COVE R STORY
C&EN REVISITS 2000 A decade ago, in its annual Chemistry Highlights feature, now called Chemical Year in Review, C&EN looked at some of that year’s key research advances in chemistry. Now, C&EN reporters have revisited six of those HIGHLIGHTED DISCOVERIES to see what became of them.
Chemistry isn’t necessarily the most photogenic of disciplines, but 10 years ago, George M. Whitesides’ group at Harvard University grabbed the chemical community’s attention with a picture of a curious electronic device sitting upon a penny. The doodad was a microelectronic device built from small modular components that spontaneously self-assemble into a threedimensional circuit. At the time, Whitesides told C&EN that it was too early to commercialize the technology. “That’s maybe three to five years away,” he predicted. A decade later, the self-assembling microelectronics still have yet to reach their full potential. “People continue to explore it in universities, but it is not something that has reached into real use,” Whitesides tells C&EN. David H. Gracias, who worked on the project as a postdoc in Whitesides’ lab, is one of those continuing to push the technology forward. Gracias, now at Johns Hopkins University, has been working to shrink the self-assembling components
and automate their laborious production. So far, Gracias says, he’s succeeded on both fronts. His lab has made modular building blocks on the 100-nm scale and produced them in a high-throughput manner. But there are still some stumbling blocks, he notes. High-throughput yields aren’t 100% yet, and his group is still grappling with how to route wires and remove
Ten years ago, self-assembling microelectronic circuits (left) had to be painstakingly made by hand. Today, machine fabrication is possible, thanks to microscale building blocks that self-fold and self-assemble (right).
heat from the highly interconnected circuits. Getting electronics to self-assemble in 3-D is still one of the grand goals of electronics fabrication, Gracias says. He likens current fabrication methods used in the industry to tiling a bathroom floor: “In two dimensions, there are only so many tiles you can put down before you run out of real estate, so people have to make smaller and smaller tiles. If you’re able to use three dimensions, you can work with bigger tiles, and you can make highly interconnected circuits.” As for the photogenic doodad that graced the cover of C&EN 10 years ago, Gracias says most of the devices—which were made from painstakingly handcrafted components—are probably in a drawer somewhere at Harvard. He recalls that back when the work was first reported, a friend remarked that the Smithsonian Institution would come looking for the devices someday. “The Smithsonian hasn’t come yet,” Gracias says, “but I do have one,” just in case.—BETHANY HALFORD
TARGETING GENES WITH ‘ZINC FINGERS’ In 2000, Yen Choo, Nobel Laureate Aaron Klug, and coworkers at the MRC Laboratory of Molecular Biology, in Cambridge, England, developed “zinc fingers” (zinc-coordinated protein-based binding agents) that regulate gene transcription by targeting just about any 18-base-pair DNA sequence. The team announced that the technology was being developed by the London-based start-up Gendaq. Gendaq “did pretty well for itself,” says Choo, who is now chief executive officer of the
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London-based stem cell biotech firm Plasticell. Gendaq made good scientific progress and was sold in 2001 to Sangamo BioSciences for $30 million, Choo notes. Sangamo later licensed research applications of customizable zinc finger technology to Sigma-Aldrich, which now markets it commercially under the trade name CompoZr (C&EN, April 5, page 20). Researchers use zinc finger technology to make a variety of genetic modifications—inserting a piece of DNA in a defined
place in the genome, creating point mutations in a specific gene, or correcting a gene’s sequence defect. “You can knock stuff in, knock stuff out, or change it,” Choo says. “Zinc fingers act very specifically to target the particular sequence you’re interested in—by virtue of the inherent specificity of zinc fingers and, in particular, of the engineering system that we developed.” Zinc fingers aren’t yet being used in any approved therapies, but Choo notes that the oppor-
tunities are there for it to happen soon. For example, Sangamo is using zinc finger nucleases in three Phase I clinical trials to knock out the gene coding for HIV-entry receptors on patient immune-system stem cells. The idea is to reintroduce the modified cells to the patient in hopes that the cells will form a new population of HIV-resistant immune cells. Sangamo has also completed four Phase II clinical trials of a zinc finger therapeutic in diabetic neuropathy.—STU BORMAN
View a slide show and videos related to C&EN Revisits 2000 at www.cen-online.org. WWW.CEN-ONLINE.ORG
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DAVID GRACIAS/HARVARD U (LEFT), LANGMUIR (RIGHT)
SELF-ASSEMBLING 3-D ELECTRONICS
FUNCTIONALIZED NANOPARTICLES FOR CLINICAL DIAGNOSTICS high sensitivity as a result of the intensity with which nanoparticles scatter light. For example, the nanoparticle method is at least 100 times as sensitive as the enzyme-linked immunosorbent assay method, a technique commonly used to detect the presence of an antibody or antigen. According to Mirkin, Nanosphere has received Food & Drug Administration clearance for five of its diagnostic tests. These include tests for early detection of respiratory illnesses and blood coagulation disorders and a test to gauge a patient’s ability to metabolize warfarin, an anticoagulant
medication. The company is also developing diagnostics for sensitive detection of markers for cancer and heart disease. Looking back to the mid-1990s, “we started with the idea of functionalizing nanoparticles with DNA to do programmed materials synthesis,” Mirkin says. The strategy, he explains, was to organize lattices using particles as atoms and DNA as bonds. “These structures turned out to have extraordinary and unexpected properties that provide major advantages for medical diagnostics,” Mirkin adds. “It’s a real success story for chemistry.”—MITCH JACOBY
CATALYTIC REACTION ACTIVATES ALKANES Carbon-hydrogen bond activation took a big step forward in 2000 when John F. Hartwig and coworkers reported an organometallic catalyst capable of directly converting normally unreactive alkanes into compounds with useful functional groups tacked on to the ends. At the time, alkane functionalization was typically carried out by catalytic photochemistry. Selective, lab-scale C–H bond activation via transitionmetal complexes was possible, but those reactions required stoichiometric amounts of expensive reagents. At the industrial scale, processes such as petroleum cracking and free-radical halogenation are used, but they create mixtures of products. Hartwig’s group, then at Yale University, working in collaboration with Thomas C. Semple of Shell Chemicals, discovered a rhodium catalyst in which the metal atom is sandwiched between labile hexamethylbenzene and pentamethylcyclopentadienyl ligands. The researchers used the complex to catalyti-
cally couple linear alkanes with commercially available borane reagents to make alkylboranes. The beauty of the borane products, Hartwig says, is that they can be easily converted to alcohols, amines, alkenes, and other derivatives using textbook organic chemistry.
“We continue to work on the end-functionalized alkanes, including some new unpublished work on the functionalization of alkyl C–H bonds with silicon reagents,” Hartwig says. “We have shown that the functionalization of unactivated primary C–H bonds with boron reagents O
+
Catalyst =
Rh
O
B
O O
Catalyst Heat
B
O O
+ H2
ALKANE ACCESS
Hartwig’s organometallic catalyst allowed the first direct conversion of normally unreactive alkanes into alkylboranes, which can be derivatized to make compounds with useful functional groups tacked on to the ends.
Organic chemists were optimistic that practical applications of industrial-scale catalytic alkane functionalizations were within reach. Indeed, Hartwig’s group—now relocated to the University of Illinois, Urbana-Champaign—and others have developed alkane functionalization chemistry that is starting to make its way into pharmaceutical and fine chemicals development.
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B
evolved into practical borylation of aromatic C–H bonds using an iridium catalyst. The resulting aryl boronate esters can be used in Suzuki-Miyaura cross-coupling, oxidized to phenols, and converted to aryl halides, aryl amines, aryl ethers, or aromatic nitriles. This chem-
occurs in ethers, amines, and alkyl halides, in addition to alkanes.” Hartwig has also collaborated with Marc A. Hillmyer of the University of Minnesota, Twin Cities, to end-functionalize polyolefins to form alcohols that can be further converted to aldehydes and amines for generating new materials. Perhaps most important right now, Hartwig says, is that the original research has
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istry has been used by several research groups, including his own, to synthesize natural products. “What is needed to make reactions of aliphatic C–H bonds truly practical is the next generation of catalysts that allows us to conduct reactions of saturated compounds with the kind of reactivity we see with arenes,” Hartwig says.—STEVE RITTER
PINAL PATEL/NORTHWESTERN U
A decade ago, Northwestern University’s Chad A. Mirkin and Robert L. Letsinger led a team in devising a nanoparticle-based method for detecting DNA that provided far greater sensitivity than standard fluorometric detection methods at the time. The advance led to the founding of a Northbrook, Ill.-based nanobiotechnology company, Nanosphere, which today makes a line of medical diagnostic systems based on the technology and sold under the Verigene trade name. The detection process relies on gold nanoparticles functionalized with DNA or RNA oligonucleotides or with antibodies that selectively bind to complementary nucleic acid or protein targets, respectively. By capturing the nanoparticle-tagged targets on a solid support via hybridization reactions, the targets can be detected with
Gold nanoparticles (13 nm in diameter) functionalized with single-stranded DNA serve as the basis for Nanosphere’s sensitive medical diagnostics.
COVE R STORY
HIGH-SPEED ORGANIC ELECTRO-OPTICS Ten years ago, the University of Washingwith architectures that are very rare in naThe devices Dalton’s team made operton’s Larry R. Dalton and coworkers turned ture,” Dalton says. ated on less than 1 V and converted electrito materials chemistry to boost the perforPutting that knowledge into practice, cal data into optical information at rates mance of electro-optic devices. The team Dalton and coworkers designed a chromoexceeding 110 gigahertz. Similarly high data designed a new type of conjugated organic phore known as CLD-1 that features a bulky rates had been reported for other polymerchromophore and used it to fabricate highsegment positioned between its electronbased devices prior to 2000, but those sysspeed electro-optic modulators, replacing donating and electron-accepting moieties. tems required much higher drive voltages, standard inorganic crystals, such as lithium The goal of that design strategy, which was which affected noise levels and limited signiobate, typically used in such devices. derived from the team’s computational nal gain. High-speed, low-voltage devices The key property of electro-optic maanalysis, was to overcome the inherent are desired for applications in fiber-optic terials that makes them attractive electrostatic interactions between and satellite communication systems and for light-manipulating applications the molecules that invariably drive for optical-switching technology. CH3 is the ability to change refractive them to align centrosymmetrically. The advances reported by Dalton’s Si O index with an applied electric field. It worked like a charm. team a decade ago, which helped meet To achieve that effect, the molecules those application goals, were commercialCH3 must be aligned in a polymer or othized by a company called Lumera, based in N er matrix such that there is no center Bothell, Wash. Lumera was later bought by CH3 of symmetry. Gigaoptics, a company with headquarters “Our breakthrough came from in Konstanz, Germany, that sells electroSi O understanding how to control the optic devices for terahertz specO noncovalent interactions that guide CH3 CN troscopy and other laser accessories lattice formation so that we could based on Dalton’s original discovCN build supramolecular assemblies ery.—MITCH JACOBY CLD-1 CN
Poly(tetrafluoroethylene), or PTFE, best known for its use in DuPont’s Teflon brand of products, has been around for 70 years. But it was only 10 years ago that Paul Smith, Theo Tervoort, and coworkers at the Swiss Federal Institute of Technology, Zurich, applied simple physical chemistry to solve a problem in PTFE processing. The team identified a narrow window of fluoropolymer viscosities that permits conventional polymer melt-processing extrusion methods to be used to make a wide range of molded PTFE products and spun fibers. PTFE is a mechanically tough polymer with unique chemical-, thermal-, and mechanical-resistance properties. Since its invention in 1938, conventional and textbook wisdom has been that PTFE, unlike most other commercial plastics, couldn’t be melt processed because of the high viscosity of its molten state. It was thought that complex
shapes such as machine parts could be made only by powder compaction, sintering, and subsequent sculpting of polymer blocks, or by adding a copolymer and fillers to allow melt processing, which is costly and diminishes PTFE’s beneficial properties.
develop the technology and license it to others. The researchers moved ahead cautiously—and with good reason. “Much of the chemical industry feels that it got burned by early investments in advanced materials, and therefore many have
A device used in high-voltage applications (third from left) was previously machine-sculpted from a PTFE cylinder (left), resulting in a mound of leftover polymer (shown between them). The same device (second from right) produced by injection molding results in no waste—the amount of Moldflon PTFE needed to make the device is shown (right). “We believe that our findings will cause a paradigm shift in fluoropolymer processing,” Smith said 10 years ago. The researchers started a company, called Omlidon Technologies, based in Wilmington, Del., to
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elected not to pursue research on novel materials,” Smith and Tervoort noted in 2000. “We did not realize at the time how accurate our statement was,” Tervoort now tells C&EN. “To our disappointment,
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no raw materials producer initially had the courage to step in to commercialize the technology,” he says. But in 2004, ElringKlinger Kunststofftechnik, one of the largest German-based fluoropolymer converters, was experiencing problems in fluoropolymer processing and realized the potential of the melt-processing development. Smith, Tervoort, and their team signed a licensing agreement, and since then “the company has been working hard to introduce this material to the market under the trade name Moldflon,” Tervoort says. Many of the anticipated applications, such as injectionmolded PTFE bearings, films, tubings, fibers, and complex parts for the chemical- and food-processing industries and automotive applications—pieces that can’t be machined—are now commercially available or at the end of their developmental stage, Tervoort says.—STEVE RITTER
COURTESY OF THEO TERVOORT
FLUOROPOLYMER PROCESSING BREAKTHROUGH
