Chemistry Highlights 2005

Each year, we at C&EN highlight some of the most significant chemical research advances that we've reported over the preceding 12 months. Like pharmaceutical chemists, we screen our library of news stories for those that seem most significant and try to ferret out the most promising hits.

We look for long-sought or surprising breakthroughs, first-of-a-kind advances, and findings that are likely to have long-lasting influence. For 2005, we've identified 24 developments that we believe meet these criteria.

The advances range all over the various chemical disciplines, from organic chemistry to molecular biology, from structural biology to inorganic chemistry, and from nanotechnology to physical chemistry. Our list helps bring into focus the extraordinary and inspiring level of accomplishment achieved by the chemistry research enterprise.

This year, organic chemistry was thrust into the limelight by the Nobel Prize in Chemistry, which honored a powerful class of catalytic organic reactions. The prize was awarded to three chemists who developed olefin metathesis: Yves Chauvin of the French Petroleum Institute, Rueil-Malmaison, France; Robert H. Grubbs of California Institute of Technology; and Richard R. Schrock of Massachusetts Institute of Technology. Olefin metathesis is a broadly applicable catalytic reaction in which two carbon-carbon double bonds react to form two new ones. In the process, substituents are exchanged and a range of other outcomes may ensue, such as ring closure, diene formation, and polymerization. Chauvin and a student suggested a mechanism in 1971, and Schrock and Grubbs later led efforts to develop key catalysts that have enabled use of the reaction to flourish.

In another catalytic organic chemistry advance, rhodium-phospholane catalysts that for the first time offer high turnover rates and high regio- and enantioselectivity in converting achiral alkenes to chiral aldehydes by hydroformylation were discovered by Clark R. Landis of the University of Wisconsin, Madison; Jerzy Klosin of Dow Chemical; and coworkers (J. Am. Chem. Soc. 2005, 127, 5040). Hydroformylation is one of the largest scale homogeneous catalytic processes used industrially, but productive and selective asymmetric catalysts were not available for it previously. The new rhodium-phospholanes show "significant progress toward practical catalytic production of chiral materials in a process that is 100% atom efficient and involves gaseous reagents that are easily separated from products," Landis said.

In total organic synthesis, a practical route developed by Andrew G. Myers and coworkers at Harvard University yielded an unprecedented series of structurally diverse analogs of the antibiotic tetracycline, including some capable of killing bacteria resistant to multiple antibiotics (Science 2005, 308, 395). No practical total-synthesis approach to the tetracyclines had previously been available. In the new method, developed in a decade-long effort, the tetracycline ABCD ring system was constructed in a way that yields mostly one diastereomer whose stereochemistry matches that of the natural product. A researcher in the field called the work "a synthetic tour de force that enormously expands the armamentarium of the tetracycline medicinal chemist."

In biochemistry, notable advances were made in protein structure determination, pheromone identification, membrane protein production, and vision elucidation.

A new method that simultaneously determines the structure of a protein and the mobility and range of motion of its backbone and side chains was developed by Michele Vendruscolo, Christopher M. Dobson, and coworkers at the University of Cambridge (Nature 2005, 433, 128). Techniques for studying protein structure and dynamics are generally carried out independently. The new method, called dynamic ensemble refinement, combines molecular dynamics and two nuclear magnetic resonance spectroscopy (NMR) techniques to make it feasible to determine structure and dynamics at the same time. The result is an ensemble of conformations that represents both the structure and dynamic variability of the native protein (such as in the researchers' ensemble structure of ubiquitin). The approach could aid drug design by making it possible to study small-molecule interactions with a range of experimentally determined protein conformations in solution, rather than with just a static, averaged protein structure. "It is becoming increasingly clear that a static picture can severely limit the success of conventional docking procedures and lead to sizable errors in estimates of binding affinities," Vendruscolo says.

At Cornell University, Wendell L. Roelofs and coworkers deduced the structure of a sex pheromone that female German cockroaches use to attract potential mates (Science 2005, 307, 1104). The simple 12-carbon pheromone, which the researchers named blattellaquinone, had eluded natural products chemists for decades. The work necessitated extraction of material from about 5,000 cockroaches and development of a special preparative gas chromatographic technique to purify the thermally unstable molecule.

In protein production, a novel bacterial protein can now be used to produce large quantities of tough-to-obtain membrane proteins. Integral membrane proteins account for a large proportion of eukaryotic genomes and play key roles in many cellular processes. It has been difficult, however, to produce properly folded eukaryotic membrane proteins in high yields in engineered bacteria, the workhorses of recombinant protein production. Senyon Choe, Roland Riek, Tarmo P. Roosild, and coworkers at Salk Institute, San Diego, discovered a bacterial membrane protein called MISTIC that sidesteps the main source of the problem, which is the inability of bacteria to export recombinant membrane proteins to the lipid bilayer of the bacterial cell membrane. They found that eukaryotic membrane proteins can be produced in bacteria when expressed as MISTIC fusion proteins (Science 2005, 307, 1317).

A new, ultrafast Raman spectroscopy method provided a revised view of early stages of the vision process. Vision begins with isomerization of the retinal chromophore in rhodopsin from an 11-cis to an all-trans configuration. The reaction is one of the fastest in nature and has been too quick for detailed structural analysis. Using femtosecond-stimulated Raman spectroscopy, Richard A. Mathies and coworkers at the University of California, Berkeley, have now obtained such structural information from vibrational spectra taken 200 femtoseconds to 2 picoseconds into the process (Science 2005, 310, 1006). They found that most of the rearrangement happens in the electronic ground state instead of in the excited state, as had been previously assumed. "An additional key feature," Mathies says, "is that the initial motions on the 50-fs timescale were revealed to be HOOP, or hydrogen out-of-plane, distortions, rather than the expected C=C torsions." The findings revised the standard view of this important reaction.

In pharmaceutical chemistry, researchers advanced efforts to stop bacterial resistance to antibiotics and to fight cancer.

A new way to make bacteria incapable of developing resistance to some antibiotics was discovered. In response to antibiotics, bacteria evolve resistance through a mechanism called "SOS damage response," a mutation pathway controlled by the protease LexA. Floyd E. Romesberg of Scripps Research Institute and coworkers showed that blocking LexA cleavage disables the pathway and makes the bacteria unable to develop resistance (PLoS Biol. 2005, 3, e176). The researchers demonstrated the technique with antibiotics that damage DNA. They are currently studying its applicability for other classes of antibiotics.

Also demonstrated this year was a novel way of fighting cancer: by interfering with proteins that inhibit apoptosis (cell suicide). Damage of a type that causes cells to become cancerous typically induces apoptosis, but many cancer cells avoid this outcome by overproducing antiapoptotic proteins. Stephen W. Fesik and Saul H. Rosenberg of Abbott Laboratories and coworkers found that the small molecule ABT-737 binds antiapoptotic proteins of the Bcl-2 family, kills lymphoma and small-cell lung cancer cells, enhances chemotherapy and radiation effects on other cancer cells, and causes tumor regression in mice (Nature 2005, 435, 677). Human trials of ABT-737 or a derivative are planned.

In molecular biology, a new way to control gene expression, by using "antigene" peptide nucleic acids (PNAs) or RNAs to block transcription of chromosomal DNA, was developed by David R. Corey and coworkers at the University of Texas Southwestern Medical Center, Dallas (Nat. Chem. Biol. 2005, 1, 210 and 216). With earlier techniques to control gene expression, agents bind double-stranded DNA or bind to or induce cleavage of mRNA. With the new technique, antigene PNA instead binds to and blocks a single-stranded DNA transcription start site. Corey and coworkers hypothesize that antigene RNA acts by a similar mechanism. The technique could complement those developed earlier for gene function studies, disease treatment, and other applications.

In structural biology, researchers gained a better understanding of amyloid fibrils and greater success in predicting protein structures.

David Eisenberg of the University of California, Los Angeles, and coworkers obtained the first detailed atomic view of amyloid fibrils (Nature 2005, 435, 773). Amyloid fibrils are associated with some 20 diseases, such as Alzheimer's and type 2 diabetes, and the structure could aid the search for therapeutics that can impede formation or accelerate breakdown of amyloid. In the structure, seven-residue protein segments bind to identical segments to form tightly interdigitating β-sheets called steric zippers. An atomic model had not previously been available primarily because of the difficulty in creating amyloid crystals large enough to be analyzed by X-ray crystallography. Eisenberg and coworkers solved the problem by growing tiny crystals and then using special techniques for structural analysis of small crystals.

David Baker and coworkers at the University of Washington, Seattle, reported what may be the best method yet for predicting high-resolution protein structures from an amino acid sequence (Science 2005, 309, 1868). The method calculates the lowest energy conformation of an amino acid sequence in two steps, first at low and then at high resolution. It was used to predict a very high accuracy (1.6-Å resolution) model of a protein in a double-blind protein structure prediction experiment called CASP6. However, it could predict only six of 16 protein structures at that level of accuracy, and the method is limited to proteins with 85 or fewer amino acids, so there's room for improvement. Baker and coworkers continue to refine the method's accuracy and consistency and believe predictions on larger proteins will eventually be accessible.

At the frontiers of planetary chemistry this year, the European Space Agency's saucerlike Huygens space probe plunged through the thick nitrogen and methane atmosphere of Saturn's moon Titan. This event provided the first close glimpse of a world where temperatures hover around -180 ??C, it rains methane instead of water, and the terrain consists of water ice and a complex hydrocarbon "dirt." After a seven-year journey from Earth, the Huygens probe survived a two-and-a-half-hour descent to Titan's surface and continued transmitting chemical data from its mass spectrometer and five other scientific instruments for 73 minutes after landing. A predominance of liquid methane surprised scientists, who expected to see higher concentrations of liquid ethane. The probe also unexpectedly measured only one isotope of argon in Titan's atmosphere.

In inorganic chemistry, some of the year's key developments came from iron-sulfur and chromium chemistries.

In work with potential implications for the development of platinum-free, and therefore relatively inexpensive, fuel cells, Christopher J. Pickett of John Innes Centre, Norwich, England, and coworkers achieved the long-sought synthesis of an inorganic complex very similar to the catalytic iron-sulfur core (H-cluster) of bacterial hydrogenase (Nature 2005, 433, 610). The complex accelerates the same reaction as hydrogenase reduction of H⁺ to H₂—albeit less efficiently. "In addition to advancing our understanding of the natural biological system, the availability of an active, free-standing analog of the H-cluster may enable us to develop useful electrocatalytic materials for application in, for example, reversible hydrogen fuel cells," the researchers write. "Platinum is currently the preferred electrocatalyst for such applications but is expensive, limited in availability, and, in the long term, unsustainable."

Evidence for the first quintuple-like bond between two metal atoms was revealed this year by Philip P. Power at the University of California, Davis, and coworkers (Science 2005, 310, 844). They found the bond in a dichromium complex containing two bulky terphenyl ligands. The researchers believe that the two chromium(I) atoms in the complex share five electron pairs in five bonding molecular orbitals. Power is cautious about using the word "quintuple" to describe the bonding, preferring to call it "fivefold bonding" because the actual bond order is likely less than five. But he hopes the discovery will be the forerunner of quintuple bonds still to be found.

In nanotechnology, the year's harvest includes a nanovalve, a nanomotor, and a nanocar.

A key bacterial channel protein was modified to create a membrane-bound nanovalve that can be opened and closed with light. The work was carried out by Wim Meijberg of BiOMaDe Technology Foundation, Groningen, the Netherlands; Ben L. Feringa of the University of Groningen; and coworkers (Science 2005, 309, 755). UV light converts the modified channel protein's closed form to the open form, and visible light closes the channel back up. Switchable pores might be useful in releasing substances from containers—for drug delivery, for example—or in nanodevices.

Feringa and colleagues at Groningen also anchored a chiral alkene onto a gold nanoparticle to create the first light-driven molecular rotary motor attached to a solid surface (Nature 2005, 437, 1337). The motor doesn't currently do any work; nevertheless, it's a step toward functional nanosized mechanical devices and perhaps systems that exploit solar energy. A propeller-like part of the molecule turns via a cycle of light- and heat-induced isomerizations.

After eight years of development, the world's first single-molecule car was launched at Rice University, Houston (Nano Lett. 2005, 5, 2330). Designed, synthesized, and tested by Kevin F. Kelly, James M. Tour, and coworkers, the nanocar is a key step toward molecular manufacturing. It consists of an oligo(phenylene ethynylene) chassis and axle covalently mounted to four fullerene wheels. The researchers used the tip of a scanning tunneling microscope to propel the car on a gold surface and showed that it actually rolls forward on its wheels instead of sliding around randomly.

In materials chemistry, a new hybrid copper-organic microporous material permits acetylene to be stored safely at a density 200 times its usual safe compression limit. Normally, acetylene is highly reactive and explodes, even in the absence of oxygen, when compressed at more than 2 atm at room temperature. The new material was designed and synthesized by Susumu Kitagawa of Kyoto University and coworkers (Nature 2005, 436, 238). A safer way to store acetylene is important because acetylene is a key starting material for the synthesis of many chemical products and electrical materials.

In molecular electronics, Robert A. Wolkow and colleagues at the University of Alberta and the Canadian National Research Council's Institute for Nanotechnology in Edmonton demonstrated control over single-molecule conductivity by showing that a surface-bound ion or other point charge generates an electrostatic field that can be used to regulate electrical conductivity in nearby surface-attached molecules (Nature 2005, 435, 658). The study broadens understanding of fundamental molecular processes and could ease development of single-molecule-based detectors and other types of molecular electronic devices.

In physical chemistry, researchers unearthed new subtleties in chemical bonding and made notable gains in spectroscopy.

John H. Weaver and coworkers at the University of Illinois, Urbana-Champaign, discovered a surprising instance in which energy from thermal vibrations (phonons) of atoms in a crystal excites an electron into an antibonding state of an adsorbate on the surface, and the excitation causes bond breakage and desorption (Surf. Sci. 2005, 583, L135). The reaction is thus both thermal and electronic in nature, blurring the generally sharp distinction between thermal and electronic bond-breaking processes. It also breaks the Franck-Condon principle, which specifies that nuclei tend to retain their initial positions and momenta during electronic transitions. The work suggests that conventional descriptions of bond formation and bond breaking at surfaces may need to be reevaluated.

Also this year, two-dimensional femtosecond spectroscopy was extended for the first time from the infrared to the visible range (Nature 2005, 434, 625). Graham R. Fleming of UC Berkeley and Lawrence Berkeley National Laboratory; Minhaeng Cho of Korea University, Seoul; and coworkers used the new technique to determine previously inaccessible mechanistic details about energy transport in a photosynthetic light-harvesting protein (see cover). According to the researchers, the methodology "opens the door to similar investigations of electronic couplings and energy transport in any photoactive assembly, macromolecule, or other nanoscale system."

Infrared spectra of the previously inaccessible low-energy part of the spectrum of protonated water clusters were obtained by Michael A. Duncan of the University of Georgia, Athens; Mark A. Johnson of Yale University; Kenneth D. Jordan of the University of Pittsburgh; and coworkers (Science 2005, 308, 1765). The work showed that the spectroscopic properties of hydrated protons are, to a previously unrecognized degree, extremely sensitive to changes in the clusters of water molecules that surround them.

In a related feat, the first broad-frequency IR spectra of protonated methane were determined by Britta Redlich of the FOM Institute for Plasma Physics, Nieuwegein, the Netherlands; Stephan Schlemmer of the University of Cologne, Germany; Dominik Marx of Ruhr University, Bochum, Germany; and coworkers (Science 2005, 309, 1219). The work demonstrated that CH₅⁺'s three-center, two-electron bonding pattern and the rotating motions of its five protons are key to understanding its spectrum.