Chemical Year In Review 2009

Phase-Switching Catalysis

C&EN produces 51 issues each year containing several hundred articles about important research advances in chemistry. Our annual Chemical Year In Review reveals our choices for some of the superlative achievements that we featured this year, including efforts to characterize and harness graphene sheets like the one shown below. It also provides an opportunity to reflect on the ramifications of these developments. Our choices, displayed in approximately chronological order, are necessarily subjective, and we do not pretend that they are comprehensive. Indeed, these studies represent only a few examples of the many ways in which chemists are pushing the boundaries of what we know and what we are capable of doing.

By simply adding or removing carbon dioxide, chemists in Scotland devised a neat trick for reversibly shuttling a homogeneous catalyst between the organic and aqueous phases in a biphasic solvent system (C&EN, Jan. 26, page 11; Angew. Chem. Int. Ed. 2009, 48, 1472). The phase-switchable catalyst designed by Simon L. Desset and David J. Cole-Hamilton of the University of St. Andrews adds flexibility to the often complicated techniques required to isolate products and recycle catalysts during homogeneous reactions. The secret to the switchability is a weakly basic amidine group, –N=C(CH₃)N(CH₃)₂, that the researchers added to the phenyl rings of triphenylphosphine. The rhodium catalyst made with the modified phosphine ligand is soluble in organic solvent. On bubbling CO₂ into an aqueous-organic reaction system containing the catalyst, the CO₂ reacts with water to form carbonic acid (H₂CO₃). The transient acid protonates the amidine groups and renders the catalyst water-soluble. Subsequently bubbling N₂ into the biphasic system drives off CO₂ and shifts the equilibrium of the catalyst-carbonic acid complex, leading the catalyst to deprotonate and making it water-insoluble again. After a reaction is completed in either organic solvent or water, the researchers separate the product and catalyst into different phases, remove the product, and then shuttle the catalyst back into the original phase for the next reaction cycle. Building switchability into basic chemicals in this manner could facilitate greener and less-energy-intensive industrial chemical processes.

Hydrogen Peroxide Direct

Pretreating the carbon support for a gold-palladium catalyst used to produce hydrogen peroxide offers a simpler, more direct method for making the commodity chemical to use in disinfection and bleaching applications, announced a research group led by Graham J. Hutchings of Cardiff University, in Wales (C&EN, Feb. 23, page 8; Science 2009, 323, 1037). Historically, methods to produce H₂O₂ directly from H₂ and O₂ have not stopped at hydrogenating O₂ to form H₂O₂, but also converted some H₂O₂ into water. As a result, the current favored process for making H₂O₂ is an indirect approach that involves sequential hydrogenation and oxidation of an anthraquinone. Hutchings and colleagues originally found that pretreating an activated carbon support with either nitric or acetic acid, then drying the support before adding gold and palladium, results in a reusable catalyst that directly produces H₂O₂ with minimal H₂O formed. They have since learned that acid treatment also improves production of H₂O₂ when TiO₂ is used as the support (Angew. Chem. Int. Ed. 2009, 48, 8512). Drawing on hydrogenation experiments and microscopy studies, the researchers proposed that the acid pretreatment leads to smaller and better dispersed nanoparticles, which somehow shuts down sites that would convert H₂O₂ into H₂O.

Dodging The Substitution Laws

Electrophilic aromatic substitution reactions replace the hydrogen atoms on aromatic rings such as benzene with various functional groups, and time-honored rules predict how substituents already on the rings influence what the reaction products will be. Matthew J. Gaunt and Robert J. Phipps of the University of Cambridge reported a method that turns those traditional rules upside-down. With the help of a copper catalyst, they obtained meta-substituted biaryl products from aromatic rings that possess an ortho/para-directing group (C&EN, March 23, page 7; Science 2009, 323, 1593). Copper seems key to the unusual selectivity—running the same reaction with a palladium catalyst gives ortho-substituted products instead. So far, an acyl amine or similar directing group is required for the reaction to work, but the team is working to extend the reaction to more diverse substrates. “These are completely unexpected results,” commented Shannon S. Stahl, an expert on copper catalysis at the University of Wisconsin, Madison. “If this selectivity pattern can be generalized and controlled in other contexts, this chemistry will have substantial utility.”

Seeing Proteins Inside Cells

The utility of nuclear magnetic resonance spectroscopy got a boost this year when two Japanese groups harnessed the technique to obtain the structure of a protein in living cells and to study proteins in human somatic cells (C&EN, March 9, page 7). The studies could open the door to a broader understanding of how proteins perform their biological functions inside cells, in both health and disease. A wide range of studies have been carried out on the conformations, dynamics, and interactions of in-cell proteins. But until this year, no one had been able to solve the NMR structure of a protein in a living cell or obtain NMR spectra of proteins in mammalian somatic cells. Yutaka Ito of Tokyo Metropolitan University and coworkers studied the metal-binding protein TTHA1718 and showed that its structure in bacterial cells differs slightly from its conformation in vitro (Nature 2009, 458, 102). And Hidehito Tochio and Masahiro Shirakawa of Kyoto University and coworkers studied the FKBP12 protein in human somatic cells (Nature 2009, 458, 106). In-cell NMR had formerly been limited to prokaryotic cells and frog eggs. The Kyoto team showed how FKBP12 interacts with immunosuppressants and that the regulatory protein ubiquitin exchanges protons more quickly inside cells than outside.

RNA May Have Had A Counterintuitive Start

Origin-of-life research made headlines last spring when chemists reported a novel recipe for making ribonucleotides with inorganic phosphate (C&EN, May 18, page 40; Nature 2009, 459, 239). The synthesis works under conditions thought to be feasible during Earth’s primordial days and may help answer the long-standing question of how a presumed period of life based on RNA instead of DNA, known as the RNA world, might have come about. Attempts to assemble ribonucleotides directly from their three components—a ribose sugar, a heterocyclic base, and phosphate—have largely failed. But Matthew W. Powner, Béatrice Gerland, and John D. Sutherland of the University of Manchester, in England, sidestepped that dilemma in their synthesis, which makes activated versions of pyrimidine ribonucleotides such as the one shown. The approach avoids free sugars and bases as intermediates by making them from a common precursor, 2-aminooxazole. During the synthesis, phosphate acts as a pH buffer, a nucleophilic catalyst, and more, shepherding the complex reaction away from undesired products. The success in putting RNA together in an unusual way suggests that scientists should think outside the box about how life’s chemicals came together—the pieces and the assembly route might not be intuitive, Sutherland says. In work that is not yet published, Sutherland’s team has found a simple way to give the ribonucleotides the ability to assemble into short stretches of properly linked RNA.

Polymers That Fold Like Proteins

Borrowing from nature’s strategy of using intramolecular interactions to fold and unfold proteins, chemists in the Netherlands created the first examples of single strands of synthetic polymers that use hydrogen bonding to reversibly fold themselves into well-defined nanoparticles. Previously, only biopolymers such as proteins and nucleic acids were capable of performing such ordered folding. E. Johan Foster, Erik B. Berda, and E. W. (Bert) Meijer of Eindhoven University of Technology fashioned the nanoparticles from poly(norbornene) copolymers in which one block has either a urea or urethane pendant group containing an ureidopyrimidinone moiety (C&EN, May 18, page 7; J. Am. Chem. Soc. 2009, 131, 6964). When they shine ultraviolet light on dilute organic solutions of the polymers, a nitrobenzyl protecting group drops off the ends of the pendant groups, freeing the ureidopyrimidinones to form a string of hydrogen bonds that force the polymers to collapse into 20-nm nanoparticles. Adding a little acid disrupts hydrogen bonds and permits the polymer chains to expand back to the original random coil form. Since the paper came out, Meijer’s group has prepared the nanoparticles in water and used methyl methacrylate-based polymers. They have also introduced a chiral motif and forged covalent bonds to “fix” the folded polymers. Meijer says the research team has an unlimited list of applications to try, ranging from powder coatings to single-chain enzymelike catalysts to drug delivery.

Disorderly Proteins Turn Predictable

Floppy, unstructured proteins, despite their lack of defined nooks and crannies, still contain regions that are prone to binding small molecules, researchers learned this year. The findings provide a potential general approach to predicting binding sites on disordered proteins and finding small-molecule drugs to target them. Intrinsically disordered proteins play fundamental roles in biology, such as in gene transcription and cell division, but researchers don’t have a straightforward way of pinpointing molecules that alter their activity. Steven J. Metallo of Georgetown University, Edward V. Prochownik of the University of Pittsburgh Medical Center, and coworkers outlined a way to do just that (C&EN, June 1, page 5; J. Am. Chem. Soc. 2009, 131, 7390). The team studied a segment of a disordered transcription factor protein called c-Myc, which is implicated in multiple cancers. Prochownik’s group previously found seven structurally diverse c-Myc inhibitors. In the new study, the team found three hydrophobic peptide stretches on c-Myc that recognize those inhibitors. Their results explain the specificity of the inhibitors and suggest ways of finding more. Since the study came out, Metallo and coworkers have found that they can link two of the inhibitors together and gain three orders of magnitude in affinity for c-Myc, which remains disordered even in the tight complex.

Seeing Molecules In A New Light

A novel microscopy technique reported this year has made it possible to visualize nonfluorescent molecules only on the basis of their ability to absorb light. Light absorption by a small number of molecules is usually too weak to detect under a microscope, so imaging is typically based on fluorescence emission. The new approach, devised by X. Sunney Xie and coworkers at Harvard University, is four to five orders of magnitude more sensitive than would normally be possible with absorption, allowing imaging of nonfluorescent compounds that would be difficult to observe by labeling with fluorescent tags (C&EN, Oct. 26, page 5; Nature 2009, 461, 1105). The technique relies on stimulated emission, or photon-induced electron de-excitation, which is the basis for lasers. A stimulation beam first de-excites a light-excited molecule and then converts the excitation energy into a photon in an amplified stimulated emission beam. This signal is generated at the common foci of two laser beams, which are scanned across or through the sample to build two- or three-dimensional images. The technique can image drugs or biomolecules such as hemoglobin, cytochromes, and melanin in living cells and organisms. Xie and coworkers “have opened up a new way to detect molecules that would otherwise be left in the dark,” commented Stefan W. Hell of the Max Planck Institute for Biophysical Chemistry, in Göttingen, Germany.

Crisper View Of Atoms And Bonds

IBM researchers improved the resolution of atomic force microscopy (AFM) so much this year that they were able to visualize all the atom positions and bonds of a single molecule for the first time (C&EN, Aug. 31, page 6; Science 2009, 325, 1110). AFM usually provides fuzzy images of the overall shapes of individual molecules, and its sister scanning-probe technique, scanning tunneling microscopy, has fared only a little better to distinguish rough details of molecular structures. Leo Gross of IBM Research, in Rüschlikon, Switzerland, and coworkers surpassed the previous AFM resolution barrier by constructing a probe tipped with a single carbon monoxide molecule. They used the tip to view the aromatic compound pentacene in fine detail, including the hydrogen atoms. Óscar Custance of the National Institute for Materials Science, in Tsukuba, Japan, a specialist in atomic resolution force microscopy, noted that until now “molecules at surfaces have been seen by AFM as structureless protrusions. These new results blast away any other molecular resolution limit accomplished to date by scanning probe microscopy.” The work opens new avenues to explore the behavior and properties of molecules at surfaces, and even the possibility of functionalizing them, Custance said. Gross and coworkers hope to develop the capabilities of functionalized AFM tips to include differentiating atom types and distinguishing bond order within individual molecules. Their long-term goal is to probe single-electron transport in molecular networks (Science 2009, 324, 1428).

Nobel Prizes Zoom In On Chemistry

The 2009 Nobel Prizes announced in October were chock full of chemistry. For the Chemistry Prize, Ada E. Yonath of Israel’s Weizmann Institute of Science, Thomas A. Steitz of Yale University, and Venkatraman Ramakrishnan of the U.K.’s MRC Laboratory of Molecular Biology were recognized for their studies on the structure and function of the ribosome, the protein-making factory of cells. Around 2000, Yonath and Ramakrishnan independently obtained the first X-ray structures of the ribosome’s small subunit, and Steitz solved the first structure of the large subunit. In the small subunit, transfer RNAs recognize protein-encoding information on messenger RNA transcribed from the genetic code; meanwhile, in the large subunit, proteins are assembled by one-at-a-time addition of amino acids.

The Physiology or Medicine Prize went to researchers who demonstrated that chromosome ends, called telomeres, and the enzyme that extends them, known as telomerase, protect chromosomes and ensure that they’re faithfully copied each time a cell divides. The discovery was made 30 years ago by Elizabeth H. Blackburn of the University of California, San Francisco; Carol W. Greider of Johns Hopkins University School of Medicine; and Jack W. Szostak of Harvard Medical School. The shortening of telomeres contributes to the complex biology of aging, whereas cancer cells have long telomeres that lend them a sinister immortality.

One-half of the Physics Prize recognized Willard S. Boyle and George E. Smith for their invention of the charge-coupled device (CCD) detector, an idea they dreamed up at Bell Laboratories in 1969. A CCD detects an array of wavelengths simultaneously with unprecedented sensitivity and has led to a revolution in optical spectroscopy and electronic imaging.

Water On The Moon

This year, space scientists were finally able to answer one of the biggest questions in lunar science: Is there water on the moon? The answer is yes. NASA announced last month that debris kicked up during the deliberate crash of the Lunar Crater Observation & Sensing Satellite (LCROSS) spacecraft did contain a sprinkling of water and possibly some organic compounds (C&EN, Nov. 23, page 31). LCROSS launched on June 18 together with a long-term mapping spacecraft, the Lunar Reconnaissance Orbiter. On Oct. 9, LCROSS sent a spent booster rocket crashing into a crater near the moon’s south pole and then hurtled itself into the crater in a planned self-destruction. Scientists had suspected water ice might exist in the permanently darkened crater, named Cabeus, and others like it. After several weeks of analysis, the team reported that both infrared and ultraviolet spectrometers had indeed found evidence of water in the plumes of debris created by the impacts—the tons of ejected material contained about 100 kg of water. Possible sources of the water include comets or hydrogen ions from the solar wind interacting with mineral oxides on the lunar surface.

Graphene In The News

An explosion in the popularity of research on graphene took place in 2009. Researchers around the globe have rushed to probe the mechanical, structural, and electronic properties of this freestanding, one-atom-thick film of carbon (C&EN, March 2, page 14). They have found graphene to be exceptionally strong and stiff, as well as a faster room-temperature conductor than any other material. Scientists have also been reporting new syntheses and applications. For example, researchers have developed ways to form graphene strips by chemically and physically “unzipping” carbon nanotubes (C&EN, April 20, page 7; Nature 2009, 458, 872 and 877; C&EN, April 27, page 30; Nano Lett. 2009, 9, 1527). The material has also been made via surfactant-guided molecular self-assembly and by thermally deoxygenating graphite oxide with an ordinary camera flash (C&EN, July 27, page 46; J. Am. Chem. Soc. 2009, 131, 11027). Some of the potential applications include conductive coatings and polymer composites, as well as ultracapacitors, nanoscale field-effect transistors, and ultrafast photodetectors (Nat. Nanotechnol. 2009, 4, 839).