectra'. Fourier transformation of spin echo modulation generates a ‘Jspectrum’ where the scalar couplings can be measured with high precision. A proton resonance of 0.028 Hz (full width) is recorded in the Jspectrum 3bromothiophene2aldehyde. Hints at the possibility of twodimensional spectroscopy, where the indirect dimension maps spinspin multiplet structure.
46) Fourier Transform Study of NMR SpinLattice Relaxation by 'Progressive Saturation'. Describes a simple scheme for determining spinlattice relaxation with a pulse scheme that operates in a steadystate regime. Variation of the pulse rates affects the observed NMR intensities by changing the balance between pulse excitation and spinlattice 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 spinspin relaxation times. This sets up a steadystate regime that causes anomalies in the amplitude and phase of the detected signals. Short pseudorandom 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 twodimensional NMR. The ‘phase twist’ lineshape (combining absorption and dispersion contributions) is described for the first time. The ‘phantom’ and ‘ghost’ artifacts are analyzed, and the shapes of twodimensional Lorentzian and Gaussian responses are illustrated.
73) Suppression of Artifacts in TwoDimensional JSpectroscopy. Describes a phase cycle to suppress artifacts (phantoms and ghosts) generated by imperfections of radiofrequency pulse sequences used in twodimensional 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 (carbon13 or nitrogen15) 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 twodimensional INADEQUATE experiment for samples with carbon13 in natural abundance. Signals from coupled pairs of carbon13 spins are separated from the much stronger signals from isolated arbon13 spins by momentary creation of doublequantum 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 phaseinverted counterpart of R. Forerunner of a host of broadband decoupling schemes.
112) Investigation of Complex Networks of SpinSpin Coupling by TwoDimensional NMR. Comprehensive analysis of Jeener’s COSY experiment. Shows how to employ timedomain 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 protonproton splittings.
118) Echoes and Antiechoes in Coherence Transfer NMR: Determining the Signs of DoubleQuantum 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 doublequantum coherence. This introduces phase modulation during evolution, permitting the sign of the doublequantum frequency to be determined.
126) Simplification of NMR Spectra by Filtration through MultipleQuantum Coherence. The sensitivity of a Nquantum coherence to the relative phases of the radiofrequency pulses allows separation of signals derived from different orders N. A twodimensional proton spectrum of a mixture of twospin, threespin and fourspin systems is filtered to show only the fourspin spectrum.
130) Evaluation of a New Broadband Decoupling Sequence: WALTZ16. 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 (WALTZ16) it achieves a decoupling bandwidth equal to twice the intensity of the decoupling field (γB_{2}/2π).
138) Gaussian Pulses. Selective radiofrequency irradiation with pulses having a rectangular envelope suffers from undesirable sincfunction 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 triplequantum coherence.
152) Computer Optimized Decoupling Scheme for Wideband Applications and LowLevel Operation (CODSWALLOP). A remarkable improvement in decoupling bandwidth of WALTZ16 is achieved by relaxing the usual settings of the pulselength parameters, and by accepting slightly larger residual splittings in the decoupled spectrum. Nonlinear numerical optimization employed. Decoupling efficiency is more than doubled.
189) BandSelective 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 (EBURP), spin inversion (IBURP), refocusing (REBURP) and universal rotation (UBURP).
195) Accurate Measurement of Coupling Constants by JDoubling. 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) UserFriendly 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 absorptionmode signals are excited. Can be extended to twodimensional spectroscopy where the detection bands are restricted in both dimensions.
240) Adiabatic Pulses for Wideband Inversion and Broadband Decoupling. First description of sausageshaped ‘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 DeutschJosza Algorithm on a ThreeQubit NMR Quantum Computer. First practical example of the use of a highresolution NMR spectrum for quantum computation. Two or more lineselective radiofrequency inversion pulses are applied simultaneously to a threespin 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 ProjectionReconstruction 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 twodimensional correlation spectra from a coupled Ndimensional spin system (Agitoxin, N = 10). Lowdimensional spectra are combined on a hypothetical Ndimensional scaffold.
301) SPEED: Singlepoint evaluation of the evolution dimension. Contrary to common belief, the evolution domain of a twodimensional experiment need not be explored comprehensively pointbypoint, provided there is prior knowledge of the chemical shifts. Measurement at a single timepoint in the evolution dimension is then sufficient to derive the complete twodimensional 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 

