SCIENCE/TECHNOLOGY
ChemistsHone New Techniques For Probing Transition-State Events • Symposium celebrates 60-year-old theory of the transition state that is at the heart of chemical kinetics and dynamics A. Maureen Rouhi, C&EN Washington
211th ACS National Meeting
NewOrieanf o sports enthusiast can be satisfied with just knowing the final score. As basketball fans would attest, the thrill lies in the passes, shots, spills, steals, and rebounds. So, too, with the chemists who met last month for the symposium on 'Transition State from Dilute Gases to Condensed Media," organized by the Division of Physical Chemistry. For them, the thrill of chemistry lies not so much in what reactants turn into which products, but in the intricacies of the journey from one to the other—a journey that almost always involves a transition state. The transition state is the heart of a chemical reaction. If one plots all the positions and energies of reactants as they evolve to products, one gets a "potential energy surface." Like a rugged mountain between two valleys, this multidimensional surface contains many paths with different energy barriers—mountain passes at various heights—through which reactants must move to become products. The specific path the reactants follow depends on their energy. Strictly speaking, in this path, the transition state is the point of no return for reactants turning into products. This classical view of the transition state—the one familiar to most chemists—is the basis of the theory of reaction
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APRIL 22,1996 C&EN
Four "snapshots" of the charge-transfer reaction of benzene and iodine. The lower panel shows the system prior to electron transfer (tj, at the moment of electron transfer (t^, at the transition state (tt)r and after an iodine atom separates (tf). The upper panel shows the femtosecond buildup (r is the time constant) of iodine atoms with time. rates developed by Henry Eyring, Michael Polanyi, and others in the mid1930s. According to the theory, a reaction's rate can be calculated if the energy and the geometry of the transition state are known. But some scientists propose to define the transition state more broadly, as the full range of configurations the reactants take as they evolve to products [Ace. Chem. Res., 28,119 (1995)]. The difference between these ideas is like that between a point and a line. The way scientists look at transitionstate events depends on whether they want to see only the familiar point at the top of the mountain pass—the realm of reaction rates—or the journey that includes that point and beyond, spilling into reaction dynamics. The symposium celebrated these ideas and all that transition-state theory has spawned, said symposium co-organizer
Gregory A. Voth, chemistry professor at the University of Pennsylvania. He and co-organizer Mark S. Gordon, chemistry professor at Iowa State University of Science & Technology, Ames, brought to New Orleans experimentalists and theoreticians bound by a common goal: understanding reactions at the most basic level whether they occur in the gas phase, in clusters and Liquids, or in biological systems. Until recently, a transition state could not be observed directly in real time because of its brief lifetime, in the femtosecond timescale. To imagine how brief that is, in a movie 32 million years long, the transition state would appear on the screen only for a few seconds. Now chemists can actually observe reactions and transition states as they evolve, as demonstrated by Ahmed H. Zewail, professor of chemistry and
Nobel Laureate seeks simplicity in theoretical expressions
"You can define a reaction coordinate globally," Marcus explained. "And then you take these thousands A graph of intersecting parabolas inof coordinates and you calculate a troduced Rudolph A. Marcus—Arthur free energy for the entire system by Amos Noyes Professor of Chemistry statistical mechanical averaging." at California Institute of TechnoloThe relationships that emerged are gy—to a packed audience at the symrelatively simple: The barrier to an posium on "Transition State from electron-transfer reaction depends Dilute Gases to Condensed Media" on the free energy of the reaction in New Orleans organized by the Diand the reorganization parameter, vision of Physical Chemistry. The expressed in terms of bond-length image encapsulates a theory for elecchanges and solvent properties. At tron-transfer reactions formulated in certain approximations, when the re1956, for which Marcus received the actant-solvent and product-solvent 1992 Nobel Prize in Chemistry. Its systems respond linearly to changes, clarity epitomizes the hallmark simthe free energies become quadratic plicity that Marcus seeks to impose functions. Plotting them against the on unwieldy and sometimes imposreaction coordinate yields two pasible problems. rabolas intersecting at the transition "When you do theoretical work, state. sometimes things look very messy/' Marcus said. "You wonder if you Marcus: cutting through complications One startling prediction of the Marcus theory is a decrease in reaccould cut through the complications." For the Nobel-Prize-winning work, move. So the energy of the system af- tion rate when the parabolas intersect Marcus simplified many complexities ter the transfer is higher. But where at the "inverted region" of the free energy plot. Most reactions proceed of a problem to describe in simple does the energy come from?" terms a reaction with thousands of coWith photoexcited systems, the en- faster as the free energy difference ordinates. The problem was the puz- ergy comes from light. But the reac- (AG) between reactants and products zling rates of reactions involving only tions Libby was trying to explain increases. The theory predicts reacthe exchange of electrons between were occurring readily in the absence tion rates will increase with AG only ions. When the ions are small, the re- of light. "That's the violation," said up to a point. Beyond that, in the inverted region, increasing AG can only action is slow. But when the ions are Marcus. big, the reaction is very fast. With electron transfers, Marcus re- slow down the reaction. ExperimenIn 1952, Willard F. Libby, then at alized, "the problem is that there are tal verification of this prediction the University of Chicago, proposed thousands of coordinates. Not just came almost 25 years after Marcus that the rates could be understood in two, but all the solvent molecules formulated the theory and probably terms of what an electron transfer and their orientations." As the reac- clinched for him the Nobel Prize. does to the ion and its environment. tion proceeds, not only are the reacMarcus continues to simplify. For Libby reasoned that when an elec- tants changing to products, but sol- example, more than 30 years after he tron jumps, the immediate environ- vent molecules are reorienting and first arrived at the free energy expresment—that is, the orientation of sol- adjusting at the same time. Calculat- sion for electron transfer, he has vent molecules—around the donor ing rates for a reaction with thou- found an even simpler way of derivsands of variables changing simulta- ing it. "When you can make it very and acceptor ions is the wrong one. It's as if the ions suddenly find neously would have been impossi- simple and everybody can visualize themselves in ill-fitting garments. ble, were it not for the order Marcus it," he said, "there's a kind of beauty there." They don't have time to adjust, be- imposed on this messy picture. cause with electrons being so lightweight compared with nuclei, at the moment an electron jumps, the nuRates slow down in clei freeze. This so-called FranckIn electron-transfer reactions, Condon principle had been applied parabolas describing the free inverted region to spectroscopy. Libby's insight in energies of reactant-solvent Free energy applying it to chemical reactions, (R) and product-solvent (P) said Marcus, was "sort of magic." systems intersect at the tranLibby suggested that the degree of sition state. As the difference foreignness of environment is bigger in R and P increases, the barwith a smaller reactant. That part rier moves down and the reseemed very right, Marcus recalled. action goes faster. A reaction "But as I looked more, there seemed defined by R and Pmax will to be something not quite right." In be going as fast as it can be1956, after grappling with the probcause the parabolas intersect lem, he saw what was wrong. And at R's lowest point. Beyond one month after reading Libby's pathat, in the inverted region, per, he arrived at his theory. the barrier moves up as the What's wrong is that Libby's scedifference between R and P nario actually violates the law of conincreases and the reaction servation of energy. "Sure the elecslows down. Reaction coordinate tron jumps," said Marcus. "Presumably the nucleus doesn't have time to APRIL 22,1996 C&EN
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SCIENCE/TECHNOLOGY
Ice lattice takes key part in ozone depletion
face can get into the lattice just as easily as a water molecule. The surface of ice particles in polar Although the model contains simstratospheric clouds actively participlifications, it provides "a simple pates in the ionization of hydrogen and plausible mechanism for exchloride (HC1), according to a simulaplaining why ionic and not molecution by researchers at the University of lar mechanisms occur in the key reacColorado, Boulder. The study suggests tions on ice crystals in [polar stratoionic mechanisms are involved in a spheric clouds] that lead to ozone key reaction leading to formation of depletion," noted David C. Clary of molecular chlorine (Cl2)—which rapthe department of chemistry at Uniidly photodissociates to ozone-destroyversity College, London, in a Science ing chlorine atoms. commentary. The key reaction is HC1 + C10N02 -> What difference does it make whethHN0 3 + C12. The events leading to er the reactions are ionic or molecular? ozone depletion begin when HC1 molIf the reactions were molecular, then ecules land on ice. What happens after even on ice they should have rates that, whether HC1 ionizes or remains comparable with those of the corremolecular, has been widely debated. sponding gas-phase reactions, which Now, Colorado chemists James T. are slow, explained Hynes. But the reHynes and Bradley J. Gertner have actions are fast on ice, and others have found through molecular dynamics thought they might be occurring on a simulation that HC1 ionizes at polar liquidlike surface on ice, just like in stratospheric temperature (190 K) after Hynes: simulation indicates ionic reaction liquid water. "In effect, people have it is incorporated into the ice lattice postulated that the reactions were [Science, 271,1563 (1996)]. (H30+) and chloride ions can be sol- ionic," Hynes said. "But no one has Hynes discussed the findings at a vated effectively. known, and our results give strong symposium on "Transition State from The crucial incorporation of HC1 in support for this view." Dilute Gases to Condensed Media." the lattice can occur because of the Hynes said their conclusions agree Ionization does not occur if HC1 is dynamic character of the ice surface with what is known about HC1 uptake simply adsorbed on top of the ice, he under polar stratospheric conditions. on ice surfaces. But a direct test of said, because the water molecules on As shown experimentally several their validity would be experimental ice can't sufficiently stabilize the re- years ago by Hynes's Colorado col- observation of the hydronium ions sulting ions. "Instead, an HC1 mole- league Steven M. George, "Water produced at the ice surface at 190 K, cule has to be incorporated a bit into molecules are continually being ad- which could be done via infrared specthe ice lattice." Ionization then oc- sorbed and desorbed," said Hynes. troscopy. Hynes said this "quite difficurs at—rather than on—the ice sur- And if the ice surface is growing, an cult experiment" will be attempted face, where the product hydronium HC1 molecule adsorbed on the sur- soon.
physics at California Institute of Technology. Zewail uses ultrafast laser techniques to observe reaction dynamics directly in real time. In New Orleans, he described his latest coup—real-time direct observation of charge-transfer reactions. Scientists have been studying chargetransfer reactions for 75 years, commented 1986 Chemistry Nobelist John C. Polanyi (son of Michael Polanyi), of the University of Toronto. They are simple and easy to understand, he told C&EN, because the force that pulls the reactants is coulombic. They are also called harpooning reactions. Like a whaler shooting a harpoon into a whale, the donor launches an electron into an acceptor, creating separate charges. And in the same manner that the whaler pulls the harpoon to bring in the whale, the positive charge on the donor reels in the oppositely charged acceptor. Among several reactions Zewail examined was that between benzene and 38
APRIL 22,1996 C&EN
molecular iodine. Zewail said many chemists in the past have tried to study this reaction. Now, for the first time, the step-by-step events of this seemingly simple reaction in the gas phase have been observed in real time. Using a broad definition of the transition state, Zewail studied the benzene/I2 reaction by following, in real time, the events from just before the reaction begins until the products form. To begin, he and his team—postdoctoral fellow Po-Yuan Cheng and graduate student Dongping Zhong—brought I2 and benzene very close to each other—only 3 A apart—by using molecular beams. "At that point," said Zewail, "we started the reaction by giving it a femtosecond laser clocking pulse." The clocking pulse, or pump pulse, is the go signal. It sets the reaction to time zero by giving reactants enough energy to begin reacting. Then a series of probe pulses "looks" at what hap-
pens after the initial energy pulse. Each probe pulse takes a "snapshot" of the reaction frozen at a given time. Then data processing translates the snapshots to a dynamic picture of how reactants evolve with time. For the benzene/I 2 reaction, the Caltech team did several experiments to get the complete molecular dynamics picture. In one experiment, for example, they used a standard beam configuration coupled with a time-of-flight mass spectrometer to monitor iodine atoms produced by the reaction. In another, they polarized the initial laser pulse and determined the distribution of recoil velocities, from which they determined transition-state geometry and reaction pathways. The Caltech chemists found a bent transition-state geometry, with the I2 axis tilted about 30° from the normal to the benzene plane. Their snapshots show that benzene expels an electron
Zewail: observing reactions in real time
Reisler: gauging reactions by final products
and drives it into I2, resulting in charge separation: I2~ and C6H6+. Then C6H6+ reels in the oppositely charged I2~. The I-I bond stretches as one end is drawn to benzene while the other tries to move away. Then an iodine atom separates, leaving iodide (I") sitting on C6H6+, the two held by an ionic bond. From the clocking pulse to the time the iodine atom emerges takes all of 750 femtoseconds (750 x 10~15 second). But that's not all. Zewail's team also found that sometimes the electron does not stay with I2~. When this happens, two other paths produce iodine atoms. While I2~ and C6H6+ are still very close to each other, but before the iodine atom separates, the extra electron on I2" can jump back, neutralizing the charge on benzene. Because the I-I bond is highly stretched during the back transfer, it breaks, producing a neutral C6H6-I complex and an iodine atom, detected in 250 femtoseconds. However, the C6H6-I complex doesn't persist, and in 1 picosecond, it breaks into benzene and another iodine atom. That iodine atoms emerge from three paths was "completely surprising," said Zewail. Knowing only that an iodine atom is a product doesn't tell much. "You don't know where it's coming from," he said. But by monitoring the transition state, they have established reaction times for each path. Thus, the scientists can tell on which reaction path an iodine atom is emerging from the transition state. Also using ultrafast lasers is chemistry professor Daniel M. Neumark at the University of California, Berkeley. He is looking at negative ions. "Spectroscopic and dynamical techniques that have been successful for neutral species are difficult to apply to negative ions,"
he said. "As a consequence, the electronic states of negative ions are poorly characterized." Neumark uses femtosecond photoelectron spectroscopy to study the transition state and the photodissociation dynamics of negative ions such as I2~. In this technique, a femtosecond laser pulse electronically excites a ground-state negative ion. As the excited ion dissociates, a second femtosecond laser pulse ejects an electron from the ion. The resulting photoelectron spectrum changes as a function of the delay between the two laser pulses, providing a dynamic picture of events as the ion dissociates. Although real-time ultrafast laser techniques have attracted much attention, they have not put out of business the indirect methods of characterizing the transition state. Some unimolecular reactions occurring under collision-free conditions can go from reactants to products without barriers in the minimum energy pathway, noted chemistry professor Hanna Reisler of the University of Southern California, Los Angeles. And without a barrier, she said, locating the transition state is not easy. To get a picture of the transition state, Reisler looks at reactions at infinite time as represented by the final products. She obtains whaf s called quantum-state distributions of the products by accurately measuring the nascent vibrational, rotational, and translational energies of each product. "Then you have to work your way backwards," she said. Sometimes, the information is so rich that "you can really get a clear picture of the region of the transition state." Reisler studied the unimolecular dissociation of nitrogen dioxide to an oxygen atom and nitrogen oxide. From changes in the patterns of product-state
Barbara: include solvent motions in theory
Simons: transition state not always the key
distributions, she deduced that when N 0 2 dissociates near its dissociation threshold, the transition state looks very much like the products: O and NO are apart but still very close to each other, with NO rotating and vibrating freely. But when the reaction occurs at higher energies, the transition state looks more like an asymmetric N 0 2 molecule with one bond very much extended. "Although the whole thing is bending wildly," Reisler explained, "it still looks like a molecule, not like separate fragments." Other chemists are applying femtosecond-timescale studies to condensed phases. For example, two groups described research on electron transfer and how intramolecular and solvent motions affect transition states and therefore reaction rates. At the University of Pennsylvania, assistant chemistry professor Norbert F. Scherer uses ultrafast laser spectroscopic methods to study reactions in APRIL 22,1996 C&EN
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SCIENCE/TECHNOLOGY
•Acceptor "§ acceptor Donor
acceptor
Donor
biological systems. In collaboration with his Pennsylvania colleague Voth, he has been looking at electron transfer in blue copper proteins, such as plastocyanin. These proteins shuttle electrons through long distances, but an analogous transfer can be made to occur between the copper atom and the sulfur atom of an adjacent cysteine residue. To study how bond motions affect electron transfer, Scherer uses shortduration laser pulses to make the Cu-S bonds throughout the sample move uniformly, rather than randomly. By observing how the uniform motion decays (or becomes random again) while the electron returns to sulfur, he can—in combination with molecular dynamics simulation of the protein—pinpoint the vibrational motions associated with the electron-transfer event and determine their effect on reaction dynamics. On the other hand, chemistry professor Paul F. Barbara at the University of Minnesota, Minneapolis, focuses on solvent motions and their effect on electron transfer. "A reliable and general way of including solvent motions into electron-transfer theory remains an active area of research/' Barbara said. "We need to understand how solvent molecules move and vibrate and how these motions influence the yield, the mechanism, and the rate of electrontransfer reactions." One system Barbara's group has examined is the mixed-valence metal dimer called RuRu. When RuRu is photoexcited, an electron migrates between its two ruthenium centers: 40
APRIL 22, 1996 C&EN
Donor
Pruning simplifies chemically modified azurin from about 130 amino acid residues (above) to about 15 electrontransfer-relevant amino acids (middle). Atomic tunneling currents reveal the electron path from donor to acceptor at atomic resolution (left, shown in solid red).
(NH3)5RuI11NCRuII(CN)5- — (NH3)5Ru11NCRuIII(CN)5The reaction proceeds about 37 femtoseconds faster in water than in D 2 0, proving "that electron transfer is faster in the presence of certain solvent motions but slower in others," Barbara said. Underlying the electron-transfer studies of Scherer and Barbara is the theory of electron-transfer reactions formulated by Caltech chemistry professor Rudolph A. Marcus. The theory, for which Marcus received the 1992 Nobel Prize in Chemistry, defines the transition state for electron-transfer reactions. It has been applied to many areas, including photosynthesis and chemiluminescence. Marcus continues to break new ground. As he told a packed audience at the symposium, one of his current interests is long-range electron transfer. Recently, he has been examining data from modified proteins synthesized by his Caltech colleague Harry B. Gray. Gray and coworkers have been modifying proteins by introducing electron acceptors at specific residues. For example, they attach a ruthenium electron acceptor to the protein azurin. The rate of electron transfer between the acceptor and the protein's natural metal center can be varied by changing the ruthenium ligands. "You know you're seeing the pure electronic effect—the electronic coupling— when you reach the maximum rate," said Marcus. Then one can examine how the coupling depends on various factors.
But because proteins are big, they are computationally unwieldy. Marcus and former Caltech collaborator Prabha Siddarth have tried to extract the electron-transfer-relevant amino acids by "artificial intelligence" techniques. Recently, another Marcus collaborator, Alexei A. Stuchebrukhov, has developed another approach. Stuchebrukhov, an assistant professor of chemistry at the University of California, Davis, uses a mathematical technique called "sparse matrix" analysis to "prune" proteins containing hundreds of residues to the few electrontransfer-relevant amino acids. The technique is based on a simple premise: Any part of the protein experiences only what its nearest neighbor is doing. In New Orleans, Stuchebrukhov showed the power of pruning with examples of azurins that had been modified by Gray and coworkers. With graduate student Iraj Daizadeh and postdoctoral fellow John N. Gelilen, he computationally probed the amino acids one by one and determined their effects on electronic coupling. The exercise pruned the protein to an electron-transfer-relevant sequence of about 15 amino acids. The method has two advantages, noted Marcus. It tells which part of the protein is important in the electron's journey. And for more elaborate approximations, the pruned protein is more practical to use than the entire protein. Stuchebrukhov did not stop at the pruned protein, what he calls amino acid resolution of the electron-transfer path. Using a method called "atomic tunneling currents," he pushed for atomic resolution. By calculating the probability that
the electron will pass (or "tunnel") through individual atoms of the protein, he identified the specific atoms through which the electron hops from donor to acceptor. Ultimately, he said, it will take atomic resolution to get a clear understanding of how long-distance electron transfer occurs in proteins. As befits any symposium claiming to be comprehensive, maverick ideas also were discussed. Chemistry professor Jack Simons at the University of Utah, Salt Lake City, attracted a big audience with a paper he purposely titled provocatively, "Reaction Paths and Transition States—Maybe Not!"—an apparent challenge to the whole idea of the transition state. "Challenge is too confrontational a word," Simons said. "I only want to bring to the audience's attention that transition states are not always the most important things to find when one is modeling or interpreting reactions." To get from reactants to products, sometimes other paths are more relevant than the path passing through the transition state. One such area, called a seam, is the region where the potential energy surface is penetrated by another. This situation exists when the energies of the ground and excited states are so close that the system can bypass the transition state. In another special area, what Simons calls a hot spot, energy transfer takes place very easily so that, again, the transition state is not important. Simons came up with the idea in trying to explain data obtained by his Utah colleague Peter B. Armentrout. Armentrout had been carrying out reactions in which he slams positive gallium ions into deuterated hydrogen (HD) to form GaD+ and a hydrogen atom. According to Simons, the expected energy cost of the reaction is about 94 kcal per mol. "Trouble is, when [Armentrout's group] shoots the gallium ions into a bowl of room-temperature HD, they find they have to accelerate the ion to more like 200 kcal of relative translational energy before it has enough oomph to react," Simons said. How can the whopping difference be explained? Taking a leap of faith, as theoreticians often do, Simons explained the discrepancy by assuming that a theory of energy transfer between vibrating bodies in resonance also applies to a collision-tovibration energy flow. (A collision can
be viewed as half a vibration; it goes but doesn't come back.) In effect, at the hot spot, Simons explained, the 'local energy level spacing" of the ion matches the vibrational energy spacing of HD. Energy leaks from the ion and transfers to HD, stretching the H-D bond and leading to a reaction that also bypasses the transition state. By most accounts, the well-attended and much appreciated four-day symposium lived up to its billing as a celebration of 60 years of transition-state theory.
Marcus came away deeply satisfied. "If s very stimulating to hear results, details," he said. "Ideas filter in when you hear people talk. You assimilate, and sometimes, something gets triggered." Zewail, who gave the symposium's opening lecture, said: "If Michael Polanyi and Henry Eyring were alive today, they would have been thrilled to see that the ephemeral transition state of their 60-year-old theory can now be captured and observed as reactants actually evolve to products." •
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SCIENCE/TECHNOLOGY
Elementalfluorine—it'snot just for destroying organic molecules anymore commercially available in diluted forms such as 10% F2 in nitrogen gas. And "modern transducer technology allows you to control the rate at which fluorine is added to a system very, very carefully," according to chemistry professor James L. Adcock of the University of Tennessee, Knoxville, who organized Ron Dagani, C&EN Washington the symposium. "If s no longer a matter ou've come a long way, baby" of opening a valve and praying." Now that fluorine can be delivered was a slogan used to advertise a brand of cigarettes aimed at up-and- at a rate that will not cause overheating coming women. But the phrase also or rampant reaction, he added, chemcould be applied to elemental fluorine. ists are free to investigate the effect of Once shunned as a fluorinating agent controlling other reaction conditions. because of its voracious, destructive re- "That's where most of the advances activity with organic molecules, elemen- have been coming." tal fluorine has come to be recognized as The destructiveness of elemental fluoa useful reagent in organic chemistry. rine is due in large part to the ease with But if s taken a while. In a 1968 article in which the F-F bond homolytically cleaves the Journal of Chemical Education, chemistry to give F radicals. Because of their small professor Clay M. Sharts of San Diego size and unsurpassed electronegativity, State University stated that "fluorination fluorine radicals attack organic molecules by fluorine is unlikely to be used in normal organic syntheses." When C&EN asked Sharts about this at the recent American Chemical Society national meeting in New Orleans, he freely admitted that all that had changed. Indeed, the one-anda-half-day symposium in the Division of Fluorine Chemistry on direct and/or selective fluorination that Sharts attended was a showcase, of sorts, for the progress that synthetic chemists have made in taming F2 and harnessing it and fluorine-containing compounds as selective fluorinating agents. The taming of molecular fluorine has been achieved by careful control of several factors, including fluorine's concentration in the reaction vessel, the reaction temperature, and the choice Adcock shows off models of his perfluorinated stellane of solvent. Fluorine is (right) and its diketone precursor.
211th ACS National Meeting
NewOreans Y
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APRIL 22,1996 C&EN
indiscriminately, breaking almost any C-H or C-C bond. In the 1970s and 1980s, this behavior was tamed in Richard J. Lagow's lab, first at Massachusetts Institute of Technology and then at the University of Texas, Austin, and also in Adcock's lab in Knoxville. The procedures they developed allowed all the hydrogen atoms in certain types of organic molecules to be replaced with fluorine, providing important routes to valuable perfluoro compounds. Lagow and his colleagues have pioneered two direct fluorination methods known as the LaMar and Exfluor-Lagow processes. The LaMar method was developed in 1969 when Lagow was a graduate student in John L. Margrave's lab at Rice University in Houston. It involves exposing the substrate to be fluorinated, in the form of a fine powder, to a gas stream containing F2. In the ExfluorLagow method (named after an Austin company cofounded by Lagow), the substrate reacts with F2 in a vigorously stirred solution of a chlorofluorocarbon. Adcock, who was a postdoctoral fellow in Lagow's lab in the early 1970s, later developed an alternative method known as aerosol direct fluorination. In this method, the substrate is condensed onto microscopic sodium fluoride particles, and this aerosol is then passed through a gaseous F2 concentration gradient inside a special reactor. Over the years, these techniques were refined to allow the synthesis of new perfluorinated molecules and to produce known perfluoro compounds in higher yields. A case in point: In 1992, Adcock used the aerosol method to make perfluo'' rodiamantane for the first time, in 8% yield, from the parent hydroPerfluorodiamantane carbon [/. Org. Chem., 57, 2162 (1992)]. Lagow and coworkers, who had prepared the first perfluorinated adamantane derivatives using the LaMar method, independently sought to fluorinate diamantane, a molecular "Siamese twin" of adamantane. Earlier this year, they reported success— and a product yield of 45%-*-using a combination of the LaMar and ExfluorLagow methods [/. Org. Chem., 61,1643 (1996)]. The product, which they call by its trivial name perfluorocongressane, is now being investigated for its unusual solid lubricant properties.
Lagow didn't mention perfluorocongressane in his Perfluorinated 'star molecule' made via 'indirect' route presentation, but he did rattle off a bevy of other fluorinated molecules his Aerosol fluorination group has made using F2. -2 CO These include W(CF3)6, long-chain acids such as Perfluorobisnoradamantane Adamantane-2,6-dione CF3(CF2)8COOH, polyethers such as C4F9(OCF2)nOC4F9 and C[CF2CKCF2)7CF3]4/ and phosphoranes such as FC[CF2PF2(CF3)2]3 the perfluorinated diketone eliminated ample, chemistry professor Richard D. and F2P[(CF2)7CF3]3. Some of the perfluo- two molecules of carbon monoxide on Chambers of the University of Durham rinated polyethers, for instance, have po- ultraviolet irradiation and formed two and his coworkers there and at BNFL tential as high-performance lubricants, new C-C bonds. The perfluorostellane Fluorochemicals, Preston, have been inert fluids, coolants, or high-tempera- was generated cleanly and almost quan- exploring ways to moderate and moditure fluids and elastomers. titatively. "We were amazed" by the fy the reactivity of elemental fluorine for specific chemical transformations. Lagow's group also has pioneered in high yield, Adcock remarked. using direct fluorination to make a wide An especially interesting feature of The British group has found that usrange of perfluoro macrocycles for the the perfluorostellane is that its 19F nu- ing F2 in highly acidic solvents like sulfirst time, such as perfluorocryptands clear magnetic resonance spectrum ex- furic acid can provide rather surprising and perfluoro crown ethers—both the hibits long-range virtual coupling. This selectivities and high yields of monofluomonomelic and dimeric varieties. Some unusual phenomenon occurs when rinated products. In his presentation, of these compounds show potential in two nuclei, coupled to a third nucleus Jock S. Moilliet of BNFL Huorochemicals medical applications such as magnetic but not to each other, appear to be cou- pointed out that using the F2/H2S04 resonance imaging and reversible ion pled to each other. "This [coupling pat- system to monofluorinate chloroaromatbinding and extraction. This diversity of tern] has been seen before, but never ics yields a different isomer than would perfluoro molecules demonstrates, as with such clarity and stark uniformity," be provided by the halogen exchange Lagow said, that "you can do an awful Adcock said. "It is a perfect example of process, in which a chloro substituent is lot with direct fluorination." this effect. And because if s a perfect ex- replaced withfluorine.Although the F2 Adcock's explorations in direct fluo- ample in a very rigid ring system, it route has its limitations, it can provide rination have focused on cage mole- opens up the possibility for theoretical compounds that are otherwise difficult cules such as fullerenes and "diamon- chemists" to develop a clearer under- to synthesize. doid" frameworks like adamantane standing of this phenomenon. Durham's Graham Sandford, another and diamantane. The latest news from While chemists like Lagow and Ad- member of the Chambers team, showed his lab is the synthesis of perfluorinat- cock largely have pursued an all-or- how using molecular fluorine together ed bisnoradamantane, a beautiful nothing approach to replacing hydro- with molecular iodine can efficiently molecule known generically as a stel- gens with fluorine, other chemists have transform carbon-sulfur bonds to carlane because it is shaped like a four- been seeking improved ways to intro- bon-fluorine bonds. The F2/I2 reagent pointed star [/. Org. Chem., 61, 1975 duce fluorine into one or two specific system also can convert heterocyclic (1996)]. "It is the smallest fluorinated sites of a molecule. In England, for ex- molecules such as pyridine to the cc-fluocage molecule made to date," Adcock ro derivative. pointed out. Yet another team member—John HutchThe bisnoradamantane structure is N-F reagents are used for electrophilic inson—reported that the most symmetrical way to fuse fivefluorination reactions membered rings into a cage. But be10% F2 in N2 can be cause of the way the rings are joined used to fluorinate the together, the molecule is more strained C-2 position in 1,3-dithan an adamantane. Since direct fluocarbonyl compounds rination of highly strained cage comcleanly and in high N, N -Dif luoro-1,4-diazoniaAf-Fluoro-obenzenepounds tends to cause ring opening, yield. The solvent in bicyclo[2.2.2]octane disulfonimide Adcock and graduate student Huqiu these reactions is forbis(tetrafluoroborate) Zhang decided to pursue an "indirect" mic acid or acetoniapproach. Their three-step route also trile. Their results inhas the advantage of being shorter than dicate that "elementhe "direct" approach, which calls for talfluorinehas been making the stellane and then fluorinatgreatlyunderestimating it. ed as a reagent for site-specific fluorinaThey accomplished the synthesis by Perfluoro[poly(pyrazino)Perfluoro(pyrolyzed tions," the British refirst preparing adamantane-2,6-dione polyacrylonitrile) pyrazine] searchers noted last and then perfluorinating it with F2 using year in a report of Adcock's aerosol reactor. As expected, APRIL 22,1996 C&EN 43
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APRIL 22,1996 C&EN
their work [/. Chem. Soc, Chem. Com mun., 1995, 21]. Even as elemental fluorine's star has been rising, chemists have been search ing for alternative fluorination reagents that are safer and easier to handle than F2 and related molecules. In the past 13 years, for example, fluorine chemists have built up a stable of so-called N-F reagents—electrophilic fluorinating com pounds that have one or more nitrogenfluorine bonds. Several of these were dis cussed in New Orleans. For example, professor Darryl D. DesMarteau of Clemson University in Clemson, S.C., focused on the fluorination chemistry of N-fluorobis[(trifluoromethyl)sulfonyl]imide, (CF3S02)2NF, which he began studying in 1984. DesMarteau noted that this reagent can selectively fluorinate a wide variety of enolates, carbanions, imines, pyridines, and other molecules. It is currently being consid ered for commercialization, he said. Last year, Ronald E. Banks's group at the University of Manchester Institute of Science & Technology in England re ported the synthesis of salts of N,N'-difluoro-l,4-diazoniabicyclo[2.2.2]octane, an electrophilic fluorinating agent that has two cationic N-F sites in each mole cule [/. Fluorine Chem., 74, 165 (1995)]. The salts the Manchester chemists pre pared were moisture sensitive, difficult to characterize, and apparently impure, according to Teruo Umemoto of Daikin Industries in Tsukuba, Japan. In New Orleans, Umemoto announced that his group has developed a high-yield, onepot synthesis of the bis(tetrafluoroborate) salt of this dicationic reagent. This salt was obtained as stable, nonhygroscopic crystals, which could be better characterized. Adcock believes Umemoto's work is a significant practical ad vance in the field. Polymeric N-F reagents, which were first reported by Banks a decade ago, also came up at the symposium. The ad vantage of polymeric reagents is that they are easily separated from the prod ucts. James DeYoung, formerly a gradu ate student in Lagow's group, discussed perfluoro(pyrolyzed polyacrylonitrile) and perfluoro[poly(pyrazino)pyrazine], structurally similar polymers that are "two of the most concentrated forms of active fluorine." The two polymers are extremely reactive with aromatics at room temperature, DeYoung said, and so the reactions have to be carried out at lower temperatures to keep them under control.
The N-F reagents were developed because of the need for less reactive al ternatives to molecular fluorine. But F2 itself is still needed to synthesize many of these reagents. The symposium also featured some developments in electrochemical fluori nation, a well-established method that is used industrially to manufacture many fluorochemicals. In electrochemi cal fluorination, anhydrous hydrogen fluoride is electrolyzed at a voltage that, rather than producing F2, produc es a high-valency metal fluoride on the anode. Fluorination occurs when the organic substrate interacts with the metal fluoride on the anode surface. "The electrochemical method has nev er been viewed particularly as a selective method," Adcock told C&EN. But Toshio Fuchigami and coworkers in the depart ment of electronic chemistry at Tokyo Institute of Technology, Yokohama, have been demonstrating how the meth od can be used for selective fluorination of heteroatomic compounds. In the first of two talks, Fuchigami described how thioketals can be converted to geminal difluoromethylene compounds using a hypervalent iodoarene chlorofluoride, RC6H5I(C1)F. The chlorofluoride is pre pared by anodic oxidation of the io doarene in acetonitrile containing fluo ride and chloride ions. In a second talk, Fuchigami intro duced a supporting electrolyte and fluo rine source for selective anodic monofluorinations of sulfur- and oxygen-con taining rings. The new electrolyte/ solvent is neat (C2H5)4NF · 4HF, which gives better results than supporting elec trolytes such as (C2H5)3N · 3HF in aceto nitrile. Higher currents can be passed us ing the new electrolyte, leading to short er electrolysis times, Fuchigami said. Higher yields of the monofluoro product (fluorine α to the sulfur atom) also are seen in some cases. The electrochemical route, like the use of metal fluorides, originally was devel oped as an alternative source of active fluorine. But as the technology for han dling elemental fluorine has improved, Adcock explained, researchers have be come more comfortable with this pale yellow gas, and they are more inclined to find ways to moderate its activity rather than to look for substitutes. Ele mental fluorine "was always so far out ... that no one wanted to tackle it," he said. "All we've done, really, is bring fluorine into the mainstream." •
