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“A Liking for the Truth: Truth and Controversy in the Work of Linus Pauling.”

February 28, 2001

Video: Keynote Address: “Timing in the Invisible” Ahmed Zewail

1:22:48 - Abstract | Biography | More Videos from Session 1


John Westall: It gives me great pleasure this morning to introduce the lead speaker for today's symposium, Professor Ahmed Zewail, Linus Pauling Professor of Chemical Physics and Professor of Physics at the California Institute of Technology, and Nobel Laureate in Chemistry in 1999.

No one can be more appropriate to lead off a symposium on Linus Pauling than Ahmed Zewail. While Pauling pioneered the understanding of the structure of the chemical bond, and won a Nobel Prize for that, half a century later Zewail has pioneered the understanding of the dynamics of the chemical bond, and won a Nobel Prize for that. At the risk of oversimplification, let me try to convey to you in just a few words the excitement Zewail's work has caused in the last decade of the 20th century, just as I imagine Pauling's work did in the earlier part of the 20th century.

Early work on bonding and structure can be seen in the early part of the 19th century when Berzelius provided a fairly satisfactory explanation of what has become known today as ionic bonding. By the early part of the 20th century, G.N. Lewis had provided the early framework for covalent bonding. When Pauling got involved in the late ‘20s and early ‘30s, there were still large questions unanswered about molecular geometry and the relation of chemical bonding to the emerging atomic theory. Not until Pauling's groundbreaking papers on the nature of the chemical bond in 1931 did the world see how the nature of the structure of molecules could be understood from the ground up with geometry consistent with the fundamental atomic theory.

Pauling's success was based on his skill as an experimentalist in the field of x-ray crystallography, his mastery of theory, and his ability to make the appropriate approximation at the appropriate time. A similar evolution and groundbreaking event can be seen in our understanding of our dynamics of the chemical bond. Dynamics encompasses vibrational motions that make or break the chemical bond. Dynamics is at the heart of chemical reactivity, and at the heart of chemistry itself. By the end of the 19th century, Arrhenius had related chemical reaction rates to temperature. Whereas Arrhenius had considered ensembles of molecules, in the 1930s it was Eyring and Polanyi who devised a transition state theory - that is, a state midway between reactants and products, and on a time scale related to the vibrations of the molecules. This time scale is on the order of 10 to 100 femtoseconds, and that is a very, very short time. A femtosecond is to a second as a second is to about 30 million years. [3:56]

For the rest of the 20th century, the world worked with this theory of Eyring, but no one ever dreamed of actually trying to observe one of these transition states at such a very short time scale. But that is exactly what Zewail set out to do, to observe the transition state and, in an extraordinary set of experiments in the late 1980s, he succeeded. By using an ingenious combination of experimental technology, theory, and appropriate approximations, he developed what amounts to a high speed camera to image molecules at the femtoscale time scale of chemical reactions, and was actually able to view chemical bonds as they were breaking.

The impact of this work has been tremendous. Rudolph Marcus, a Nobel Prize-winner from the early 1990s, has said of Zewail: "Zewail's work has fundamentally changed the way scientists view chemical dynamics. The study of chemical, physical, and biological events that occur on the femtosecond time scale is the ultimate achievement of over a century of effort by mankind, since Arrhenius, to view dynamics of the chemical bond as it actually unfolds in real time."

Ahmed Zewail is currently Linus Pauling Professor of Chemistry and Professor of Physics at the California Institute of Technology, and Director of the National Science Foundation Laboratory for molecular science. He received his B.S. and M.S. degrees from Alexandria University in Egypt, and his Ph.D. from the University of Pennsylvania. He was appointed to the faculty of Caltech in 1976, and in 1990 was appointed Linus Pauling Chair at the Institute. Professor Zewail has numerous honorary degrees from all over the world - he is a member of several national academies of science, he has won top awards from national chemistry and physics organizations, only one of which I'll mention, the 1997 Linus Pauling Award from the Northwest sections of the American Chemical Society, which was awarded in Portland. [6:39]

Pauling's work culminated in the Nobel Prize for chemistry in 1954 with the citation for his research into the nature of the chemical bond and its application for the elucidation of the structure of complex substances. Zewail won the Nobel Prize in chemistry in 1999 with the citation for his studies on the transition states of chemical reactions using femtosecond spectroscopy. It is now my great pleasure to introduce for today's keynote lecture Professor Ahmed Zewail. [7:20]

Ahmed Zewail: It's a great pleasure to be here and to be part of this wonderful centennial. In fact, I think with what you've heard from John I should really sit down now, as you have the whole story of why I'm going to talk today. It's really very special to me, because I do have a very special relationship to Linus Pauling, not only that I sit in his chair at Caltech, but for a variety of reasons. As a matter of fact, I fly tomorrow morning from here because at Caltech we also are celebrating the centennial of Linus Pauling, and I do chair the session in the morning.

Everybody knew about Pauling, and everybody knew about Pauling's achievements, but I think, as Steve said, there's something about Pauling in terms of his personality and his way of doing things that people really don't know about. It comes out in the biographies much better, but from my daughters to people I have seen at Caltech who are in the late stage of their lives, who just get so excited when they meet Linus Pauling. He was a fair man, a very decent human being, and the word I use around our house, he was a very civilized human being. When you sit with Linus, you can talk about the world, and you can enjoy talking to him about the world, but I always find in him civility and decency.

His scientific contributions are very well known, but I would like to make a link between some of the work that Pauling has achieved in chemistry and biology. It is appropriate to tell you that I didn't know of Pauling when I arrived at Caltech, all that I knew was his name; I arrived at Caltech in 1974. But this is one point that I want to touch on, especially since we have two historians with us today who wrote about the biography of Linus; that's his relation to Caltech. When I arrived in 1974, there were rumors around the campus that Linus was not too happy about his departure from Caltech, and of the incident that took place. Things get messed up in the public press a lot and people say things that are not really true, because I dug into some of the historical minutes of the faculty and what Lee DuBridge said. But as a young assistant professor I didn't know any better so I thought it just didn't make any sense, that Pauling, who really was and still is a giant in chemistry, was not visiting Caltech. I was fortunate to be tenured very shortly at Caltech, when I became part of the establishment, so I thought we should do something about it.

And so, I had the great honor to chair and to organize…I like this photo of Linus, actually, giving a lecture at Caltech; this was February 28, 1986, and that was his 85th birthday. I thought that this was a great occasion to bring Linus to campus. He came back and was just so excited; Linus Jr. was with us, and could see his father speaking from the heart. I gave him the stage in the evening to say whatever he wanted to say about Caltech, and he did give it to us. It was just a very special occasion, and I also organized the 90th birthday for Linus at Caltech, and I think if Linus did not come back to Caltech to share his great moments, it would have been a mistake in the history of Caltech and science. I even crowned him the Pharaoh of Chemistry, and I believe that he loved this picture. I think it's here, isn't it? It cost me about $500 to do this, because I had to go to Hollywood and try to fit his face into one of Ramses II.

If you want to learn about all of this, I also edited a book on Linus called The Chemical Bond: Structure and Dynamics, and that is really the focus of my lecture today. I want to take you from the wonderful and important era, which Jack Dunitz will be talking to you about, of structures that are static, meaning there is no way of looking at the movement of the atoms in these structures, into a case where we try to understand the dynamics of how these atoms move as a bond breaks and forms. By the way, the highest honor I received was from Linus, when he wrote to me saying he considered me his friend. Linus Jr. must recognize his father's handwriting. In 1991, he sent me a book, and wrote to me "To my friend Ahmed." I treasure this. [14:39]

In his lecture at Caltech, Linus showed the structure of sodium chloride that was believed to be by Mr. [William] Barlow in 1898. This is the structure of table salt. I am showing this because there is an analogy between the beginning of Linus' work on structural chemistry, and what we were trying to do in dynamic chemistry. Looking at the structure of sodium chloride with two atoms probably seems trivial, especially during the era of the Braggs and the work that was done with x-ray crystallography. When we started it was also with table salt, sodium chloride, sodium iodide, to try and understand the dynamics of this chemical bond, but also we received a lot of criticism in the early days, that this was trivial; these are two atoms, and not much is going to be found from this. Of course, you know the work on structure by Linus has led, for example, to the structure of hemoglobin. The picture is not as pretty as you normally see, but this is the protein structure of deoxyhemoblogin. And in fact you will see at the end of my talk that we can also look at the dynamics of proteins, DNA and the like. [16:24]

It is remarkable to me that I read very recently - I didn't know that Linus wrote this - but he received the Nobel Prize in 1954 and shortly after the award he was asked to reflect on what chemistry will be in the coming 50 years. Remember, he spent all this time studying the structure, the architecture, of molecules, but he had the vision, and I think that this was the first time that anybody has seen this Scientific American article, that "the half century we are just completing has seen the evolution of chemistry from a vast but largely formless body of empirical knowledge into a coordinated science. The new ideas about electrons and atomic nuclei were speedily introduced into chemistry, leading to the formulation of a powerful structural theory which has welded most of the great mass of chemical fact into a unified system. What will the next 50 years bring?" This is Pauling speaking 50 years ago, mid-century. "We may hope that the chemists of the year 2000 will have obtained such penetrating knowledge of the forces between atoms and molecules that he will be able to predict the rate of any chemical reaction."

So even though Pauling was immersed in static structures and their study, his eye was on the next century, and maybe the next century Nobel Prize. That is precisely what I want to talk to you about today, is how we look at the forces that control the motions of atoms and molecules, whether it's in chemical or biological systems, and can we distill some concepts out of this, just like Pauling was trying to understand hybridizations and so on, that teach us something about the dynamics of chemical bonding, and hence the forces and how to predict rates and the dynamics. [19:05]

The work I will talk about relates to the Nobel Prize that we received in 1999, and incidentally, there is an incident in history here that I think I told some of the speakers at dinner last night. When we received the Nobel Prize, Caltech had a big party, as they did for Linus, and one of my colleagues, Vince McKoy, noted that Linus was born February 28, 1901, and I was born February 26, 1946, so two days away from Linus. He received the prize in 1954, we received the prize in 1999, and both in October, so we were both almost 50 years of age when we received the Nobel Prize. This is remarkable where Caltech is concerned, because both Pauling and myself started at Caltech as Assistant Professors, they did not "buy us from the outside," as they say. I thought you would be intrigued by this: when the prize was announced, it was everywhere because our work also touches on physics, and so many of the physics magazines wrote detailed articles, and here is a distinguished one from England; it surprised me, as you will see, that England would write something like this. "Ahmed Zewail receives the 1999 Nobel Prize for Chemistry…" and it goes on to say "laser-based techniques that allow the motion of atoms inside molecules to be followed during chemical reactions." It goes on, very complimentary. And then it says "Zewail was born in Egypt in 1496." I told the Nobel committee in Sweden that it is really remarkable that it took them 500 years to give me the Nobel Prize.

Here is the journey in time. I think for the people in the audience who are not used to seeing this number, you certainly hear and you know by now… Here could be 12 or 15 billion years of the Big Bang, and then you come down to our lifespan, which is about 100 years or so - your heart beats in one second. But to go from here [present day] to there [Big Bang] is about 1015, and I am going to take you from the heart into a molecule inside the heart, or eye specifically, and you have to decrease by 15 orders of magnitude to see the beats of this molecule, as you see the beats of your heart. The timescale is fast, and I wrote a review which is probably useless, but I thought it's interesting that if you go from this age of the universe, and you count back from the age of the Earth to the human lifespan to your heart (1 second), and then you go to the microscopic world (sub-second), into how molecules rotate, vibrate, and how the electrons move. In this whole microscopic world here, we reach 10-15 or so seconds, where on the opposite end you reach 1015, and the remarkable thing is the heart is the geometric average of the two. As humans, we are in a very unique position. [23:50]

It's very difficult to study history; I thought it was very easy, but it turns out it is very difficult, and it takes some time to get the facts. I showed this in the Nobel lecture, because it gives five milestones, snapshots, of an evolution over about six millennia. The first time we know of the concept of measuring time is the calendar, which was developed in 4200 BC. In fact some historians say that it is 4240 BC, so it is almost 6000 years ago, which we knew what a year is, what a day is, what a month is. What an hour is was measured using sundials in about 1500 BC. You can use a shadow from an obelisk or a sundial and know what the time of day is. The mechanical clock was developed in Europe around 1500 AD, and all of this was still in seconds or longer, so up until then we could only measure as accurately as a second.

One of the most famous experiments in the history of measurements was done by Edward Muybridge in 1887. Mr. [Leland] Stanford, the Governor of California, was very interested in horses and hired Muybridge to find out the actual nature of the motion of the horse as it gallops. Mr. Muybridge designed this camera, which had a shutter speed of about 1/1000th of a second. This was done in Palo Alto, where there is a plaque commemorating it. In so doing, as the horse galloped the shutter was opened, and Muybridge was able to take a snapshot of the horse proving the contention of Mr. Stanford, that all four legs are off the ground at the same time. I believe this was the very beginning of fast photography and motion pictures. In the 1800s, this was a very important development.

To go into the word of molecules, and to be able to see transition states, just as Muybridge saw the transition state of the horse moving, you need an increase of about 12 orders of magnitude in time resolution, and we only can do this with these lasers, as you will see in a few minutes. This was done in 1980, and it may be called femtoscopic. [27:16]

So, why is it that this is important to chemistry and biology - the dynamics of the chemical bond? It turns out, the dynamics of any chemical bond, whether it is in a chemical system or a protein or DNA, is totally controlled by the fundamental vibrational time scale, as you heard from John. This vibrational time scale, and there is some philosophy that one can dwell on here, determined by Planck's constant and so on, but fundamentally, two atoms connected by a spring will move in a spring-motion on a time scale of 10-13 seconds, and the shortest possible time for any molecule in this universe will be 10-14 seconds. All the way from hydrogen molecules to protein molecules, the time scale will be from 10-14 seconds to 10-12 seconds. Molecules can rotate in the laboratory without you seeing it in a picosecond 10-12 to 10-9, and everything longer than this we consider in the Stone Ages; it's not interesting to us. So on that time scale you will see many interesting phenomena in chemistry and biology that happen.

This is the end of time resolution for chemistry and biology, because if you look here, even molecules that are linking undergo collisions on a time scale of 10-14 seconds. A molecule can break a bond and make a bond on this time scale as well. The eye has a molecule called rhodopsin which divides and allows you to see, and that happens in 200 femtoseconds. The way we get photosynthesis to work, and the electron to transfer inside the green plant, is on the order of femtoseconds. So this is the fundamental time scale, and if we were to understand the dynamics of the chemical bond we must understand this time scale. Luckily, that is the reason behind all of this, and to be totally truthful, this is the way we were thinking about it. We were making real approximations - what I like to call the "back of the envelope" type of calculation - and we didn't go to big computers and do quantum calculations and all of that stuff, because I always feel that there is beauty in the simplicity of science, and if we are not able to distill it into the essence of science, it seems to me that we are fuzzy about it.

What I just told you is general to any molecular system; if you think of the chemical binding energies that we have, that Pauling would have calculated with his slide ruler, and then if I activate a chemical bond, I can calculate the energy in this bond. And if I have the energy I can calculate the speed at which the atoms should move in principal. For all chemical and biological systems, you'll find that this speed is about one kilometer per second. Even in the spring that I mentioned, the two atoms would collide with each other at about one kilometer per second, or 105 centimeters per second. If we're going to look on the molecular scale to understand the dynamics of the chemical bond, we have to understand that the distance scale is about an Angstrom, or 10-8. You can see, without any fancy quantum mechanics at this point, potentials and forces and all of that, that if you put these two numbers together (105 and 10-8) you come up with a time resolution of 10-13 seconds.

Therefore, our idea is simple: if we can reach a time resolution just like x-ray crystallography and electron diffraction, if we can get the de Broglie wavelengths or the special resolution less than the bond distance, you would be able to see bonds and atoms. Here, we can also say that if our time resolution is 10-14 seconds, then we can freeze this motion, we can do what Muybridge did, because now this time scale will be shorter by a factor of ten than the time it takes the atoms to move in the molecule. More scientifically, we say that the time resolution here is shorter than the vibrational period of the molecule, or the rotational period of the molecule. And that, in its totality, defines the field of femtochemistry, and now there is something called femtobiology, and so on. [33:07]

So this is a simple picture of the problem, but for the physicists in the audience the problem is much more intriguing and much more fundamental. It is remarkable that Pauling recognized, right after Schrödinger wrote his famous wave equation in 1926 in Zurich - which we shall celebrate in April - very quickly recognized that if you think of matter as particles, you can also think of them as waves. De Broglie, with brilliant intuition, used the quantization equation and Einstein equation and came up with this very simple thesis that lambda is equal to h over p, which Einstein reviewed. So for each momentum of a particle, there is an associated wave, lambda. When people study matter as light, and we made this mistake too, they are always thinking of Schrödinger's Eigen states, the wave character of the system, wave mechanics, Schrödinger wave equation. But that is not what I am interested in, because what I am interested in is to be able to see the atoms in motion, and to understand the fundamentals of these dynamics. I don't want to go to the delocalized wave picture and calculate Schrödinger equations and come at the end without a simple picture describing the particle behavior of these atoms in motion, moving from one configuration into the other.

So how can we make matter behave in a fundamental way as a particle and not as a wave? If we look at what is known as the uncertainty principle, which is seen here, that you cannot do precise measurements of the position of the particle and momentum simultaneously. Similarly, you cannot make a precise measurement of time and energy simultaneously. We understand this from Mr. Heisenberg, there is no problem. But the chemist had difficulty understanding how we can shorten the time, Δt, because this would be at the expense of the energy, ΔE, and therefore we ruined the quantum state of the molecule, the nature of this molecule.

What was not recognized, was that this is in fact a beautiful way of locating atoms in space, because in a crude way if you think of how ΔtΔE=hbar and ΔxΔp=hbar, don't think of this alone, just think of the two together, and say that the momentum and energy are related (which they are). If you combine the two, you'll find that if you shorten the time, Δt, you can make Δx very small. That is the only way in this universe that we know of to localize atoms in space. We are not in violation of the uncertainty principle here, but if you do it cleverly, combining time and energy, you can show clearly that you will localize this nuclei to better than a tenth of an Angstrom. The chemical bond distance is about an Angstrom, so we have a factor of ten in space and should be able to see the motion of these atoms as the bond breaks and forms.

It has a long history in physics, and in fact it goes back to the 1800s - there is an experiment in 1801 by Mr. [Thomas] Young on light, not on matter. If you take two slits, with light behind them, then you will see these fringes, and it is very similar to what we can now do with matter and molecules. We can take a femtosecond pulse, which is acting like the light, and we can take all these wave functions of the molecules - this, by the way, is two atoms and a spring moving - and we can take these waves and try to do this interference experiment on this matter, and all of a sudden you see what's called a "wave packet," meaning that we localize all of these vibration states in one place, which becomes a classical picture. We can speak of a spring in this point in space, and that it is coming back, and we can see this motion.

Early in the field, it was thought that this energy is too broad and ugly, and there are occasionally objections over the uncertainty principle. Actually, without the uncertainty principle, it would be impossible to see the nuclei moving on this time scale.

This, by the way, was also of concern to the big minds in 1926. This letter was from [Ernest] Lawrence to Schrödinger, pointing out that this idea of connecting the classical mechanics of Newtons, and understanding the particle instead of the wave behavior, "you will be unable to construct wave packets." This was 1926, and in 1980 not only can you do it on chemical systems and create this wave packet, but the field has expanded so much that you can also do it on liquids, solids, gas phase, and clusters - this has been observed by many people around the globe. [40:45]

The way we do this experimentally is tricky, because there are no cameras like Muybridge's that will allow you to open and close mechanically in a femtosecond; it's just impossible. The way we do this is to use an idea of creating pulses of light in femtoseconds and then delay, as a series of pulses - so this red here is delayed from the yellow - and the first one, the yellow, will set off the clock and give us a time zero for the change. With a whole series of pulses we can "photograph" what is happening here as a function of time. We do it this way, using the speed of light, because it turns out that when we delay this pulse in relation to this one by one micron in the laboratory, it's equivalent to 3.3 femtoseconds because of the speed of light: 100,000 km per second, and actually this is fabulous on the femtosecond time scale. The shortest pulse nowadays that you can generate in the laboratory, and this is done in Europe, is four femtoseconds. So we have four femtosecond pulses, we can clock them to better than three femtoseconds, and therefore any molecular system can be studied in this way.

I'd like to show you the laser arrangement we have used. I've made it sound so simple, but of course when you try to do the first experiments... I'll show you one of the first illuminating experiments: two atoms and a spring, nothing fancy in this. If I solved for the Schrödinger wave equation from 1926, it would tell you that you must calculate the probability distribution function for how to find the spring in space. And so, if this is the distance, you'll find that this probability is everywhere; that would be the Schrödinger wave equation. Simply put, the probability of finding the spring anywhere is essentially the same. According to wave mechanics, in the microscopic system, that is the quantum mechanics of that system, delocalized over all of space.

On the other hand, if we give this spring an impulse of a femtosecond, then what you see is the solid bell shape of the curve, the wave packet I told you about. What this means is that the two atoms at that time are localized in space at 2.7 Angstroms. If I waited there for a long time, this bell shape will move into the other side, so the spring stretched. Waiting longer, it will come back to the compressed shape. Therefore, by simple logging of all these, just like Young's experiment, we are able to see this as if the system follows classical motion with the spring compressing and stretching. This, of course, is what we saw experimentally - stretching, compressing, stretching, you can even see the anharmonicity of it, and you can measure it with accuracy of about 10 femtoseconds.

Of course, we wanted to move into the real world of chemistry, as John told you. In 1931, Henry Eyring and Michael Polanyi (the father of John Polanyi) made a prediction about the energy landscape of how chemical bonds will break and form. Of course, this entire journey occurs in about 50 femtoseconds. We wanted to freeze the system as the atoms of a hydrogen molecule get together to make a chemical bond and break a chemical bond, to freeze them in the transition state, which would have been a dream in 1931.

Again, a paradigm case that illustrates this point is two atoms in the process of separating from each other, breaking a chemical bond. I was stimulated by Linus' book, The Nature of the Chemical Bond. He had this example where he compared the alkyl halides in terms of the covalent potential and the ionic potential. Pauling's point was that depending on the metal and the halogen, these two curves can cross or not cross. If they cross, the bond will be a mixture of covalent and ionic character; if they do not cross, and the ionic is too far, then the bond takes on one of the two. So in the femto age, we can prepare this structure far from the equilibrium - Pauling was interested in the equilibrium, static structure - putting a wave packet here in the covalent region. But as the spring tries to break, it will move from the covalent to the ionic, with a chance of breaking the bond, but it might also reform the bond again, and so on.

This is history now: the two atoms here, electron jump, some go out and break the bond, others like each other very much and will bounce back, and we can see this resonance motion in the laboratory as a function of time in a beautiful, classical way. In fact, the beauty of this experiment is that it was done with about 10 million molecules, but what you see is the behavior of a single molecule. By using these very short pulses, we were able to prepare all of these atoms together coherently, as if all 10 million are glued together, moving, breaking and remaking chemical bonds all in harmony. If all 10 million are behaving slightly differently in time, we would never see this resonance motion; that is the beauty of this experiment, which is the analogue of Linus' thinking about the nature of the chemical bond in sodium chloride. [48:13]

Of course, the field has progressed so much that I don't have time to go through many examples, just a few, and end up with where we're going in the future. For example, this is an experiment that was published from our lab on the analogue of hemoglobin, done by synthesizing these picket fence structures because we wanted to see how the molecular structure is going to influence the dynamics of oxygen-binding into the heme. This was an interesting experiment in its own right, because we can study this under physiological temperature, at room temperature, in water. The other ones I showed you were fundamentals, so we had to isolate the molecules from the rest of the world in molecular beams and so on.

Here, we study this in water and the idea was to see why the hemoglobin binds oxygen and at what time scale, and what the recombination time, the probability of this oxygen rebinding again, is. We used the femtosecond resolution to start the motion, kick out the oxygen, and then probe the recombination and the dynamics. This was published in Angewandte Chemie and the results were very striking; the electrochemistry was also done in collaboration with Fred Anson, my colleague, and this is a very valuable system because the peptide bonding and the hydrogen bonding help to understand the relationship between the structure and dynamics.

I'd like to show you a transient femtosecond in a complicated system; here is the picket fence, porphyrin, and we study the electron transfer into the metal. The time scale is 250 femtoseconds, with no oxygen and no base; with hemoglobin as well, you need to have a base, amidazole, which comes from the other end. Not only is porphyrin important for this oxygen binding and separation, but the amidazole as well. Here is the one with no oxygen and no base, and a case with base; it doesn't change that much. But once we bubble oxygen at room temperature, just as it would happen in the body, we see that the transients are completely different. In fact, the oxygen leaves the heme in 2 picoseconds. The first charge is in 500 femtoseconds, and the oxygen leaves in two picoseconds. Furthermore, we couldn't find the oxygen recombining at all in up to 15 picoseconds. In an experiment that was just finished, we see it recombine in 15 microseconds. The issue, then, is why oxygen does this in such a molecular assembly, called supra-molecular chemistry, and how we relate that structure into the dynamics, but this is not the subject to dwell on here. [52:00]

This is a recent experiment published in PNAS, and I'm very intrigued by this problem, as I think Linus was from the structural point of view. But I am so fascinated by this idea of "molecular recognition." I do believe that you will see exciting things in the next ten years or so, because I don't think that the answer is simply in the molecular structure of the two entities. How does a protein recognize a molecule, which is a drug in this case, and how do the drug molecules go into the DNA? These are all very weak forces, including the hydrophobic forces, which we are trying to shed some light on, meaning that water molecules around this cavity help the molecule to move around and go into the protein. We just published a couple of papers trying to elucidate this process, because they all happen at the femtosecond time scale.

Finally, in your genetic material for example, an electron can move into DNA, and there are claims in the literature that this might damage the DNA and cause all kinds of problems, including cancer. What is interesting about the chemical and physical aspects of it is there are some claims that if an electron comes here it might move inside the DNA as if it's a free metal; in other words, a conductor. DNA would be conducting electrons at very high rates, and that would mean it's acting like a metal. We decided to collaborate with my colleague Jackie Barton, who does a beautiful system here in terms of genetically modifying bases inside the DNA duplex. We did a series of femtosecond experiments where we can excite one of the bases in DNA to allow an electron to move, measuring the speed at which it does this. Of course, we can genetically modify this so we can study it as a function of distance, as a function of the base pair, and as a function of the driving energy, and all of this has been done.

Just to show you something dramatic, we took a duplex of DNA; here is the amino purine and next to it is guanine. You can see that as we add adenine one base pair between the two, or three, or four, how the femtosecond dynamics drastically change as we add one more base pair between the two bases we are studying. Electron transfer happening inside the DNA is efficient, but it is also highly localized to three to six or so, and we can give the dynamics while not believing that it's an efficient molecular wire. This is what we concluded in the last paper, but there are interesting dynamics taking place, and it relates to the motions of the base pairs, the structure of the base pairs, and the driving force of the base pairs. [55:39]

So where is this going? In 1980, I conjectured - because we didn't have femtoseconds in those days - in a Physics Today article, that if we have sufficiently brief and intense radiation that we may be able to fulfill a chemist's dream to break particular bonds in large molecules. The idea here is that if we can localize a nuclei on the length and timescale of the actual chemistry, maybe we can intervene in that critical moment and modify the chemical outcome.

Now, it turns out that we, and others, have demonstrated this in small systems, but that is not what I am interested in. The issue is whether you can do it in really large molecular systems. A couple of years ago we published an article in Science where we used a femtosecond pulse to look at the chemistry in the Norrish reaction, known to chemists, and varied the molecular size, but it was exactly the same reaction. We showed that if we can use femtoseconds to deposit the energy, and then probe it, that in theory you should expect a decrease in speed by four orders of magnitude for this size [largest] compared to this size [smallest]. However, at most you see a factor of two or so. The point here is that in the future we might be able to beat the so-called "statistical behavior of molecules" by at least three or four orders of magnitude, and we are continuing to study this general area in the control of molecular chemistry. If we can do that, I think we will be on the way to something very exciting.

There is another area that my group is focusing on, and in fact in the January 19 issue of Science there is an article with the latest on this subject; that is, x-ray crystallography and electron diffraction can be used to give you static molecular structures. Our drive, or interest, right now is to figure out if we can get into much more complex biological systems, more so than chemical systems, in order to understand problems that I'm intrigued by, such as protein folding - there is a lot of conjecture in the literature right now and it's an active area, but we really don't understand it. Can we probe on the level of the atoms and molecules? What happens, for example, when a protein goes from one state into the other? Can we learn about the landscape, about the enormous selectivity that exists in biological systems that does not necessarily come into play in chemical systems?

In order to open all of these areas, my group's thinking is to try to find new techniques that will allow us to see very complex systems, to understand some of the principles of these dynamics which might not be as simple as forming chemical bonds. In so doing, we decided to combine femtosecond lasers with the Einstein idea of the photoelectric effect to create an electron pulse, focused very quickly into a beam of molecules. Now, rather than taking a static picture of the molecular structure, we're taking a snapshot. If we can get the pulse to be especially short, we should be able to see this snapshot at that particular time, just as we did in the femtosecond domain.

I had a brave graduate student at the time by the name of Chuck Williamson - who is here today - who was told when he joined my group that this was a hopeless experiment to do, and as he told me once it's a "no to the power of ten" experiment. I think one of our first diffraction images taken was lousy, at a time scale of 10 or 20 picosecond pulses, barely showing diffraction images.

This is also a message to students, because whenever you start something new all of the experts will tell you it's not going to work, it's useless, and so on. But don't listen, just keep going. There were many experts in diffraction who told us that this is hopeless, that we wouldn't get anywhere, and that they knew all about it. We started to barely see diffraction images, which were improved during the tenure of Chuck, as well as two outstanding post docs working on this. The rings became much better, and one of the beautiful things about diffraction is that you can really fit the radial distribution function and scattering function theory into the experiment, and compare using iteration methods until you get some good information about the molecular structure. We are now getting the molecular structure at that particular instant in time. [1:01:59]

One of the systems that we studied recently is the illumination of halogens from ethane to form ethylene, its fluorinated derivative. In the process of doing this, you can break the first bond and then the second bond, and in so doing the literature conjectures that the intermediate formed is this bridge structure. The electronic structure during the course of the chemical reaction will change, and this atom, the iodine in this case, will be between the two carbons. So we thought that this [bridge structure] is a possibility, but so is this structure, that the whole problem is a dynamics problem; namely, that you can break the first chemical bond very quickly, but the second one might break on a time scale that is shorter or longer depending on the rotation around the carbon-carbon bond. This will determine what you will get out in terms of stereochemistry and the earlier studies that people have done.

We followed this with diffraction, focusing on a given bond - in this case, the carbon-iodine bond - to see how this would evolve with time. I'll just show you the latest, which is beautiful in my opinion. You can get the molecular scattering and the radial distribution function. This is the intermediate, assuming that there is a rearrangement of the electronic structure. There is no agreement between theory and experiment - theory is green, experiment is black. On the other hand, if we just simply say that the first bond breaks, then the second, on a time scale that is shorter than the rotation around a carbon-carbon bond, we get very good agreement between theory and experiment, establishing that this is the intermediate.

As we can learn from diffractionists, we can refine more and more by iteration and are able to find the bond distances and the angles for this particular intermediate; this is now not a stable structure at infinite time, but this is taken at five picoseconds after initiation. It is also very interesting that we can find the bond distances in this intermediate. You try to form a pi bond and break a sigma bond, and therefore you should see this bond in the intermediate become shorter compared to the initial parent while this one becomes longer, which is what we see experimentally. Of course, after you do all of this you look at theory, which is in better agreement with what you got experimentally.

We just published a paper by Hyotcherl Ihee and myself in Angewandte Chemie. It's a beautiful piece, because this is the reaction known for iron pentacarbonyl; people sometimes stretch it and use it as a hemoglobin model for liberating these ligands to make five CO's plus iron. They are all intermediates which we can freeze and see at a given time, which Hyotcherl did with Jim Cao, a post doc at Florida State. You see here that we can trap the FeCO4, measuring the diffraction data very accurately, showing that the structure and the state proposed for the generation of this intermediate is not correct. For example, you can see the A1 state and the B state, which doesn't agree at all with the B2 triplet, but it beautifully agrees with the singlet state and we can get the molecular geometry of this molecule. There are probably about 50 to 100 papers on the state and structure of this. [1:06:43]

I want to show you what I consider a new breakthrough; this is the one that came out in Science. This is a brand new apparatus; after Chuck left we had to build a new one because he knew all the tricks with the old one, and we couldn't get it to work as efficiently. We decided to build this brand new one, and have five outstanding people working on it, which you will see in a minute. We call this apparatus the Third Generation Diffraction Machine; in addition to the usual diffraction - here the electron is generated in this way, sent to a CC camera here - we also have a mass spectrometer which we can use to identify the whole species and fragments that are coming out in the chemical reaction. There is also a femtosecond system, and the remarkable thing is that we have achieved 500 femtoseconds with a very good electron density, but we have published 1 +/- 0.2 picoseconds in Science. You can see clearly that these are the electron pulses coming out, and we can measure the separation and pulse widths precisely.

The beautiful thing about this apparatus is its reliability; we can now look at structures that we previously couldn't even dream of seeing. We can see for the first time that these diffraction images change from the two-dimensional CCD camera in front of your eyes. This is not computer enhanced. In these six images, you can start to see the rings form as a function of time. This is an incredible enhancement of sensitivity and reliability that allows us to study quite different molecular structures. The most recent article in Science studied a molecule without heavy atoms - we usually look at molecules with heavy atoms - but we just studied, for example, a cyclic hydrocarbon, and there will soon be a paper with very exciting complex molecular structures that are being trapped at very short times. Again, connecting to Linus; he was very interested in electron diffraction at Caltech, and the Caltech group was the first to use these new techniques in the United States. We are now just following in his footsteps, but adding the element of time to try and understand what is happening.

Time has been part of the theme in this lecture. It is amazing that none of us have thought of the usefulness of time resolution in areas such as medicine and biology; the highest atomic clock in the world is achieved using femtosecond pulses, and you can get an accuracy of 10-15 through femtoseconds. I have been told that the most femtosecond lasers sold are not to chemists or physicists, but to hospitals, because now they can image these very fine tumors using femtosecond lasers. In the world of microelectronics you can use femtosecond pulses to lift a piece of material on the micron scale without dissipating heat into the microchip, in the same way that you can deposit energy into a molecule without letting it leak. There are all kinds of interesting applications for this, but when we started we hadn't really thought about them.

I was intrigued by reading this book recently. Unlike scientists, who are very conservative and work hard, here is our friend [Newt] Gingrich who said, making a prediction about the future, "The first settlements beyond our galaxy will have occurred by 2500. We will have left our solar system by 2200. We will have permanent colonies on the moon and Mars by 2100." Fantastic! He really knows what we are going to do in the future.

One is fortunate to be at a place like Caltech, where Linus told me personally that he really enjoyed his scientific work and interacting with outstanding people. It is also very fortunate to have more than 100 people from all over the world interacting on this idea that I have tried to convey to you in one hour; namely, a voyage through time. Thank you. [1:12:23]

John Westall: Thank you very much for the voyage through time. I believe we do have a discussion section this afternoon at 5:00, but we have a few minutes right now if you would like to entertain any questions related specifically to this talk.

Audience Question #1: For the reaction of diomethane, is that a gas phase reaction?

Ahmed Zewail: We wanted to do it in the gas phase so that we could compare it with quantum mechanics equation, but if you do it in the gas phase it is much more difficult because we have to do it in a molecular beam. So it was gas phase, and that is the reason the experiments are extremely difficult.

Audience Question #2: How many oxygens leave the heme in your experiments? I was wondering if you could speculate on how far it goes away, and why it takes so long to go back.

Ahmed Zewail: Very good question. When I told you 1.9 or 2 picoseconds for the oxygen, I was actually hiding something; I don't know yet what the real time scale is for the bond to break between the oxygen and the heme. That could be about 100 or so femtoseconds, but the molecule then undergoes a torque, rotating into the pocket structure itself, and then might have moved fast to another location before recombining very slowly. So now we do a polarization experiment to reorient the configuration to see how much of the two picoseconds are due to that initial torque. This way, we might be able to separate the time scale for the first breakage from what it will take for the motion. But we do know the time for the recombination is extremely long.

Audience Question #3: [unintelligible]

Ahmed Zewail: It is very possible. It is very well known in solids that you can get one dimensional and two dimensional energy and electron transport, and people have studied this for years and years. The issue is, when you consider DNA as a polymer, would you really get an efficient one-dimensional electron transfer within it? The chemical idea there is that pi-stacking would help you to go through. But if you think about it from a biological point of view, would that be good? Do you want to transfer damage over very long distances, for example? Then the question becomes a physics question: can we measure how fast the carriers move from one spot on the DNA to another spot over a given distance? When we measure the rate at which these carriers are moving, and you know the voltage, you can find the mobilities just do not compare. It is very possible that a protein localized at a given point will be efficient at this point but not at others, and we have not examined that.

John Westall: I believe that all the examples you have shown were unimolecular systems. Of course it would be interesting to apply the same techniques to bimolecular systems, but then there are issues establishing the coherence necessary to make the whole thing work.

Ahmed Zewail: Right. We have done that, John, and many people have followed this, but I just didn't have the time. Let me just show you an example of what we did. The problem in molecular recognition, which we are now interested in, is that if you have a drug, for example, trying to recognize DNA, most of the kinetics that have been measured - and thermodynamics and everything - are actually dominated by a diffusion-controlled process. As you know, in a bimolecular process you will be taking too much time, a millisecond or so, but the actual process could be in the femtosecond range.

To get around this - we have done this with the late Dick Bernstein - in order to not be held hostage by this millisecond and microsecond diffusion of reagents, you expand two reagents together in the molecular beam. Using a precursor such as HI or HCl or HCr, and CO2, and mixing the two to dissociate HI, for example, you can liberate hydrogen. Now you are looking at the hydrogen reaction with CO2.

What we did was to expand these two together, liberate the hydrogen by using a femtosecond pulse to remove the iodine, and then you are looking at these bimolecular collisions between hydrogen and CO2. We can see the transient complex, and in fact we measured this as a picosecond for the birth of the hydroxyl radical and the carbon monoxide. This is a theoretical calculation that has been done recently to try and understand the fundamentals. People have also used ethylene, and other systems have been studied like this.

Audience Question #4: [unintelligible]

Ahmed Zewail: Right, and in fact this is what stimulated us about the oxygen recombination, was this system of Mulliken, which took 50 years to find the nature of what happens in the encounter between iodine and benzene. This is truly a bimolecular, and you can inject an electron there, and it recombines and you break a bond. Mulliken suggested that the I2 on the benzene was lying down, the iodine was lying down, but every textbook thought it would be axial. We did the experiment to find the femtosecond dynamics, but we also did an orientation experiment, and in fact, the iodine is pointing essentially into carbon, and not the x-axis; 32 degrees is the angle, and you actually suggested that to me a long time ago, Jack.

John Westall: Well thank you very much for your attention, thank you Professor Zewail for a very interesting lecture. [1:22:35]


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