《天然药物化学》课程教学资源（文献资料）Ernst, Richard R. - The Success Story of Fourier Transformation in NMR

Ernst,Richard R.:The Success Story of Fourier Transformation in NMR Richard R.Ernst Eidgenissische Technische Hochschule,Ziirich,Switzerland This chapter could also be entitled:How to be successful ing my ich)fron the e Han 195 beloved futur It was.so to sa a n had s g 4 years. HANS PRIMAS AND HIS NMR SPECTROMETERS Hans H.Ginthard.at that time Associate lead of the Labor set out all now ntre that he wass d by 1953 ht.At the the pract olid state 6 and he developed shaped pol gnet(Figure ter was als om MR roscopy div becam eter und der the which is a memb the uker of this type were sold in Europe during the following up.In some sense high-resoltion Bruk er-Spec bye-c s,L Encyclopedia of Magnetic Resonance in 2007 by John Wiley Sons,Ltd

Ernst, Richard R.: The Success Story of Fourier Transformation in NMR Richard R. Ernst Eidgen¨ossische Technische Hochschule, Z¨urich, Switzerland This chapter could also be entitled: How to be successful by borrowing clever ideas. During my undergraduate studies at the Swiss Federal Institute of Technology in Zurich ¨ (ETH Zurich) from 1952–56, the term nuclear magnetic ¨ resonance was never even mentioned, and when I started my thesis with Professor Hans H. Gunthard in 1958 after ¨ some healthy military training I knew nothing about my beloved future companion NMR. It was, so to say, a marriage arranged by my thesis advisor. Fortunately, an extraordinarily gifted, truly ingenious scientist, Hans Primas, was just in the course of finishing the construction of the first Swiss high￾resolution NMR spectrometer. I had the enormous luck to work under his guidance on my Ph.D. thesis for the following 4 years. HANS PRIMAS AND HIS NMR SPECTROMETERS Professor Hans H. Gunthard, at that time Associate ¨ Professor in the Laboratorium fur Organische Chemie, later ¨ Head of the Laboratorium fur Physikalische Chemie, was an ¨ enormously enterprising and stimulating leader (Figure 1). He set out to introduce all powerful modern spectroscopic tools into the Swiss university chemistry. It should also be mentioned here that he was strongly encouraged by Professor Leopold Ruzicka who was heading the Laboratorium fur¨ Organische Chemie with much foresight. At the early date of 1953, Professor Gunthard asked Hans Primas to pioneer ¨ the construction of a high-resolution NMR spectrometer useful for chemical applications (Figure 2). During a brief stay at the University of Zurich in 1953 with Professor Hans ¨ Staub, who was a former co-worker of Felix Bloch at Stanford, and with his associate Ernst Brun, Hans Primas was exposed for the first time to the practical aspects of NMR, here in the hands of enterprising solid state physicists. The 25 MHz proton resonance spectrometer that Primas and Gunthard constructed used a 0.6 T permanent magnet (Figure ¨ 3), spherical sample containers to improve the magnetic field homogeneity,1 – 4 and a field flux stabilizer.5 It was an important event when in 1956, Gunthard and Primas convinced ¨ the Swiss company Trub-T ¨ auber, with its scientific director ¨ Dr. L. Wegmann, to manufacture and commercialize this spectrometer under the name KIS I.6 Several instruments of this type were sold in Europe during the following years. Hans Primas decided to continue his engineering ventures by designing a high-field instrument working at 75 MHz proton Figure 1 Professor Hs.H. Gunthard, the spinning nucleus of the ¨ research group in 1958 Figure 2 Professor Hans Primas working on his electronic design for the 25 MHz NMR spectrometer in 1958 resonance, and he developed a new concept of shaped pole caps for electromagnets to achieve high-field homogeneity by avoiding local saturation.7 This spectrometer was also commercialized as KIS II, operating at a proton resonance frequency of 90 MHz. The company Trub-T ¨ auber was dissolved in 1965, and ¨ its NMR spectroscopy division became the germ for the well-known Swiss company Spectrospin AG in Fallanden, ¨ which is a member of the Bruker group. In some sense, the instruments built by Hans Primas are the ancestors of the modern high-resolution Bruker-Spectrospin spectrometers. Besides numerous instrumental innovations, Hans Primas also contributed during this time to new theoretical concepts such eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

2 RICHARD R ERNST which e with ak co o nting o to us,and w missed th lity ntin astochastic resor ce ex rim t.Our aim wasn THE SENSITIVITY DEFECT OF NMR signal-to for ty pectr ase tha cnhanc Sp cial oG-E optim and ele Eeonicfiei ic experim nts were dail 3 The 6 kG pe for the 25 MHz aPhD the nd noise figures than any working spectrometer would have age spectra. the ide through the samesp ctrum.In this wa missed som FIRST VENTURE IN STOCHASTIC RESONANCE in the fall of 193 at Varian Associates in Palo Allo for my I never even started my first thesis subject po osed by yuidance of Dr.Weston A.Anderson, thard analys and the ch as Bitte that were alre ame from Hans Prm who at that tim hat time was working the spectrum ttmevaninge FOURIER TRANSFORM NMR SPECTROSCOPY mentioned the in007by John WileySons,Ld

2 RICHARD R. ERNST Figure 3 The 6 kG permanent magnet for the 25 MHz proton magnetic resonance spectrometer in 1958. The coils for the magnetic flux stabilizer are visible on the pole pieces. The probe assembly is directly attached to the preamplifier. The radiofrequency transmitter stands on top of the magnet as a generalized perturbation theory in operator form8 and superoperator concepts for calculating NMR spectra.9,10 FIRST VENTURE IN STOCHASTIC RESONANCE I never even started my first thesis subject posed by Professor Gunthard in 1958, i.e. a group theoretical analysis ¨ of NMR spectra. After extensive ventures into electronics and the construction of NMR probe assemblies, frequently burning my fingers with solder and high voltages, I finished my graduate studies in 1962 with a purely theoretical investigation of stochastic magnetic resonance. The pertinent ideas for this study came from Hans Primas, who at that time was working on the theory of quantum mechanical systems with a stochastic Hamiltonian,11 inspired by the work of Norbert Wiener12 and others. The application of stochastic excitation for obtaining spectral information with an inherent multiplex advantage was not considered at that time. Rather, stochastic excitation was intended for decoupling purposes. By a broadband excitation of all spins except for one within a homonuclear spin system, broadband spin decoupling of this selected spin was attempted. Sweeping a broadband frequency source with a narrowband hole in its spectrum through the entire spectral range should lead to a completely decoupled homonuclear spectrum, which could be observed with a weak coherent irradiation in the center of the hole. It was disappointing for us to recognize that the principle only functions for weakly coupled spin systems, a situation that needed, in our view, anyway no further simplication. Weak coupling was too simple to appeal to us, and we missed the possibility of inventing stochastic heteronuclear decoupling. No wonder that we never did a stochastic resonance experiment. Our aim was more a theoretical excursion to explore the nonlinear stochastic response of a quantum mechanical system by means of an example.13 THE SENSITIVITY DEFECT OF NMR Anyone who performed NMR experiments in the 1950s will remember the exceedingly low sensitivity of NMR at that time. A signal-to-noise ratio of 5:1 for the spectrum of a 1% ethylbenzene solution was considered to be excellent. Indeed, nobody could envision the 1000-fold increase that would happen in the next 30 years. We thought a lot at that time about sensitivity enhancement techniques. Special low-noise preamplifiers using ceramic tubes of the type 7077-G-E- 60-17, optimized probe assemblies, and electronic filtering techniques were considered.14 Noise calculations of probes and of complete spectroscopic experiments were a daily routine in the laboratory of Professor Gunthard. This was ¨ normally the last resort for completing a Ph.D. thesis if the constructed spectrometer did not perform properly. However, this taught us more about response theory, Fourier transforms, and noise figures than any working spectrometer would have done. This was the time of the computer of averaged transients, CAT, which helped to improve sensitivity by the coaddition of slow passage spectra.15 At that time we advanced the idea of using one ultraslow passage instead of repeated scanning through the same spectrum. In this way we missed some important facts that became clear to me only after my arrival in the fall of 1963 at Varian Associates in Palo Alto for my postdoctoral years. Under the guidance of Dr. Weston A. Anderson, I started extensive investigations of rapid scan performance conditions based on numerical solutions of the Bloch equations. They revealed the possibility of significantly enhancing the sensitiv￾ity per unit time by rapid and repetitive scanning through the spectrum,16 – 18 facts that were already well known to scientists such as Bitter19 and Jacobsohn and Wangsness.20 However, at that time nobody recognized the possibility of using computers to remove the distortions which the rapid scan introduced into the spectrum. FOURIER TRANSFORM NMR SPECTROSCOPY I remember in the spring of 1964, when the calculations of performance conditions were in full progress, Wes Anderson came to me and mentioned the possibility of applying eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

RICHARD R.ERNST 3 6 1964A ID and a CW spectrum The Fourier trasform of the FID has py titive pul :for the simulta excitation of all nuclea d and using a computer to y Wes Ander evious c idea tes,Palo A C1024 a IBM card puncl The were performed during the re 5). derson was ssful results that surp icc.b al and no e,after tic tape at the .and plotted on Calcom plotter.nobody

RICHARD R. ERNST 3 Figure 4 Dr. Weston A. Anderson and his Little Devil Prayer Wheel which he constructed for multiple channel NMR spectroscopy in 1963 repetitive pulses for the simultaneous excitation of all nuclear resonances and using a computer to analyze the response. I was asked to sign, as a witness, the important notebook pages by Wes Anderson that contained the principles of pulse Fourier spectroscopy. I was not very aware at that time of Wes’s previous work on the Wheel of Fortune (Figure 4); in fact, I never saw it. I do not remember whether Wes showed me at the same time or slightly later the highly important patent application by Russell Varian21 which already contained the basic idea. There was no rf pulse equipment available at Varian at that time as everybody was fully devoted to continuous wave spectroscopy. However, as a result of masterly support by the electronic engineer William Siebert, within two months a proton-pulse spectrometer with 300 W pulse power using a fluorine field/frequency lock without any magnetic field modulation was assembled. The crucial first experiments were performed during the summer months of 1964 while Wes Anderson was on an extensive journey abroad (Figure 5). When he came home, I was able to hand him the first successful results that surprised me as much as him. However, there was no reason to be overenthusiastic and we certainly did not think in terms of a champagne party. When one considers the cumbersome treatment of the data acquired in a time averaging CAT 400 computer, into paper tape, being converted into punched cards at IBM San Jose, then converted to magnetic tape at the Service Bureau Corporation, Palo Alto, Fourier-transformed on an IBM 7090, and plotted on a Calcom plotter, nobody Figure 5 Early experiments performed on 16 September 1964. After a few experiments on benzene, a complicated spin system, 1-bromo-4- fluorobenzene, was also treated on the first day. The figure shows the FID and a CW spectrum. The Fourier transform of the FID has been lost Figure 6 The author in front of the modified DP-60 NMR spec￾trometer on which the first Fourier transform NMR experiments were performed at Varian Associates, Palo Alto, CA, in 1965. The author is acting as a human interface between the time averaging computer C1024 and an IBM card punch could have been convinced by us of a time-saving advantage! Later, we had our own card punch to shorten the data pathway (Figure 6). Nevertheless, we decided to publish the work in the Journal of Chemical Physics. However, we had no success; the paper was rejected twice, being considered too technical and not of sufficient originality. We then submitted the paper to Review of Scientific Instruments on 9 July 1965 where, after further revision, it was finally accepted on 16 September 1965.22 I also discussed the subject at the 6th Experimental NMR Conference in Pittsburgh, 25–27 February 1965. In eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

4 RICHARD R ERNST autom an ac was deve loped XL or the worke ou e of little originality ion of sfo▣ RETURN TO THE HOMELAND in 171. m-only spectrometer H onto the market in t at the Un and the cmade progess dimcull.had to suprie anll HETERONUCLEAR NOISE DECOUPLING swave oper pos mortem d to rate years fro 11968 eared to be a goal to m n a flourine-pro The ne binary random t none with an epoch-making breakthrough nce. ospolhrizationhclbato urther and other 的 ered much later using composite pulse sequences. COMPUTERIZED SPECTROSCOPY lowly emergi Fin opy. and I stu ved.and I i aced it wit油the hel uch a eet ter,the A-60.This prohib ed the use of puls ENC.2 March tation at the 8t of pulse tic Re in007 by John WileySons,Ld

4 RICHARD R. ERNST general the response was not overwhelming, except from a few people with foresight like Oleg Jardetzky. The Varian management was also not too excited. With little enthusiasm, an accessory was developed for the HR-100 spectrometer; however, that never performed properly. Even the newly developed XL-100 concept, which was worked out in the following years, was designed with a field-modulation system that prohibited the implementation of pulse Fourier transform spectroscopy. Ultimately, it was the competitive German company Bruker Analytische Messtechnik with Toni Keller and Professor Gunther Laukien which demonstrated and sold ¨ the first properly designed Fourier transform equipment in 1969. With much foresight, they brought the first Fourier￾transform-only spectrometer HX 90 onto the market in 1971. HETERONUCLEAR NOISE DECOUPLING Being out of better ideas for the time being, it was tempting in May 1965 to try some of the ideas left over from my thesis,14 thus justifying post mortem my otherwise spoiled best years. Broadband spin decoupling indeed appeared to be a worthwhile goal to me, especially for heteronuclear spin systems. The first experiments concentrated on a flourine–proton system. The necessary binary random noise was taken initially from the even/odd character of the last digits in the Palo Alto telephone directory, modulated onto the radiofrequency carrier, and applied to the protons, observing the fluorine resonance at the same time.23 This led to the initial pseudonym phone-book resonance. Only later was I informed by R. Whitehorn (Varian Associates) that binary noise could be generated in a more convenient and predictable manner by shift register generators24 that were used from September 1965 onwards. Numerous further modulation schemes such as repetitive 180 ◦ and other pulses were used and it was found that primarily the spectral properties had a significant effect, but otherwise the type of sequence was immaterial. There was no indication whatsoever in my experiments for the dramatic improvement that was discovered much later by Malcolm Levitt and Ray Freeman25 using composite pulse sequences. COMPUTERIZED SPECTROSCOPY Until 1966, Varian Associates did not possess even a single computer, and all the Fourier NMR experiments I undertook at Varian used off-company data processing. Finally, in October 1966, the first PDP8 computer with 4096 words of 12-bit memory arrived, and I interfaced it with the help of William Siebert to the most widely used routine NMR spectrometer, the A-60. This prohibited the use of pulse Fourier transform experiments for which the A-60 is unsuited by design. Numerous other applications were programmed and tried in a rapid sequence in view of a presentation at the 8th ENC, 2–4 March 1967, in Pittsburgh. The experiments included signal averaging with automatic drift compensation by searching for the TMS line, resolution enhancement by convolution, spectra analysis by multiplet identification, coding of spectra for a subsequent automatic library search, automatic 2D shim mapping, and automatic shimming by use of the simplex search algorithm. Except for the automatic shimming procedure,26 this work was not published at that time as it was felt to be of little originality. A later account can be found in Ref. 27. RETURN TO THE HOMELAND My return to Switzerland in the spring of 1968 proved to be a scientific disadvantage. Unsuitable equipment and the lack of support at the Laboratorium fur Physikalische Chemie, ¨ ETH Zurich, made progress difficult. I had to supervise an ill- ¨ suited Varian 220 MHz spectrometer that was strictly limited to continuous wave operation without a field/frequency lock system. With a streetcar line in the neigborhood, this turned out to be a disaster. Despite a homemade lock system, the spectrometer never performed satisfactorily. Scientific output was low, and after two years of struggling I was affected by a nervous breakdown in 1970. Looking back, I am tempted to rate my years from 1968 to 1974 as the dark Middle Ages after the productive and inspiring classical years in Palo Alto. We tried numerous new approaches, but none with an epoch-making breakthrough. (Personally, I became interested in the mysterious and fascinating Tibetan art during this time period.) With my first graduate student, Thomas W. Baumann (thesis 1969–74), we ventured on our first exploratory excursion into solid state NMR, constructing a 1.5-T solid state spectrometer. We devoted much time on cross polarization in the laboratory frame (35Cl → 1H) and in the rotating frame (1H → 13C). Our time-consuming solid state activities became more exciting in 1973 with the work of Luciano Muller which will be described ¨ later. My second graduate student, Dieter Welti (1970–76), together with Max Linder, explored the use of paramagnetic shift and relaxation reagents in NMR, using borneol and 1-propanol as model compounds. The question of accurate structure determinations using the multifaceted shift and relaxation effects was our primary interest.28 Just to keep our obstinate HR-220 Varian spectrometer busy, we started a series of investigations on simple molecules dissolved in a nematic phase. After the study of a few four-ring compounds by Christian Oertli, we explored, together with Alexander Frey, the distortion of cubic molecules by liquid crystalline solvents.29 Again the determination of molecular structures was our main interest. I was still interested in the slowly emerging Fourier trans￾form spectroscopy, and I studied some subtle effects of pulse excitation such as the equivalence of slow passage and pulse spectroscopy,30 saturation effects in Fourier spectroscopy, together with my first postdoc Robert E. Morgan,31 and the causality principle in Fourier spectroscopy, together with my third graduate student Enrico Bartholdi.32 Motivated by the notorious field instability in Zurich, we also proposed at that ¨ time the usage of difference-frequency measurements to avoid the need for a field/frequency lock system.33,34 Another series of studies was devoted to the application of pulse spectroscopy to chemically induced dynamic nuclear eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

RICHARD R.ERNST 5 9 This was the e thesis of Stefa STOCHASTIC RESONANCE n,in Jur nd m sample e皮 ed stochastic n nce fo 1971- a ed by Kurt A.M nd M Experiments have orrelation func nmdidime sion ion wo-pu spectroscopy THE DAWN OF TWO-DIMENSIONAL SPECTROSCOPY xpriments were performed nely fortunate ev ublished. we thought that our computin a storage and w ing We hac s a ben iting for.I onhis subiect which uaelyvd at ic o omp NC) The n-reconstrc ion method using ctic fi ients in com pulse into account.He ce This led to the nt of Fourier zeu 18 1975.and issued on lanuary 24 1978 As I was acting Encyclopedia of Magnetic Resonance in 2007 by John Wiley Sons,Ltd

RICHARD R. ERNST 5 polarization (CIDNP). It appeared to us very natural to investi￾gate time-dependent phenomena with time-resolved measure￾ment techniques. This was the subject of the thesis of Stefan Schaublin (1971–76). For a short period he was supported ¨ by Alexander Wokaun.35,36 This work also led to the recog￾nition of the important intensity problems when investigat￾ing nonequilibrium populations by pulse experiments.37 Later, these studies were extended to stopped flow experiments by Rene O. K ´ uhne and Thierry Schaffhauser. ¨ 38 STOCHASTIC RESONANCE Pursuing my old love and motivated by a correspondence with Wes Anderson, in June 1968 I started the first attempts to compute and measure NMR spectra via stochastic noise excitation of the sample and by Fourier transforming the cross-correlation function that relates input and output noise.39 The first experiments already used shift register sequences as sources of binary pseudorandom noise.24 At virtually the same time, Reinhold Kaiser also proposed stochastic resonance for recording spectra, but using Gaussian noise to excite the spin system.40 Subsequently, the theory of stochastic resonance was worked out in great detail in the thesis of Enrico Bartholdi (1971–75) and by Alexander Wokaun.41 Experiments have been performed by Kurt A. Meier and Marco Genoni. Although the properties of higher correlation functions were well known to us at that time, we did not recognize that they contain multidimensional information that could be used and displayed in the form of 2D spectra. This became obvious to us however, in the course of the early calculations of Enrico Bartholdi in 1972 in the context of two-pulse 2D Fourier spectroscopy.42 THE DAWN OF TWO-DIMENSIONAL SPECTROSCOPY The participation of Thomas W. Bauman at the AMPERE Summer School in Basko Polje, Yugoslavia, in September 1971 was an extremely fortunate event. Being a meticulous scientist, he brought home a careful script of the lectures, among them one by Jean Jeener that attracted my attention immediately: a simple two-pulse experiment that produced revealing 2D spectra by 2D Fourier transformation of a 2D set of response signals (Figure 7 and 8). This was exactly the technique I had been waiting for. I had been thinking for some time about systematic computer￾controlled double resonance experiments, but appreciated the complexity of the resulting 2D spectra should they follow the shape of the famous Anderson–Freeman plots.43 The Jeener two-pulse experiment appeared not to have this disadvantage. Enrico Bartholdi, who had just started his graduate stud￾ies, was willing to perform some analytical calculations on two-pulse experiments, taking relaxation into account. He confirmed the principal usefulness of the experiment and studied its features in detail. We did not plan to perform Figure 7 Professor Jean Jeener, the inventor of two–dimensional Fourier transform NMR Figure 8 Thomas Baumann (right) and the author trying to understand the notes of the AMPERE Summer School on the two-pulse experiment proposed by Jean Jeener in 1971. In the background is the modified DP- 60 Varian NMR spectrometer on which the first two-dimensional NMR experiments were performed experiments for two reasons. First we considered 2D spec￾troscopy as Jeener’s property and waited for his results to be published. Second, we thought that our computing equipment, with 16 000 words of memory, was inadequate for two-dimensional data storage and processing. We had some correspondence with Jean Jeener on the experiment in 1973, and he showed us a rough draft of an unfinished paper on this subject which, unfortunately, was never pub￾lished. In 1974, I attended the 15th Experimental NMR Confer￾ence (ENC) and heard on 30 April 1974 an exciting lecture by Paul Lauterbur entitled Zeugmatography–Spatial Resolu￾tion of NMR Signals. He discussed the attainment of images by the projection–reconstruction method using continuous wave experiments. I immediately recognized that time domain experiments with switched magnetic field gradients in com￾plete analogy to 2D spectroscopy would be the method of choice. This led to the concept of Fourier zeugmatography or Fourier imaging with a patent filed orginally on March 18, 1975, and issued on January 24, 1978. As I was acting eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

6 RICHARD R ERNST 1.12-TRICHOROETHANE f 1.1.2-trichl ed in 8h olute value Figure 10 One of the very first 2D Fou shows two strong diagona 4 Bruker SPX4-100 p d by Anil scopic work of Walter P.Aue 9:the detection of mul ember 1974.which weor no Malle his tpe 2D and of w my own soft anD16000 ple qua for s（1974-78)H performed for the ers c 9ip equipped with e10 arly 5 in.m with one:Ray Freeman and his in our research p in Zurich) ced the and merit m freed from our redit for the initial phase in the development of 2D NMR ion We had The secpy far sonance in 1978 that produce re like of 2D exchange spe wa in fact the first tha scientists it他the small molecule towhich we were limited in o PLAYING WITH A NEW TOY eak pe We were indeed fascinated by the wealth of new pos this imp an vere worked an Macura,Yong-Ren Huang,and D cvclopedia of Magnetic Resom cn007by John WileySons,Ld

6 RICHARD R. ERNST Figure 9 Early 2D spectrum of 1,1,2-trichloroethane recorded on 10 September 1974 with the Jeener two-pulse sequence on the spectrometer illustrated in 8. The absolute value spectrum using letter￾coded intensities in a contour representation shows two strong diagonal peaks, two cross peaks, and two axial peaks at that time as a consultant, I assigned it to Varian Asso￾ciates. I was now sufficiently motivated to perform 2D spectro￾scopic and imaging experiments. At the same time, I was also asked by Kurt Wuthrich to present some introductory remarks, ¨ possibly on our own work, at the VIth International Confer￾ence on Magnetic Resonance in Biological Systems, Kander￾steg, 16–21 September 1974, which we organized together with Joachim Seelig. As I did not have anything biological to talk about, I decided to perform rapidly the first 2D and Fourier imaging experiments, both with biological applications in view. I undertook the initial 2D experiments myself on a modified Varian DA-60 spectrometer equipped with a Varian 620i computer with 16 000 memory words (16 bits) using my own software (Figure 9). Using a teletype for letter-coded contour maps, I obtained the first halfway decent spectra on 1 July, 1974. The Fourier imaging experiments were performed together with Anil Kumar on a Bruker SPX4-100 spectrome￾ter equipped with a Varian 620/L-100 computer with 12 000 memory words, using the x- and y-shim coils of the Varian 15 in. magnet for the switched field gradients44,45 (Figure 10). It was little wonder that my rapidly concocted contribution was rated as premature at the Kandersteg conference! Some￾times, however, even prematurely born children survive and excel. This was indeed the end of my dark middle ages. We had been freed from our one-dimensional narrow-mindedness and had again room to move in new dimensions. Modern times had started without being noticed at that instant. We had some difficulty in appreciating the future as far as these new horizons were concerned, but we very much enjoyed playing with a novel toy that produced fascinating 2D plots and images. We felt at this moment more like graphic artists and playboys than scientists. PLAYING WITH A NEW TOY We were indeed fascinated by the wealth of new pos￾sibilities offered by the 2D spectroscopy concept. Numer￾ous homonuclear schemes were explored in the thesis Figure 10 One of the very first 2D Fourier images of two coaxial water-filled sample tubes, recorded by Anil Kumar on 10 July 1974 on a modified Bruker SPX4-100 spectrometer. The plot uses letter-coded intensities work of Walter P. Aue (1974–79): the detection of mul￾tiple quantum transitions,42 homonuclear broadband decou￾pling and J -resolved NMR spectroscopy together with Jiri Karhan,46 and phase separation techniques together with Peter Bachmann and Luciano Muller. ¨ 47 Heteronuclear exper￾iments were performed by Luciano Muller in his thesis ¨ work (1973–77), partially together with Anil Kumar.48 – 51 Andrew Maudsley showed for the first time the possibil￾ity of indirect detection of low-γ nuclei,52,53 and Alexander Wokaun expanded the techniques and applications of multi￾ple quantum spectroscopy54 – 57 in his thesis (1974–78). He showed for the first time the possibility of phase cycling for the selection of individual orders of multiple quantum coherences,55 and demonstrated the usefulness of multiple quantum relaxation.56 Competition was not yet a real problem during these early years. Few scientists believed in the future of 2D spectroscopy—with one exception: Ray Freeman and his extremely talented graduate student Geoffrey Bodenhausen (who did his earlier studies in our research group in Zurich). ¨ In the design of powerful heteronuclear 2D experiments, in particular, they were very strong,58 – 60 and merit much of the credit for the initial phase in the development of 2D NMR spectroscopy. The second major 2D spectroscopy technique, 2D exchange spectroscopy, originated from a discussion with Jean Jeener at the Gordon Conference on Magnetic Resonance in 1978. He confessed on this occasion that the three-pulse scheme of 2D exchange spectroscopy was in fact the first that came to his mind before proposing the two-pulse experiment at the AMPERE Summer School in Basko Polje in 1971. With the small molecules to which we were limited in our laboratory, it proved difficult to detect cross-relaxation cross peaks, but Beat H. Meier found it quite easy to observe chemical exchange cross peaks.61,62 The special features of this important experiment were worked out subsequently in great detail by Slobodan Macura, Yong-Ren Huang, and Dieter Suter.63 – 68 eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

RICHARD R.ERNST 7 2 mas EXPLORING THE WEALTH OF MODIFIED 2D TECHNIQUES While the previous devel nt of 2D spectro oy had Chri His work in this area is sum d in 2D spectr and (ii)to decrea their complexity.I ha 03 and 104 tisaowpnnghatMalianaLleitalolkeninZneh zer an to allow their manua me more an orga ntr Zolta y Ge with Gunthe es Bcat U. ment on al the of ar I-deserved cross references to for th d b COLLABORATION WITH KURT WUTHRICH AND rk in our THE APPLICATIONS F 2D SPECTROSCOPY TO MOLECULAR BIOLOGY tant work of Axel Bothner-By ESY 1975.the high-field NMR center with tfects by Cle th a of 61 this point for both an in196 Accordion spectro excha ould be joint larger simplif progr yama,a brillia s the 05 of joint projec rted by ETH Zr n Malcolm H.Lev er,d d ththe late vith Luk this ord d Kogler. m ade a NMR selpcctra by 2D ensen,are J-filters ctra were re rded in the spin adays clo pe me by res rictin the cle is 10.100704700 Encyclopedia of Magnetic Resonance in 2007 by John Wiley Sons,Ltd

RICHARD R. ERNST 7 Also, at the same time several solid state 2D experiments were investigated, but this work will be summarized later. EXPLORING THE WEALTH OF MODIFIED 2D TECHNIQUES While the previous development of 2D spectroscopy had been more or less sequential, the following period rather resembled little Max in Paradise who does not know which fruit to pick and eat first. Development during this time had, in essence, two goals: (i) to increase the information content of 2D spectra; and (ii) to decrease their complexity. I had little personal impact on these developments. A group of extraordinarily creative co-workers determined the direction of our future research efforts. I became more an organizer and trouble shooter. The first step in increasing the information content was the introduction of a relayed homonuclear coherence transfer step by Geoffrey Bodenhausen together with Gunther Eich ¨ 69,70 where a two (or more) pulse sequence leads to a multistep coherence transfer, important for the elucidation of crowded NMR spectra. Similar heteronuclear procedures were proposed by Philip H. Bolton almost simultaneously.71 The next development was total correlation spectroscopy (TOCSY) in the rotating frame tested for the first time by Lukas Braunschweiler.72 Here all the resonances of a coupled spin system are connected by cross peaks. This allows the easy recognition of complete families of coupled spins. Subsequently, considerable work in our group has been devoted to rotating frame experiments, as well as extend￾ing the important work of Axel Bothner-By on ROESY.73 Christian Griesinger has introduced procedures for the elim￾ination of frequency-offset effects74 and of cross-relaxation effects by Clean TOCSY.75 He introduced the invariant trajec￾tory approach for the description of radiofrequency-perturbed experiments.76 Jacques Briand further improved Clean exper￾iments by the introduction of Clean CITY,77 and Rafael Bruschweiler suggested a novel cross-relaxation measurement ¨ technique called T-ROESY.78 Another neat experiment, called Accordion spectroscopy and worked out by Geoffrey Bodenhausen,79 increases the information content of 2D spectra by incorporating exchange￾type information into the 2D peak shape. The resulting spectra effectively represent projected 3D spectra. An even larger class of experiments allows the simplifi- cation of overcrowded 2D spectra for facilitating their anal￾ysis. The most successful and general type of simplification scheme is multiple quantum filtering, introduced by Ole W. Sørensen80,81 with contributions from Malcolm H. Levitt.82,83 The techniques of multiple quantum spectroscopy84 and coherence-transfer-pathway selection85 are related. In this context Geoffrey Bodenhausen, together with Lukas Braun￾schweiler and Herbert Kogler, have made a very significant contribution. Further filtering procedures, mainly due to Ole W. Sørensen, are J -filters86 and Z -filters.87 The names of Christian Griesinger and Ole W. Sørensen are nowadays closely connected with exclusive correlation spectroscopy or ECOSY,88 – 90 a technique that leads to simplified multiplet patterns in 2D spectra and allows ready determination of J coupling constants. The ultimate forms of ECOSY are bilinear and planar COSY experiments, introduced by Thomas Schulte-Herbruggen, Zoltan L. M ¨ adi, and Ole ´ W. Sørensen.91 In this context, the symmetry features of 2D spectra, worked out again in contributions by Ole W. Sørensen and Christian Griesinger together with Claudius Gemperle, Serge Boentges, and Beat U. Meier,92 – 94 are important. A very drastic simplification of 2D (or 1D) is achieved by spin topology filtration, investigated by Malcolm H. Levitt and Christian Radloff.95 – 99 Here, the coupling network topology is used as a criterion for peak rejection. In parallel to these predominantly homonuclear experiments, heteronuclear experiments have also been worked out by Ole W. Sørensen.81,100 – 102 His work in this area is summarized in Refs. 103 and 104. It is not surprising that Malcolm H. Levitt also left in Zurich ¨ some composite pulse traces.105 – 108 Instead of simplifying 2D spectra to allow their manual analysis, it is often possible to devise computer routines for their automatic analysis. Major contributions in this field have been made by Geoffrey Bodenhausen, Beat U. Meier, Zoltan L. Madi, and Serge Boentges. ´ 109 – 113 It is not possible to mention all the contributions of an astonishingly creative group of enthusiastic co-workers here nor is it possible to make well-deserved cross references to other highly productive research groups. COLLABORATION WITH KURT WUTHRICH AND ¨ THE APPLICATIONS OF 2D SPECTROSCOPY TO MOLECULAR BIOLOGY At the end of 1975, the high-field NMR center with the Varian HR-220 spectrometer under our supervision was replaced by a new high-field NMR center with a Bruker HMS- 360 spectrometer under the supervision of Kurt Wuthrich. It ¨ was desirable at this point for both sides to continue and intensify the collaboration that had existed in a loose form since the inauguration of the high-field NMR center in 1969. It was easy to select 2D spectroscopy as the subject of mutual interest, as it became clear that its application to molecular biology could be fruitful if only the enormous technical difficulties could be solved. In December 1976, a joint project was started with Peter Bachmann, a very experienced spectroscopist and computer programmer, and Kuniaki Nagayama, a brilliant young Japanese scientist. This was the beginning of an extremely fruitful series of joint projects lasting for 101/2 years. Initially, the projects were supported by ETH Zurich. ¨ However, due to a financial bottleneck in the school, the later phases were financed by Spectrospin AG and the Kommission zur Forderung der wissenschaftlichen Forschung. ¨ The initial studies concentrated on the simplification of biomolecular NMR spectra by 2D J -resolved NMR,114 – 117 and by the use of selective spin decoupling.118,119 The first correlation spectra were recorded in the spin-echo-correlated (SECSY) mode to save performance time and computer memory by restricting the ω1 domain.120 A major breakthrough in 1980 was achieved by Anil Kumar, who had joined the project during his second stay in Zurich. ¨ eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

8 RICHARD R ERNST He demonstrated that cross relaxation in macr been ACTIVITIES IN SOLID STATE NMR Togethe nd known from liquid-state NMR Solids ha urther compan ID NOE ts to at Slobodan Ma lucky.A elated.butno d sign was o th and sep of cross peaks ec l the success of 2D an out the rules for the context was the oricn mo contributed to more applied projects. ces by Doug Burum and Max Linder EXTENSION TO THREE DIMENSIONS d by Pablo HR of the high-field NMR i e n tun h d.Ho ective 3D experiments are to exp the me groups.in particular by R.Kaptein and A.Bax the tionalaganiccontcdorbisternthiotectrecme)tniodid CONFORMATIONAL DYNAMICS OF BIOMOLECULES inge crystals,and secondly thei cctra We have dynami ylic din and the retical co deration spin order tra ogen b an he h onc Re in 2007 by John Wiley Sons,L.td D0-10100D070470090emh05

8 RICHARD R. ERNST He demonstrated that cross relaxation in macromolecules can be detected surprisingly well with the experiment presently known under the acronym NOESY.121 This is the 2D version of the 1D transient NOE experiment that Gordon and Wuthrich had previously introduced for studies of proteins. ¨ 122 It is the same experiment that had earlier been used by Jean Jeener, Beat H. Meier, and Peter Bachmann for the exploration of chemical exchange networks.61,62 Together with the correlation experiment in the original form proposed by Jeener and known as COSY, Kurt Wuthrich, Gerhard Wagner, ¨ and co-workers had all the required tools in their hands in 1980 to develop their ingenious highly successful sequential assignment procedure for biopolymers,123 a task they had already pursued previously using more cumbersome one￾dimensional NMR techniques.124 Further work undertaken in this series of joint projects concerned quantitative comparisons of 1D and 2D NOE measurements,125 strong coupling effects,126 an extension of previous 1D NOE build-up rate studies122,127 to 2D NMR,128 triangular multiplication,129 and symmetrization.130 The successor to Anil Kumar, Slobodan Macura, was an expert on 2D exchange studies and contributed significantly to the suppression and separation of J cross peaks in NOESY spectra.131,132 Further important improvements by multiple quantum filtering and multiple quantum spectroscopy were achieved by Mark Rance.87, 133 – 136 Norbert Muller worked ¨ out the rules for the appearance of forbidden relaxation￾induced cross peaks in 2D spectra,137,138 and of cross peaks in multiple quantum filtered spectra.139 Finally, Michael H. Frey contributed to more applied projects.140,141 EXTENSION TO THREE DIMENSIONS For a long time, 3D spectroscopy appeared to be out of reach because of performance–time and storage–space limitations. The first attempts by Christian Griesinger and Ole W. Sørensen in this direction, partially in collaboration with the research group of G. Marius Clore and Angela M. Gronenborn, therefore used selective excitation techniques.142 – 144 Later, however, it was found that nonselective 3D experiments are also quite feasible.145 This parallels the work by other research groups, in particular by R. Kaptein and A. Bax. CONFORMATIONAL DYNAMICS OF BIOMOLECULES During the course of the past five years, our interest has shifted away from the design of pulse sequences for the manipulation of multidimensional spectra. We have become more interested in the study of the intramolecular dynamics of biomolecules. This is a field where much progress is still needed before the motional modes relevant for biological activity can be sufficiently well characterized. To date, much of our work has concentrated on the cyclic decapeptide antamanide, and relevant contributions have been made by Christian Griesinger, Zoltan L. Madi, Rafael Br ´ uschweiler, ¨ Martin Blackledge, Jurgen Schmidt, Matthias Ernst, Ping Xu, ¨ and Tobias Bremi in collaboration with the research groups of Martin Karplus and Wilfred van Gunsteren.146 – 152 ACTIVITIES IN SOLID STATE NMR Since my return from California in 1968, our involvement in solid state NMR has been considerable. I often mentioned that although about 70% of our efforts went into solids about 70% of our results came from liquid-state NMR. Solids have proved to be harder and more brittle in our hands than liquids! After some initial exploratory studies by Thomas Baumann from 1969 to 1974 which have been mentioned earlier, Luciano Muller together with Anil Kumar and Thomas ¨ Baumann produced results in 1974 for our very first Physical Review Letter, 153 describing a particularly neat example of transient oscillations in cross-polarization experiments together with a simple explanation.154 We have not always been so lucky. A somewhat related, but not uninteresting paper on cross polarization with a pulsed radiofrequency field, received a devastating comment from a referee and was never published. After the success of 2D spectroscopy in liquids, and following some very early work by the research group of John S. Waugh,155,156 we also tried to explore possibilities in liquid crystals157 and in solids.158 Perhaps the most relevant contribution in this context was the orientation of tensorial interactions based on ridge patterns in 2D powder spectra obtained by Max Linder (thesis 1979–82) and Alfred Hohener. ¨ 158 Taking advantage of the newly developed windowless dipolar decoupling multiple pulse sequences by Doug Burum and Max Linder,159 heteronuclear high-resolution correlation experiments in solids were also explored by Pablo Caravatti, Geoffrey Bodenhausen, and Lukas Braunschweiler.160,161 After the closure of the high-field NMR center in 1975, we converted the HR-220 spectrometer into a solid state 14N apparatus to observe resolved 14N double quantum spectra in the hope of developing applications to biomolecules. This turned out to be more difficult than expected. However, these experiments did allow Peter Brunner and Michael Reinhold to explore the mechanism of cross polarization of double quantum transitions.162,163 The attempts of Thierry Schaffhauser to study the one￾dimensional organic conductor bis(tetrathiotetracene) triiodide by proton and carbon-13 resonance in collaboration with Bruno Hilti of Ciba-Geigy AG also turned out to be more difficult than we had thought.164,165 Firstly, it was difficult to obtain sufficiently large single crystals, and secondly, their conductivity led to disastrous arcing. Two focal points characterize our more recent solid state NMR research under the guidance of Beat H. Meier: hydrogen￾bond dynamics in carboxylic acid dimers,166 – 174 and the investigation of spin diffusion in disordered solids combined with theoretical considerations about spin order transfer.174 – 188 Our interest in the dynamics of hydrogen bonds has been spurred by Federico Graf who joined our group in 1979 after completing a Ph.D. in EPR with Hans H. Gunthard and a ¨ postdoctoral period at IBM San Jose. We wanted to gain more insight into the proton transfer dynamics in a simple double-minimum system and in the contribution of tunneling to eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

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RICHARD R. ERNST 9 eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051

10 RICHARD R.ERNST 2 44 (a)Grou anh of p and m 11 13 Mcier Beat H.14 Ra Mark I5 Kessler.Hors 24 Schulte-Her 15 Annalisa 29 Bach ark 40 R Schick. 5 Xi-Li.W te.Tilo 47 Welti.Dicte Malcolm H.54 Zhang. 55 Baldus.Marc 56 Stockli.Armin 57 Meicr Beat U.58 Suter.Dieter The ex tal NMR an Thank to his and hi efforts H.Meier everal possibilities in h gh his ork of Armin Stck the su 4. es for zero-field re ing the ascinating techniqu I order in Cara CONCLUSIONS vablecew To be honest,we hav made a living not only by borrowing was logical.However.in one-sided view of NMR r e er co c Res

10 RICHARD R. ERNST 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Figure 11 (a) Group photograph of present and many former co-workers at the Nobel Prize Symposium, March 1992, Centro Stefano Francini, Ascona, Switzerland. The persons, numbered in sketch (b), can be identified from the following list. 1 Nagayama, Kuniaki 2 Wokaun, Alexander 3 Jeener, Jean; Prof. (guest) 4 Ernst, Richard R. 5 Robyr, Pierre 6 Aue, Walter 7 Macura, Slobodan 8 Blackledge, Martin 9 Muller, Ir ¨ ene 10 ` Klein, Jeannette 11 Bodenhausen, Geoffrey 12 Schaffhauser, Thierry 13 Meier, Beat H. 14 Rance, Mark 15 Kessler, Horst; Prof. (guest) 16 Muller, ¨ Luciano 17 Griesinger, Christian 18 Gemperle, Claudius 19 Schweiger, Arthur 20 Sierra, Gustavo 21 Bruschweiler, Rafael 22 H ¨ ohener, Alfred 23 ¨ Madi, Zoltan 24 Schulte-Herbr ´ uggen, Thomas 25 Kumar, Anil 26 Reinhold, Michael 27 Signer, Paul 28 Pastore, Annalisa 29 Bachmann, Peter ¨ 30 Schaublin, Stefan 31 Wacker, Thomas 32 Linder, Max 33 Sebbach, J ¨ ochen 34 Kreis, Roland 35 Counsell, Christopher 36 Schmidt, Jurgen 37 ¨ Boentges, Serge 38 Baumann, Thomas 39 McCoy, Mark 40 Radloff, Christian 41 Schick, Martin 42 Kogler, Herbert 43 Xu, Ping 44 Muri, Marcel ¨ 45 Xi-Li, Wu 46 Levante, Tilo 47 Welti, Dieter 48 Forrer, Jorg 49 Karhan, Jiri 50 Sørensen, Ole W. 51 M ¨ uller, Norbert 52 Sch ¨ onenberger, Christian ¨ 53 Levitt, Malcolm H. 54 Zhang, Shanmin 55 Baldus, Marc 56 Stockli, Armin 57 Meier, Beat U. 58 Suter, Dieter ¨ the dissipative transfer. The experimental NMR and neutron￾diffraction measurements are associated with Beat H. Meier, first in his thesis work from 1978–84;166 – 169 , 189 and later through his supervision of the work of Armin Stockli ¨ 170,172 and Pierre Robyr.174 Of great importance to the success of this project was the support given by Rolf Meyer,171 – 173 one of the unrivalled experts in the computation and analysis of intramolecular dynamics,190 as well as the support by Albert Furrer, Peter Fischer and their team regarding the use of neutron diffraction.167 – 170 Hydrogen-bond dynamics turned out to be a critical test case for our understanding of nuclear spin relaxation in solids. The transfer of spin order through the network of dipolar interactions appeared to us to be one of the most important, interesting, and useful features of NMR in solids. Being a typical many-body problem, it is difficult to treat theoreti￾cally. Attempts in this direction have been made by Dieter Suter175,178 and Malcolm H. Levitt179 in our group. On the other hand, spin diffusion has turned out to be an ideal tool for studying local order in macroscopically disordered mate￾rials, such as polymers, polymer blends, and glasses. After some initial demonstration examples treated by Pablo Cara￾vatti, Janos A. Deli, and Geoffrey Bodenhausen,176 the work of Pablo Caravatti (thesis 1981–86) concentrated on polymer blends investigated by proton spin diffusion177,191 in collabo￾ration with the polymer expert Peter Neuenschwander. The limited achievable resolution of proton resonance was soon recognized to be a grave drawback, and the desire to use carbon-13 instead was only logical. However, in natural abundance 13C spin diffusion can be exceedingly slow and isotopic enrichment is not always possible. This motivated Beat H. Meier to start an extensive program on techniques to accelerate spin diffusion for dilute spin systems. Thanks to his and his co-workers’ efforts, we have today several possibilities in hand to increase the spin-diffusion rate, such as rotor-driven spin diffusion as developed by Marco G. Colombo and Thomas Burmeister,180,181 radiofrequency￾driven spin diffusion as explored by Pierre Robyr,182 and the use of xenon-129 probes as investigated by Marco Tomaselli.186 The question of the reversibility of spin-diffusion dynam￾ics has been addressed by Shanmin Zhang.183 He has also proposed indirect measurement techniques for spin diffusion.184,185 This work on spin dynamics has been well summarized and extended in a recent review by Beat H. Meier (in press). Finally, a short but exciting excursion in the lowlands of zero-field resonance should also be mentioned. Following the footsteps of Alex Pines and his team,192,193 Roland Kreis and Albert Thomas have further explored the possibilities of this fascinating technique.194,195 CONCLUSIONS To be honest, we have made a living not only by borrowing clever ideas. Particularly in the later phases, numerous new concepts have been created in-house by a number of incredibly gifted co-workers. Thus our research group has been lucky in two respects, the influx of brilliant ideas and of even more brilliant individuals (Figure 11). This essay certainly provides a one–sided view of NMR history. Because of lack of space, it is impossible to do justice to all former co-workers and even less to other research groups. eMagRes, Online © 2007 John Wiley & Sons, Ltd. This article is © 2007 John Wiley & Sons, Ltd. This article was previously published in the Encyclopedia of Magnetic Resonance in 2007 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470034590.emrhp0051