Monday, March 21, 2011

Taking the guesswork out of understanding complex, multi-molecule transformations

Multicomponent reactions (MCRs) that chemically combine three or more molecules into a brand new product are faster and generate less waste than traditional step-by-step synthetic procedures, making them invaluable in efforts to improve efficiency and sustainability. Since 1921, chemists have used an MCR called the Passerini reaction to produce bioactive, peptide-like chains made from three partners: carboxylic acids, carbonyl compounds, and cyanide-bearing molecules. However, a full understanding of this process has eluded researchers because its multipart workings are difficult to detect experimentally.

Now, Satoshi Maeda and Keiji Morokuma from Kyoto University and Shinsuke Komagawa and Masanobu Uchiyama from the RIKEN Advanced Science Institute in Wako have developed a computerized way to better identify the hidden mechanisms of one-pot, multi-step . Their technique, the artificial force induced reaction (AFIR), systematically squeezes and joins model compounds together in order to rapidly detect signatures of real MCR energy barriers.

According to Maeda, detailed theoretical understandings of MCRs have been scarce because most calculations require excellent estimates of transition state structures—intermediate and often highly strained geometric arrangements between molecules that correspond to the energetic peak of a reaction barrier. “Consequently, a trial-and-error process based only on [chemistry-based] intuition is unavoidable,” he says.

The AFIR method, on the other hand, requires no such presumptions. Maeda explains that when two molecules are pushed into each other with a weak force, they spontaneously relax into ‘dents’ in the potential barrier created by attractive electronic interactions between the reactants. By methodically pressing over all possible orientations, and inducing an artificial reaction from the relaxed positions, AFIR searches can identify every stable reaction pathway in a system.

To the team’s surprise, applying AFIR calculations to the Passerini reaction revealed that four components, not the long-thought three, must be involved (Fig. 1). Since the reaction barriers were so high, the researchers realized that an additional carboxylic acid—a known proton transfer catalyst—had to participate in the transition states leading to the final product. This finding should enable design of Passerini reactions with improved structural selectivity, notes Maeda.

Once perfected, the researchers anticipate their technique will make MCRs even more widespread. “Unlike standard methods, giving only pathways that are easy to find, the AFIR method has a unique ability to find unknown pathways in MCRs systematically,” says Maeda. “Information on reaction pathways is very important even for processes that do not normally occur, because chemists can initiate such reactions by controlling conditions, modifying substituents, and introducing new catalysts.”

More information: Maeda, S., et al. Finding reaction pathways for multicomponent reactions: The Passerini reaction is a four-component reaction. Angewandte Chemie International Edition 50, 644–649 (2011). http://onlinelibra … 336/abstract

Provided by RIKEN (news : web)

Finding shows potential way to protect neurons in Parkinson's, Alzheimer's, ALS


Cell biologists pondering the death of neurons -- brain cells -- said today that by eliminating one ingredient from the cellular machinery, they prolonged the life of neurons stressed by a pesticide chemical. The finding identifies a potential therapeutic target to slow changes that lead to neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.

The researchers, from The University of Texas Health Science Center San Antonio, found that lacking a substance called caspase-2 were better able to withstand pesticide-induced damage to energy centers known as mitochondria.

Caspase-2 appears to be a master switch that can trigger either cell death or survival depending on the amount of cellular damage, the team found. Neurons that lacked caspase-2 showed an increase in protective activities, including the efficient breakdown of obsolete or used proteins. This process, called autophagy, delays cell death.

"This research shows, for the first time, that in the absence of caspase-2 neurons increase autophagy to survive," said study co-author Marisa Lopez-Cruzan, Ph.D., investigator in the cellular and department at the Health Science Center.

Evidence suggests that mitochondrial dysfunction plays an important role in neuronal death in conditions such as Parkinson's disease, , amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Huntington's disease.

"Identifying initiators in the cell death process is important for determining therapeutic approaches to provide the maximum protection of neurons during neurodegenerative conditions," said senior author Brian Herman, Ph.D., vice president for research and professor of cellular and structural biology at the Health Science Center.

The team studied neurons from young adult mice. This was intended to model the early changes that take place in .

The research is in the March 11 issue of the .

Dr. Lopez-Cruzan, director of Dr. Herman's laboratory, came up with the idea that caspase-2 protects cells from mitochondrial stress. Meenakshi Tiwari, Ph.D., postdoctoral fellow, expanded upon the initial work and is first author of the paper.

Provided by University of Texas Health Science Center at San Antonio

Finding the correct dosage of medication by breath analysis

Using a mass spectrometric method, ETH Zurich researchers are able to measure metabolites of a common epilepsy medication directly in exhaled breath. This simplifies testing of patients and represents a step towards personalised medicine.

Spoiled meat, pesticides on vegetables or fruit, melamine in milk: there are very few fields of chemical analysis which ETH Zurich Professor Renato Zenobi has not already investigated using mass spectroscopic methods. He has now added another analysis method, which is based on , to this series: breath analysis to track down of a widely used drug for treating epilepsy.

“Breath contains hundreds of chemical substances”, says Zenobi, and adds that breath analysis has great potential for medical diagnostics. However, the Professor of Analytical Chemistry at ETH stumbled upon the topic of epilepsy by chance. He says that one of his former coworkers was dependent on the anti-epileptic valproic acid (VPA). This active ingredient suppresses epileptic seizures. However, to clarify the correct dose of the medicine for a patient, the latter must have blood samples taken every few weeks to measure the VPA concentration. In the future, this tedious procedure could be replaced with non-invasive breath analysis, because Zenobi has shown that VPA metabolites are detectable in patients’ breath. Medicines and their metabolites can leave the body through the kidneys or, to a certain extent, via the lungs.

Obtaining test results directly and easily

The test the method, developed by Zenobi’s former postdoctoral associate Gerardo Gamez and in collaboration with researchers from China and Bremen and the Swiss Epilepsy Center, is similar to previous analytical methods originating from this group at ETH Zurich. All that is needed to test a person’s breath is for them to blow into a small tube. The breath passes through a heated Teflon tube to an area where the exhaled air is ionised by protonation. The chemical compounds, now carrying a charge, are aspirated through a small orifice into the mass spectrometer, where they are then separated and measured according to their mass. There is no need to pre-treat or store the samples.

Currently, however, the analysis instrument is still unwieldy and nowhere near as practical as an alcohol testing device used by the police. This is because a mass spectrometer also contains pumps, which generate the vacuum needed inside the instrument. “Nevertheless, this method is direct and simple, non-invasive, painless and represents an important step towards personalised medication”, says the ETH Zurich professor.

First test scores a direct hit

First of all, the researchers tested Zenobi’s coworker who suffers from epilepsy, as well as healthy persons as controls – and scored a bull’s-eye. The spectra produced by the mass spectrometer for the breath of epilepsy patients showed two distinct signals not found in the breath of healthy persons. However, if a dose of VPA was administered to healthy volunteers, the same signals were found in their breath as in the case of persons being treated with VPA.

Further detailed investigations showed the researchers that the peak caused by the heavy molecule was attributable to a VPA metabolite with an ammonium group bound to it. The second peak corresponded to exactly the same compound after ammonia had been split off. The VPA metabolite was previously unknown to the research world. Thus the ETH Zurich chemists have, in one stroke, discovered both a new metabolite and a new biomarker for VPA in breath.

Non-invasive diagnosis is increasingly important

Furthermore, the researchers compared the VPA values from blood tests with the breath analyses. This revealed that patients treated with VPA always exhale the metabolite, and that its concentration in exhaled breath correlates with that of free VPA in blood: the higher the blood value, the stronger the signal in the mass spectrometer. Finally, the MS analysis also yielded information on how quickly the body degrades VPA. According to Zenobi, the VPA level decreases exponentially with time.

The importance of non-invasive diagnosis in modern medicine is growing strongly. It is often easier to apply and is less stressful for patients than invasive methods such as blood sampling or biopsies. Renato Zenobi is also convinced that his new diagnostic method has a future for patients treated with VPA.

“However, the method is so widely and universally applicable that it can also deal with many other substances in breath”, he says. The ETH Zurich professor can therefore well imagine that someday every medical practice will have a mass spectrometer that will enable a wide variety of diagnoses.


There are around 70,000 epileptics in Switzerland, 15,000 of whom are children. Five percent of the whole population suffer an epileptic seizure at least once in their lifetime, and one percent become ill with epilepsy. There is not just one form of epilepsy; doctors distinguish up to 30 different types. Up to 70 percent of all types of epilepsy can be treated well with medication. Valproic acid is an anti-epileptic which was developed around 1970. Together with carbamazepine, it is the medicine most commonly used to treat : more than half of all the epileptics in Europe are still treated with these two drugs. However, many new anti-epileptics have been developed and introduced in the last 10 years.

More information: Gamez G, Zhu L, Disko A, Chen H, Azov V, Chingin K, Krämer G & Zenobi R. Real-time, in vivo monitoring and pharmacokinetics of valproic acid via a novel biomarker in exhaled breath. ChemComm., 2011. Doi:10.1039/c1cc10343a

Provided by ETH Zurich

Novel approach uses ion-molecule collisions, deposition to create sought-after material


(Once only possible with expensive liquids and large amounts of waste, scientists can now create an efficient, easy-to-separate catalyst with small amounts of material, thanks to an innovative approach from Pacific Northwest National Laboratory. Dr. Julia Laskin and Dr. Grant Johnson employed collisions between ions and molecules within a mass spectrometer, a popular analytical technique, to manipulate ruthenium-centered ions in the gas phase. The resulting highly reactive ions, which cannot be generated easily in solution, were then gently deposited onto a selected surface. The product is a catalytically active material that may one day be used in fuel cell and solar energy storage applications.

"Using the unique capabilities of a we can manipulate an ion in the gas phase and obtain a material that is unattainable in solution," said Johnson, a physical chemist and a Linus Pauling Distinguished Postdoctoral Fellow at PNNL.

When it comes to producing fuels, whether bio- or petroleum-based, catalysts drive the reactions, thereby reducing cost, inefficiency, and waste. Scientists at PNNL and elsewhere are working to design catalysts that combine the selectivity of homogenous catalysts with the ease of use of . Heterogeneous catalysts, which are less selective, are commonly used because they are easy to separate from the reactants and products. This study shows a new approach that allows scientists, for the first time, to create unique, easy-to-separate catalysts.

Laskin and Johnson selected the tris(bipyridine) complex to study because of its applications in solar energy conversion and oxidation catalysis. The complex has a ruthenium metal atom surrounded by a set of three ligands, strings of atoms that wrap around the ruthenium center. With all three wrappers in place, the catalyst is fairly unreactive. However, removing one of the wrappers and partially exposing the metal center makes the complex catalyze reactions that turn simple chemical feedstock, such as ethylene, into valuable chemical intermediates such as ethylene oxide. "This ruthenium complex has been a hot topic lately," said Laskin.

In this study, the scientists began by putting the ruthenium-centered catalyst into the gas phase using electrospray ionization. Then, the ions were focused through an ion funnel. They accelerated the ion beam to cause the ions to collide with gas molecules inside the vacuum chamber. The collisions caused the to snap off, exposing the catalytically active ruthenium core. The ions were then passed through powerful oscillating electric fields that separated out the desired unwrapped ruthenium ions.

The researchers directed a beam of the desired ruthenium ions at a surface, a carboxylic acid terminated self-assembled monolayer atop a very thin layer of gold. They transferred the surface into a time-of-flight secondary ion mass spectrometer (TOF-SIMS). Using the data from the in situ TOF-SIMS, they determined that the unwrapped ruthenium-centered catalysts adhere strongly to the surface and exhibit behavior that is consistent with the catalytic oxidation of ethylene to ethylene oxide.

The team is continuing to investigate the possibilities of generating new catalytic species in the gas phase and depositing them onto surfaces. This work will further the controlled preparation of materials that are necessary for advancements in catalysis and .

More information: Johnson GE and J Laskin. 2010. "Preparation of Surface Organometallic Catalysts by Gas-Phase Ligand Stripping and Reactive Landing of Mass-Selected Ions." Chemistry: A European Journal 16, 14433-14438.

Provided by Pacific Northwest National Laboratory (news : web)

Accounting for scale in catalysis

Accounting for scale in catalysis


The thickness of the RuO2 catalyst, along with heat and mass transfer, affect the speed with which carbon monoxide is converted to carbon dioxide.

( -- Depicting a catalyst's behavior in the real world just got a lot easier, thanks to scientists in the Institute for Interfacial Catalysis (IIC) at Pacific Northwest National Laboratory. They used complex calculations to describe the surface temperature of a reaction based on the thickness of the catalyst, the heat transferred in the reaction, and the transport of the reactant. Their research provides an accurate and reliable computational model of conditions found in the real world. These multi-scale simulations can predict the limitations imposed by environmental variables in real-world situations, improving catalysts for many important practical applications.

In industry, cost is always a primary consideration. Technologies such as oil refining, pharmaceutical manufacturing, and production and storage of energy are very expensive enterprises. Catalysts are used to speed up and to efficiently provide the desirable reaction results for those industrial processes. Much of the research done in the catalysis arena is focused on making the more selective for the desired product, and reducing the amount of energy required for the chemical reaction. In this new work, researchers have used to extend the reaction modeling from the of the chemical reactions, to the macro-scale level of the overall catalytic process. By moving closer to real-world operational conditions, this research supports the need to design better catalysts and optimize the reaction conditions in catalytic reactors.

Ruthenium dioxide (RuO2) has been widely investigated for many important industrial reactions. Previous modeling of RuO2 reactions has focused on the elementary surface reactions at the microscopic scale. With these models, scientists can predict the catalytic kinetics under constant reaction conditions. However, in a real , the reaction conditions such as temperature and pressure can often change as the catalytic reactions proceed. For example, accounting for possible changes in surface temperature of the reaction and the mass transfer of the gas reactant through and over the catalyst have not been considered. And until now, these factors have been difficult to account for due the different time and length scales of the computational techniques.

Using carbon monoxide oxidation on the RuO2 catalyst as an example, IIC scientists were able to demonstrate that the macroscopic reaction kinetics of the oxidation processes are dramatically affected by catalyst size and surrounding reaction environments. Their catalytic reaction model showed that both heat and mass transfer can change the reaction dramatically. If the reaction heat is not effectively removed, the catalyst itself will overheat and deactivate. Such high temperatures can lead to the growth in size of the catalyst particles, reducing the number of catalytically active sites where the take place. If very high temperatures occur during overheating, evaporation and loss of the catalyst can result.

The thickness of the catalyst on the support has a significant effect on the ability of catalyst to withstand changes in the reaction environment. At the nanometer size, the catalyst reaction may proceed too quickly and then easily deactivate because the heat generated by the reaction cannot be effectively removed. The models show that by increasing the thickness of the catalyst, the reaction heat generation and removal are often less of a problem.

In this study, the researchers also considered mass transport of the gas reactants to, from, and through the catalytic reaction zone. To keep the reaction going, the reactant molecules must move to the surface of the catalyst for adsorption, and the product molecules also need to quickly leave the same region after desorbing from the catalyst surface. These movements of gas-phase reactants and products can also provide effective ways to add or remove heat from the catalyst surface. By understanding and effectively managing this mass transport, catalyst activity, selectivity, and durability can be optimized.

With this research, the IIC scientists at PNNL have developed an accurate and reliable for in-reactor catalytic processes. They demonstrated the necessity to include heat and mass transfer in the surrounding reaction environment and their effects on the reaction kinetics.

The researchers plan to extend the current multi-scale model under reactive flow conditions. Extending the model will allow scientists to determine the effects of fluid flow and gas-phase reactions on the in-reactor catalytic performance.

More information: Mei D and G Lin. 2010. “Effects of Heat and Mass Transfer on the Kinetics of CO Oxidation over RuO2(1 1 0) Catalyst.” Catalysis Today. DOI:10.1016/j.cattod.2010.11.041

Provided by Pacific Northwest National Laboratory (news : web)

Expert shares fundamental discoveries of water's behavior on metals

Previous research into the behavior of water films, specifically molecularly thin ice films on metals, has left many fundamental questions unresolved, questions Sandia National Laboratories' Dr. Konrad Thürmer is beginning to unravel. Studying the interactions between ice and metals helps to decipher the basics of catalysis, corrosion, fuel cells, and the formation of clouds. Thürmer's talk was hosted by Pacific Northwest National Laboratory's Frontiers in Chemical Physics and Analysis Seminar Series. This series brings experts from around the world to discuss current research.

As part of his talk, Thürmer discussed his team's latest research into how nucleates and grows on surfaces at different temperatures. This research was performed using scanning tunneling microscopy, a technique that, under typical conditions, destroys the delicate water films. Therefore, the team had to develop an innovative non-destructive approach to obtain the images they wanted.

Thürmer and his team began with platinum at 140K, or -207 degrees Fahrenheit. They added a tiny amount of water and watched the ice form. The assumption was that the water would form layers of bulk-structured water. They got surprisingly different results. Instead, the scientists saw the ice undergo a delicate process that began with a lace-like two-dimensional structure and ended with terraced film morphologies.

The lace-like structure contains pentagons and heptagons, as well as the expected hexagons. By conducting theoretical calculations, the team found that this varied arrangement formed because the water molecules twist to create a flat, irregular low-energy structure with no broken bonds. The structure of the water films they observed may help explain results seen, but unexplained, in other water-on-metal systems.

The discussion on ice nucleation along with current research on surface diffusion, screw dislocations facilitating the growth of metastable cubic , and proton arrangement were well received by the audience. "Thürmer's team is doing novel work that is getting at the real molecular-level structure of water on surfaces," said Dr. R. Scott Smith, a senior physical chemist who attended the seminar. "This work is near and dear to our hearts."

Provided by Pacific Northwest National Laboratory (news : web)

Oscillating gels could find many uses (w/ Video)


Self-oscillating gels are materials that continuously change back and forth between different states — such as color or size — without provocation from external stimuli. These changes are caused by the Belousov-Zhabotinsky chemical reaction, which was discovered during the 1950s. Without stirring or other outside influence, wave patterns from this chemical reaction can develop within the material or cause the entire gel itself to pulsate.

Irene Chou Chen, a doctoral candidate in the lab of Krystyn J. Van Vliet, the Paul M. Cook Career Development Associate Professor of Science and Engineering, has been studying exactly how adjusting the size and shape of these gels can affect their behavior.

By integrating experiments with computer simulations conducted by collaborators Olga Kuksenok, Victor Yashin and Anna C. Balazs at the University of Pittsburgh, the MIT researchers have shown that pattern formation within the material can be controlled by changing the gel's size or shape. When the reaction is restricted to a sub-millimeter-sized gel, the material exhibits chemical oscillations that cause it to mechanically swell and shrink. Lasting for several hours, these self-sustained oscillations exemplify chemomechanical coupling — where cause mechanical changes. The work will be published in the March issue of the journal Soft Matter as part of a special focus on “active soft matter.”

The self-sustained pulsations could enable unique applications for this material, the researchers say, such as using it as an environmental sensor or as an actuator that could react to specific conditions. The simulations developed by the University of Pittsburgh group could also help to make such applications easier to implement.

Provided by Massachusetts Institute of Technology (news : web)