Molecules of the year - C&EN Global Enterprise (ACS Publications)

Editorial 1155—16th St., N.W., Washington, DC 20036 (202) 872-4600 or (800) 227-5558 EDITOR-IN-CHIEF: Bibiana Campos Seijo EDITORIAL DIRECTOR: Amanda Yarnell PRODUCTION DIRECTOR: Rachel Sheremeta Pepling

What made headlines in 2017

SENIOR ADMINISTRATIVE OFFICER: Marvel A. Wills

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BUSINESS NEW YORK CITY: (212) 608-6306 Michael McCoy, Executive Editor Rick Mullin (Senior Editor), Marc S. Reisch (Senior Correspondent), Alexander H. Tullo (Senior Correspondent), Rachel Eskenazi (Administrative Assistant). BOSTON: Ryan Cross (Assistant Editor). CHICAGO: (917) 710-0924 Lisa M. Jarvis (Senior Correspondent). HONG KONG: 852 9093 8445 Jean-François Tremblay (Senior Correspondent). LONDON: 44 1494 564 316 Alex Scott (Senior Editor). WEST COAST: (315) 825-8566 Melody M. Bomgardner (Senior Editor) POLICY WEST COAST: (925) 519-6681 Jyllian Kemsley, Executive Editor WASHINGTON: Cheryl Hogue (Senior Correspondent) Britt E. Erickson (Senior Editor), Andrea L. Widener (Senior Editor) SCIENCE/TECHNOLOGY/EDUCATION WASHINGTON: Lauren K. Wolf, Executive Editor, Deputy Editorial Director Celia Henry Arnaud (Senior Editor), Stuart A. Borman (Senior Correspondent), Matt Davenport (Senior Editor, Multimedia), Emma Hiolski (Contributing Editor), Kerri Jansen (Assistant Editor, Multimedia), Tien M. Nguyen (Assistant Editor), Stephen K. Ritter (Senior Correspondent). BERLIN: 49 30 2123 3740 Sarah Everts (Senior Editor). BOSTON: (973) 922-0175 Bethany Halford (Senior Editor). CHICAGO: (847) 679-1156 Mitch Jacoby (Senior Correspondent). WEST COAST: (626) 765-6767 Michael Torrice (Deputy Executive Editor), Sam Lemonick (Assistant Editor) JOURNAL NEWS & COMMUNITY (510) 768-7657 Corinna Wu (Senior Editor) (651) 447-6226 Jessica H. Marshall (Associate Editor) ACS NEWS & SPECIAL FEATURES Linda Wang (Senior Editor) EDITORIAL PROJECTS EDITOR: Jessica Morrison AUDIENCE ENGAGEMENT EDITOR: Dorea I. Reeser EDITING & PRODUCTION Kimberly R. Bryson, Executive Editor Sabrina J. Ashwell (Assistant Editor), Craig Bettenhausen (Associate Editor), Melissa T. Gilden (Assitant Editor), Taylor C. Hood (Assistant Editor), Manny I. Fox Morone (Associate Editor), Alexandra A. Taylor (Assistant Editor) C&EN MEDIA PRODUCTION LAB Robert Bryson, Creative Director, Head of Media Production Lab Tchad K. Blair, Head of UI/UX Design Robin L. Braverman (Senior Art Director), Luis A. Carrillo (Web Production Manager), Ty A. Finocchiaro (Senior Web Associate), Yang H. Ku (Art Director), William A. Ludwig (Art Director), Kay Youn (Art Director) C&EN BRANDLAB Rajendrani Mukhopadhyay, Executive Editor Jeff Lee (Senior Editor), Kirsten Dobson (Marketing Manager), SALES & MARKETING Stephanie Holland, Assistant Director, Advertising Sales & Marketing Natalia Bokhari (Advertising Operations Manager), Sondra Hadden (Senior Marketing Manager), Joyleen SanFeliz Parnell (Advertising Operations Associate), Quyen Pham (Lead Generation Associate), Ed Rather (Recruitment Advertising Product Manager), Shelly E. Savage (Recruitment Advertising Associate) ADVISORY BOARD Deborah Blum, Raychelle Burks, Jinwoo Cheon, Kendrew H. Colton, FrançoisXavier Coudert, Cathleen Crudden, Gautam R. Desiraju, Paula T. Hammond, Matthew Hartings, Christopher Hill, Peter Nagler, Anubhav Saxena, Dan Shine, Michael Sofia, William Tolman, James C. Tung, Jill Venton, Helma Wennemers, Geofrey K. Wyatt, Deqing Zhang Published by the AMERICAN CHEMICAL SOCIETY Thomas M. Connelly Jr., Executive Director & CEO Brian D. Crawford, President, Publications Division EDITORIAL BOARD: Nicole S. Sampson (Chair), ACS Board of Directors Chair Pat N. Confalone, ACS President Allison A. Campbell, Cynthia J. Burrows, Jerzy Klosin, John Russell, Gary B. Schuster Copyright 2017, American Chemical Society Canadian GST Reg. No. R127571347 Volume 95, Number 49

et ready for the biggest chemistry-related stories of 2017. If you enjoyed our Dec. 4 issue, which brought you highlights of what happened in the world of pharma during the year, you are going to love this issue too. This year has been incredibly busy—as I said in my last editorial, a whirlwind—but also quite unusual because of the confluence of a series of circumstances affecting different parts of the world: A new administration in the U.S., the Brexit controversy in the U.K., and much more. So what made headlines? There is simply too much to list here—you’ll have to read this issue—but for the purpose of this editorial I’m going to pick some personal favorites. The first thing that comes to mind is the March for Science. Seldom have we seen scientists take to the streets to celebrate science and the role it plays in everyday life. Scientists who took part called for evidence-based policy-making, appropriate funding for scientific research, and greater government transparency for scientific matters. It was an unprecedented global event, with more than 1 million participants from about 600 cities around the world that held rallies. But it wasn’t without controversy. Many in the scientific community resist the notion that scientists should participate in public life in this fashion and see these activities as a politicization of science. In terms of scientific advancement, the fields of machine learning and quantum computing started to deliver on their promises, with significant advances announced this year (see page 20) and likely to continue into 2018. Also noteworthy is the evolution that we have continued to observe in the field of flow chemistry, which has made inroads in the pharmaceutical industry with the manufacture of a chemotherapy drug candidate (see page 23). When it comes to chemicals that made headlines this year, there was global controversy around regulation and safe use of pesticides like chlorpyrifos, glyphosate, and dicamba. But one could say that opioids, at least in the U.S., dominated the agenda. Deaths by overdoses skyrocketed this year, and the issue is now widely referred to as a serious national crisis.

In 2017 we lost many notable scientists. I’d like to spare a thought for Ronald Breslow, Mildred Dresselhaus, Isabella Karle, George Olah, and Gilbert Stork, among many others (see page 39). They exemplify the best of the chemical enterprise and will be sorely missed. Besides what made headlines in 2017, in this issue we also take a look back at the fate of research from a decade ago. Can you remember what was trending in terms of chemical research in 2007? If you guessed the elucidation of G protein-coupled receptor structures and the role they play in drug discovery, you guessed right (see page 42). And for first time this year we look forward and ask a selection of C&EN writers and editors to predict what will be in the limelight in 2018. There are some interesting suggestions, including Steve Ritter’s prediction that “chemistry’s cold war,” the divide between science and public policy, “will continue to grow and get chillier” and Britt Erickson’s suggestion that there will be further lawsuits on the reform of the U.S.’s Toxic Substances Control Act (see page 40). For a bit of fun and lighthearted reading, turn to page 28. We selected the most interesting and innovative chemical structures that chemists made in 2017 and asked people to vote on their favorites. A complex polysaccharide won the poll with 34% of the vote, followed very closely, with 32% of the vote, by a pair of unusual trinitrogen structures. What was your favorite? As the year draws to an end, the team and I would like to thank you for your loyalty to C&EN and for your continued support of our journalism.

Editor-in-chief @BibianaCampos

Views expressed on this page are those of the author and not necessarily those of ACS.

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C&EN | CEN.ACS.ORG | DECEMBER 11/18, 2017

Reactions ▸ Letters to the editor Bird problem In the Nov. 20 issue, herring gull is cited as one of the species that scientists are watching for possible environmental impacts (page 26). However, I have been a birder for over 45 years, and I knew immediately that the photo of the “herring gull” on the cover and in the accompanying ar-

The equilibrium and kinetics studies are not necessarily in conflict, however. The equilibrium study of Horváth and colleagues indicates that orthoperiodate predominates in aqueous solution over a wide

range of pH values (Inorg. Chem. 2017, DOI: 10.1021/acs.inorgchem.7b01911). The equilibrium quotient for formation of metaperiodate is much smaller than had been generally accepted in previous kinetics studies. Metaperiodate, though present at low concentrations, insufficient to be unambiguously detected in equilibrium studies, can manifest its presence in aqueous solution. For example, the subtle role of this species is in accordance with ... [an] independent kinetics study reported on complex formation of an iron(III) hydroxo

New Version!

ticle cannot be such. The bird is obviously (to a birder) an adult bird, and thus to be a herring gull would have a larger, thicker yellow bill with a bright red spot on the lower mandible. The bird in this photo, with a thin, small, greenish-colored bill lacking any clear marking (as well as several other factors), is more likely a blacklegged kittiwake, a species also mentioned in the article.

R. Martin Smith Madison, Wis.

C R E D I T: I STO CK P H OTO

Periodate chemistry I read with interest the Oct. 2, 2017, article (page 6) about new studies of aqueous periodate equilibria which found no evidence for metaperiodate (IO4–) in aqueous solution. Kinetics studies tell a different story. Two independent temperature-jump studies (J. Phys. Chem. 1964, DOI: 10.1021/ j100794a057; Z. Naturforsch., B: J. Chem. Sci. 1977, DOI: 10.1515/znb-1977-0127) and a corroborating 17O NMR line-broadening study (J. Am. Chem. Soc. 1965, DOI: 10.1021/ja01096a008) indicate the existence of a rapid meta-orthoperiodate hydration-dehydration equilibrium in acidic media.

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dimer with periodate ion (Dalton Trans. 2004, DOI: 10.1039/B313341A).

Kenneth Kustin Chapel Hill, N.C.

Women in chemistry Bibiana’s editorial in the Nov. 13 issue on the giants of chemistry (page 2) connected well with my current reading. My oldest daughter, upon graduating from college, was given this book by a classmate: “Nobel Prize Women in Science” (Carol Publishing Group, 1993) by Sharon Bertsch McGrayne. My daughter left the book

Corrections ▸ Nov. 27, page 35: The ACS Comment in the C&EN print edition contained an incomplete headline. It should have read, “Friends in need: ACS’s role in disaster relief.” ▸ Dec. 4, page 45: The ACS Comment incorrectly stated that the ACS Defined Contribution Retirement Plan was frozen in 2009. The ACS Defined Benefit Pension Plan was frozen that year.

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with her old man when she moved on. Beginning with Marie Curie and followed by Lise Meitner, the book takes the reader through biographies of 11 additional Nobel Prize-winning women and their respective struggles to compete in the male-dominated scientific communities during much of the 20th century. The book aptly describes what each accomplished scientifically and how each overcame great gender discrimination obstacles. Eve Curie’s “Madame Curie” (Da Capo Press, 1937) is a great

ACS 2016 IRS FORM 990 AVAILABLE The American Chemical Society’s 2016 IRS Form 990 is now available on the ACS website. To access the information, go to www. acs.org/acsirsform990. Please scroll toward the bottom of the page to access the 2016 form and related “Guide to Schedule J” for explanatory information regarding ACS executive compensation. If you have any access problems, please contact [email protected].

resource on the life of her famous mother. A paperback copy updated in 2001 is readily available. In 2012, I offered a lifelong learning course over four evenings on the life and accomplishments of Madame Curie at Michigan State University. This course was well attended.

Paul R. Loconto Okemos, Mich.

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Concentrates Chemistry news from the week

▸ Highlights In utero immune response linked to sexual orientation Chemists forge green path to alkylated amines DNA origami makes micrometer-sized structures Lightning triggers nuclear reactions Nobel Prize winner introduces skin care line Outlook good for chemical industry in 2018 CSB sued for lack of reporting rule Brazil asbestos ban impacts U.S. imports

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CATALYSIS

Catalyst treatment could boost exhaust cleanup Steam enhances platinum catalyst’s durability and knack for scrubbing CO from engine exhaust The catalysts that clean up automotive emissions typically consist of particles of platinum and other precious metals anchored on oxides. Because only the metal atoms at the particle surfaces come in contact with reactants and catalyze reactions, catalyst manufacturers strive to make these particles as tiny as possible. But these supported catalysts come with trade-offs. Dispersing the precious metal as finely as possible can go too far, and the catalysts can become unstable: The metal particles diffuse, coalesce, and lose their catalytic oomph. And the catalysts are often inactive when the temperature of the exhaust is low, which is the case when today’s engines start on a cold morning and will regularly be the case with future energy-efficient engines. A new study on automobile exhaust cleanup describes a way to bypass those problems in a catalytic two-for-one deal. Researchers have shown that a simple procedure can stabilize a platinum-based automotive catalyst and reduce the temperature at which it can thoroughly strip CO from engine exhaust (Science 2017, DOI: 10.1126/science.aao2109). Such a treatment could help clean up emissions from future engines designed to recover energy lost in hot exhaust, which results in lower temperatures of the gas that passes through the catalytic converter. In the run-up to the new study, a team led by University of New Mexico chemical engineer Abhaya K. Datye took dispersing metal particles on an oxide support to the

extreme. In 2016, the group reported that isolated platinum atoms on ceria could convert CO to CO2, a key reaction in engine-emissions cleanup. But the catalyst worked weakly. So the team, which includes Yong Wang of the Pacific Northwest National Laboratory, searched for chemical and physical treatments that would boost the Pt-CeO2 catalyst’s activity without causing it to fail quickly, a common occurrence during catalyst development. Eventually the group found that heating the catalyst to 750 °C in steam drastically improves its ability to mediate CO oxidation. Specifically, in contrast to the untreated catalyst, which needs to be heated to roughly 210 °C to begin oxidizing CO and achieves 100% CO conversion at 320 °C, the treated catalyst begins working at just 60 °C and reaches 100% conversion at 148 °C. Furthermore, the treatment makes the catalyst durable: It showed no signs of deactivation even after 300 hours of testing. Microscopy and spectroscopy analyses indicate that the steam enhances CO-oxidation performance by creating catalytically active sites featuring ceria-bound Pt-OH groups. “This discovery could help advance the technology for vehicle exhaust conversion,” remarks Bruce C. Gates, a catalysis specialist at the University of California, Davis. “The authors’ catalyst characterizations provide deep insights and point the way forward.” The characterization work also raises intriguing questions for further study, he adds. For example,

Exposing this catalyst to steam at high temperature creates oxygen vacancies at the catalyst surface (top). Water dissociates there (middle), forming PtCe-OH groups (dashed lines, bottom) which are active sites for CO oxidation. Gates proposes that researchers should examine the nature of the sites on ceria at which platinum bonds and determine if they are defects. He also wonders if a metal cheaper than platinum would work similarly.—MITCH JACOBY DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

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Science Concentrates NEUROSCIENCE

Mother’s immune response linked to sons’ sexual orientation Antibodies against male-specific proteins could help explain why having older brothers increases a man’s likelihood of being gay The greater number of older brothers a man has, the more likely he will be homosexual. Researchers have observed this so-called fraternal birth order effect across societies and over time. Now scientists report a possible biological mechanism behind it. They found that mothers of gay men with older brothers have elevated levels of antibodies against a male-specific brain protein (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1705895114). The findings support the hypothesis that a mother’s immune response could shape brain structures in male fetuses that are involved in the development of sexual orientation, the researchers say. The fraternal birth order effect is one of the most robust correlations uncovered in sexual orientation research, and this study is an important first step in understanding the biology underlying the effect, says Qazi Rahman of King’s College London, who was not involved in the work. Anthony F. Bogaert of Brock University and Ray Blanchard of the University of Toronto first observed the phenomenon in a Canadian population in 1996. The

Mothers’ immune systems may target brain proteins encoded on the Y chromosome (shown) in male fetuses. two psychologists had a hypothesis about the biology underpinning the phenomenon. They thought that mothers’ immune systems might treat a specific protein in male fetuses like a foreign invader and this response would grow stronger with each boy born to the same mother. Eventually, the immune response would influence the developing brain of a son born later among a line of male siblings.

To test the hypothesis, the psychologists teamed up with some immunologists and collected blood samples from 54 mothers of gay sons, 72 mothers of straight sons, 16 women with no sons, and 12 men. Mothers of homosexual sons had higher levels of antibodies for the protein neuroligin 4 Y-linked than did mothers of heterosexual sons, and mothers of gay sons with older brothers had even higher levels. Not a lot is known about the function of the neuroligin protein except that it helps form connections between brain cells and facilitates communication between them. Because the study’s sample size was small and the observed effect was modest, Rahman thinks the experiment should be replicated on a larger scale to confirm the results. Bogaert says it’s important not to think of this mechanism as a disorder—as something pathological caused by a mother’s immune response. “An atypical biological process creating a trait doesn’t mean that the trait it produces necessarily needs fixing,” he adds. In general, he says, work on uncovering the biological basis for sexual orientation has helped the gay rights movement. “It suggests that sexual orientation is not a choice,” Bogaert says. “It also resonates with gay people’s lived experience—that they have felt different from early on in their lives.”—MICHAEL TORRICE

MATERIALS

A porous material that sucks up record-breaking amounts of methane could pave the way to more economical natural-gas-powered vehicles (Nat. Mater. 2017, DOI: 10.1038/nmat5050). Cars powered by methane emit less CO2 than gasoline guzzlers, but they need expensive tanks and compressors to carry the gas at high pressure. Certain metal-organic framework (MOF) compounds can store methane at lower pressures because the gas molecules pack tightly inside their pores. So MOFs, in principle, could enable methane-powered cars to use cheaper,

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lighter, and safer tanks. But in practical tests, no material has met a U.S. Department of Energy gas storage target of 263 cm3 of methane per cm3 of adsorbent at room temperature and 64 atm. A team led by David Fairen-Jimenez at the University of Cambridge has now developed a synthesis method that endows a well-known MOF with a capacity of 259 cm3 of methane per cm3 under those conditions, at least 50% higher than its nearest rival. The MOF, HKUST-1, contains copper nodes connected by 1,3,5-benzenetricarboxylate linkers. Fairen-Jimenez’s team

made lumps of HKUST-1 using a sol-gel process. The researchers mixed the MOF’s precursors in ethanol, centrifuged the particles that formed, and then allowed them to dry overnight at room temperature. Fairen-Jimenez estimates that a car’s gas tank would need about 60 kg of this MOF to operate. So far, he and his team can produce hundreds of grams of high-capacity HKUST-1 using a continuous flow version of their synthesis method, and their spinout company, Immaterial Labs, aims to achieve kilogram-scale production next year.—MARK PEPLOW, special to C&EN

C R E D I T: BI O P H OTO AS S OC I AT ES /S CI E N C E S O URC E

MOF sets methane storage record

GREEN CHEMISTRY

Chemists forge green path to alkylated amines Process uses microbe-derived amino acids to produce the industrially important building blocks

to these amino acids, ethanol, isopropanol, and other simple alcohols act as both solvents and reactants. The chemists initially used a ruthenium catalyst but also way to make these industrially crucial Chemists use alkylated amines to build demonstrated the reaction with a catalyst building blocks. plastics, pharmaceuticals, and more. containing iron, a more abundant metal. Making alkylated amines is so energy Unfortunately, making these important In either case, the catalyst borrows a intensive because it requires the Haberbuilding blocks on a large scale is energy Bosch process, which converts atmospher- hydrogen atom from the alcohol and prointensive and relies on nonrenewable duces a carbonyl intermediate that then reic nitrogen to ammonia at around 500 °C. feedstocks. Now a team of researchers reacts with the amino acid, shedding port a green approach to syntheAlcohols a water molecule. The resulting sizing the molecules. Value-added ( )10 OH imine intermediate then takes a Tao Yan, Ben L. Feringa, and Amino acids amines H2O hydrogen back from the catalyst, Katalin Barta of the University Dodecanol OH producing an alkylated amine. OH of Groningen describe an envi( )10 N H2N Iron catalyst The researchers demonstrated ronmentally-friendly catalytic H O O their method by synthesizing process that uses alcohols to Glycine Surfactant a surfactant from glycine and add alkyl groups to amino acids 1-dodecanol using an iron catalyst. Feringa To add alkyl substituents to ammonia, harvested from microbes (Sci. Adv. 2017, says they believe the technique has broad chemists use molecules derived from fosDOI: 10.1126/sciadv.aao6494). The method potential beyond surfactants. The chemretains the chirality of the amino acids and sil fuels and reactions that often generate ists have filed for a patent on the method as much waste as they do useful products. releases water as its only waste product. and are looking for partners to explore Yan, Feringa—who shared the 2016 NoCalling the research “nothing short of adapting it for industrial uses. bel Prize in Chemistry—and Barta instead revolutionary,” Paul T. Anastas, the direc“This shows, once again, that green let nature do the hard work of reducing tor of Yale University’s Center for Green chemistry is just simply better chemistry,” nitrogen: They isolated amino acids from Chemistry & Green Engineering, says the Anastas says.—SAM LEMONICK bacteria. As for adding alkyl substituents approach could mean a cheaper, cleaner

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Science Concentrates NUCLEIC ACIDS

DNA origami hits the big time New set of techniques enables the massproduction of micrometer-sized DNA structures

SUSTAINABILITY

A greener way to get lithium? A newly improved sorbent could offer an environmentally friendly way to get lithium from a relatively untapped resource in the U.S.: the brine produced by geothermal power plants (Environ. Sci. Technol. 2017, DOI: 10.1021/acs.est.7b03464). These plants pump hot water from deep geothermal deposits and use it to generate electricity, leaving behind a salty solution that can contain hundreds of parts per million lithium—a commodity in demand for lithium-ion batteries. Passing the brine through a sorbent that captures the lithium ions before pumping the brine

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back underground could collect the metal without the heavy environmental impacts of typical extraction methods, which can generate large amounts of acid or salt waste. The sorbent in the new study is made out of layers of [LiAl2(OH)6]+ with chloride ions and water in between them. Voids in the structure can fill with additional lithium ions but are too small to let in competing cations like sodium. Using a simulated brine solution, Parans Paranthaman of Oak Ridge National Laboratory and colleagues captured 91%

of the initial lithium in the brine with the improved sorbent and found that the material is strongly selective for lithium over sodium and potassium. York R. Smith, a metallurgical engineer at the University of Utah, notes that this sorbent has a lower capacity than alternative sorbents that have been tested. He adds, however, that the researchers’ use of lithium chloride to release lithium from the sorbent instead of acid, as is required for other sorbents, is attractive from an environmental perspective.—DEIRDRE

LOCKWOOD, special to C&EN

C R E D I T: KL AUS WAGE N BAU E R , CH R IST IA N S I GL & H EN D R I K D I ET Z

8 x 8 panel about 650 nm wide (Nature 2017, DOI: 10.1038/nature24655). The team decorated the tiles’ staples with additional chunks of DNA, creating patterns (includDNA structure ever made (Nature 2017, Molecular architects have developed a ing a version of the “Mona Lisa”) that were quartet of methods that could propel DNA DOI: 10.1038/nature24651). Peng Yin of Harvard Medical School and visible under an atomic force microscope. nanotechnology into wider use. Together, DNA architects tend to work with mere the techniques offer a tool kit to mass-pro- colleagues built more complicated shapes micrograms of material, insufficient for by using short strands of DNA with four duce larger and more complex “DNA oritesting biomedical applications such as unique binding domains, which snapped gami” structures than ever before, paving drug encapsulation and delivery. To scale together with other strands like Legos the way for applications from drug delivup production, Dietz’s team used virus(Nature 2017, DOI: 10.1038/nature24648). ery systems to nanoelectronics. es called bacteriophages to make single The team developed a software tool called “I think people will now see that DNA strands of DNA containing a scaffold, Nanobricks that allowed them to delete nanotechnology is not just a small box of staples, and built-in scissors called DNATinkertoys,” says Hao Yan at Arizona State specific bricks from the mixture to leave zymes. When activated by zinc ions, these University, who was not involved in the re- cavities in the resulting cuboid structures, scissors snipped out the components so fashioning shapes such as a teddy bear. search. “Now they will see some hope that that they were ready for self-assembly. The third construction method, called you could use this for real applications.” When the team amplified the viral DNA fractal assembly, began with flat tiles of In DNA origami, a long “scaffold” of strands inside Escherichia coli in a 2 L ferDNA origami that could interlock with single-stranded DNA is folded into a prementation vessel, the components assemtheir neighbors, ultimately forming an determined shape by hundreds of shorter bled to form 163 mg of a 70-nm“staple” strands, which long nanorod. If this process bind to specific positions were run at a contract biotech on the scaffold. facility, the researchers estiTo create larger DNA mate that DNA origami could structures, Hendrik Dietz be produced for a mere 18 cents of the Technical University per milligram, at least 1,000 of Munich and coworkers times as cheap as conventional used DNA origami to make methods (Nature 2017, DOI: various building blocks, 10.1038/nature24650). including wedge-shaped “With mass production in “V bricks.” These could place and the ability to make self-assemble into a range these integrated structures, I of 3-D shapes, including a hope progress will be faster,” dodecahedron with a mass Dietz says.—MARK PEPLOW, of 1.2 billion daltons that DNA-based components self-assembled to form this 1.2-billionDietz reckons is the heftiest dalton dodecahedron (right), as seen by electron microscopy (left). special to C&EN

SYNTHESIS O

Final twist in marine toxin structural saga

H

NH O

O

O H O O

H H O H HO O H

OH

H

Researchers synthesize azaspiracid and correct its structure In the mid-1990s, scientists started to notice cases across Europe of people falling ill from a new kind of shellfish food poisoning. The culprit, researchers discovered, was a family of marine toxins called azaspiracids. The structures of these amorphous toxins have been difficult for chemists to pin down, though some have come very close. A pair of papers from the laboratory of Craig J. Forsyth at Ohio State University now corrects the stereochemistry of a key position in azaspiracid-3 and details a total synthesis of the reassigned structure (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/ anie.201711006; Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201711008). A synthetic route to the azaspiracids along with accurate structures could help scientists develop assays to detect the toxins in food. Forsyth’s lab had been working on an

OH

O

azaspiracid synthesis in 2004 when K. C. Nicolaou, then at Scripps Research Institute California, reported a 96-step synthesis that revised the azaspiracids’ originally reported structure. Using the 2004 structure as a target, Forsyth’s group devised a new total synthesis. But when the chemists used liquid chromatography to compare their newly synthesized azaspiracid-3 with an authentic sample, they found that the compounds’ retention times didn’t match. After some head-scratching, Forsyth says, they suspected that the stereochemistry of an alcohol group may have been misassigned in the 2004 structure. Forsyth’s team definitively set the stereochemistry of the C20 alcohol, whereas the Nicolaou synthesis could have yielded either stereoisomer, possibly leading to a misassignment.

Azaspiracid-3 The researchers chemically inverted the alcohol’s configuration, and were “overjoyed” when the resulting compound’s retention time matched that of the natural product. While previous total syntheses did succeed in making the correct natural product, they had misassigned one of the molecule’s 19 stereocenters. Nicolaou, now at Rice University, congratulated the team for their “meticulous” efforts that led to azaspiracid’s final structural revision. “That they were able to decipher the last detail for the correct structure as they did is a testament not only to their brilliant and scholarly work but also to the current powerful state of the art of total synthesis and the modern, high-resolution analytical techniques that support it.”—TIEN NGUYEN

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Science Concentrates ELECTRONIC MATERIALS

▸ Cell-based hormone replacement Women whose ovaries stop functioning because of either menopause or disease can experience health effects that go beyond the loss of fertility, including osteoporosis and obesity. The standard treatment—hormone replacement with estrogen alone or in combination with progestin—can mitigate those problems. But the treatment comes with other risks, including an increased chance of breast cancer and heart disease. A team led by Emmanuel C. Opara of Wake Forest School of Medicine is developing bioengineered polymeric capsules that mimic ovarian follicles for use as a

Electric eel inspires soft power source The knifefish Electrophorus electricus, better known as the electric This soft power source combines four types of hydrogel. eel, can generate electricity to stun its prey thanks to specialized organs that generate power via ion flux—no batteries required. The structure of these organs provided a jolt of inspiration to researchers led by Michael Mayer of the Adolphe Merkle Institute at the University of Fribourg, who wanted to create a soft power source. The electric eel’s organs contain thousands of alternating compartments containing either potassium or sodium ions separated by membranes that keep the ions apart. When the knifefish charges up, the membranes let the ions flow, creating a burst of power. To create ion gradients in their system, Mayer and colleagues used three-dimensional printing to pattern a substrate with alternating spots of hydrogels loaded with either sodium chloride or pure water (shown in red and blue, respectively). On a different substrate, they dotted cation-selective and anion-selective hydrogels (shown in green and yellow, respectively). When overlaid, the system of dots creates a conductive pathway that can generate up to 110 V (Nature 2017, DOI: 10.1038/ nature24670). The researchers note that because the materials are biocompatible, they have the potential to power implantable medical devices, such as pacemakers. “To get there, we are looking for talented Ph.D. students and postdocs,” Mayer says.—BETHANY HALFORD

This ovarian-follicle mimic delivers cellbased hormone replacement therapy that could replace current drug therapies at lower doses and with fewer side effects.

the hormone pellets or in rats whose ovaries were still intact.—CELIA ARNAUD

cell-based method of hormone replacement (Nat. Commun. 2017, DOI: 10.1038/s41467017-01851-3). To make these artificial ovaries, the researchers encapsulate two types of hormone-producing ovarian cells—granulosa and theca cells—in separate layers of cross-linked alginate (a polysaccharide) with layers of poly-l-ornithine between. They tested the capsules by implanting them in rats whose ovaries had been removed and comparing the performance with rats whose ovaries had been removed and treated using hormone-containing pellets at high and low doses of estrogen with or without progestin. After 90 days, rats that received the cell-based therapy had similar body weight, fat percentage, bone mineral density, and uterine morphology as rats with intact ovaries. These positive effects were achieved with hormone levels in the blood that were lower in rats receiving the cell-based therapy than in rats receiving

NUCLEAR CHEMISTRY

10


▸ Lightning triggers nuclear reactions Nearly 100 years ago, physicists proposed that high-energy processes occurring during thunderstorms might trigger nuclear reactions. But limitations in detector technology and difficulties in making measurements during thunderstorms have prevented researchers from recording direct experimental evidence of such nuclear reactions—until now. On Feb. 6, a team led by Teruaki Enoto of Kyoto University tracked two cloud-to-ground lightning strikes during a thunderstorm over the coast of the Sea of Japan. Using data recorded at monitoring stations near the lightning strikes, which include time- and energy-correlated signals of γ rays, neu-

trons, and positrons, the team concludes that it observed γ-ray-induced photonuclear reactions (Nature 2017, DOI: 10.1038/ nature24630). Specifically, the researchers detected telltale signs that γ rays, which are produced in thunderclouds as intense electric fields drive high-energy electrons into airborne molecules, can knock a neutron out of an 14N nucleus, creating an 13N isotope. That isotope is unstable: It decays into a neutrino, Lightninga positron, and a generated γ rays stable 13C nucleus. can trigger nuclear Upon collision with reactions in an electron in an atmospheric atmospheric molmolecules. ecule, the positron and electron undergo annihilation and produce a pair of γ rays with a characteristic energy of 0.511 MeV. The researchers note that related processes generate 14C and 15N isotopes. These

CR E D I T: T H O MAS S C HRO ED ER /A N I RVAN GU H A (SO F T- P OW E R S O U RCE ); N AT. CO M M U N . (DI AG RA M ); LYO H A1 23/ W I K I M E DI A COM M ON S (LI GH T N I N G)

BIOTECHNOLOGY

findings broaden understanding of atmospheric electrical phenomena and reveal a previously unrecognized natural source of radioactive isotopes on Earth.—MITCH

JACOBY

CATALYSIS

▸ Uranium doubles up as a catalyst

C R E D I T: COU RTESY O F ST E P H E N L I D D LE ( 3 -D MO D E L) ; A DA PT ED FRO M N AT. CH E M . (M OTO R M O L ECU L ES); CAS E Y K E N N E DY (CRAN B E R R I ES )

Reversible, two-electron redox processes in which a substrate is added and subsequently eliminated from a transition metal are a defining feature of most catalytic cycles. This behavior is typically unheard of, though, when it comes to lanthanide and actinide metals. The f-block metals are used as catalysts, but they tend to exhibit irreversible one- or multielectron oxidation or reduction steps, and the complete redox sequence hasn’t been observed in one re-

MOLECULAR MACHINES

Motor molecules made into muscles Chemists have gotten a lot of mileage out of the Nobel Prize-winning, light-activated motor molecules invented in Ben L. Feringa’s lab at the University of Groningen. Feringa has used them to create molecule-sized cars that scoot along a surface, and others have incorporated them into polymers or used them to drill holes in cancer cells (see page 24). Feringa’s group has now managed to get these molecule-sized machines to flex some muscle. His team created a water-soluble version of the motor that assembles into fibers. In the presence of calcium ions, these fibers organize into macroscale strings made mostly of water that flex in response to ultraviolet light. They can even lift a small weight: a 400-mg piece of paper (Nat. Chem. 2017, DOI: 10.1038/nchem.2887). As with previous versions of Feringa’s motors, these molecules rotate via isomerization around a double bond when hit with UV light. The motor molecules pack closely together in the self-assembled fibers and expand a little bit in the presence of the light, causing the string to bend. “You amplify a tiny motion from the molecular level all the way up to the macroscopic level,” Feringa notes. While others have made artificial muscles using molecular machines covalently linked to polymers, this is the first time that such muscular systems have been assembled entirely from small molecules.—BETHANY HALFORD

but the findings provide a pathway to discovering new lanthanide and actinide catalysts—for example, to synthesize aniline derivatives.—STEVE RITTER

POLLUTION This dimeric uranium(V) complex, joined at the center by azobenzene, provides the best evidence yet for transition-metal redox behavior in an f-block element. action system. Researchers led by Stephen T. Liddle of the University of Manchester and Laurent Maron of the University of Toulouse have now found evidence that a uranium complex can satisfy all the criteria of classical single-metal, two-electron oxidative addition-reductive elimination, and they make a case that uranium can mimic traditional transition-metal catalysis (Nat. Commun. 2017, DOI: 10.1038/s41467-01701363-0). The researchers added azobenzene to a uranium(III) triamide complex they previously reported to form a dimeric uranium(V) imido complex, which readily expels azobenzene back out upon heating. The researchers confirmed the oxidation and reduction steps using a combination of structural, spectroscopic, magnetic, and computational studies. The reaction sequence is not yet optimized, Liddle says,

▸ To trap fertilizer in cranberry bogs, just add salt Phosphorus from fertilizer can readily escape farms by hitching a ride on sediment particles suspended in water runoff. Cranberry bogs, in which farmers use water to help harvest the scarlet berries, are no different. Scientists with USDA and the University of Massachusetts Cranberry Station are working to keep phosphorus in cranberry bogs to reduce the amount of the nutrient in water and limit harmful algal blooms downstream. The team

reports that aluminum sulfate treatment can trap phosphorus in the sediment of irrigation ponds and cranberry bogs, preventing it from draining away (J. Environ. Qual. 2017, DOI: 10.2134/jeq2017.04.0134). The researchers, led by Casey D. Kennedy of USDA’s Agricultural Research Service, tested the ability of various salts to remove phosphorus from pond water. Certain salts can neutralize negative charges on sediment particles, causing them to clump together and settle out of the water. This process locks residual phosphorus away so it’s unavailable to plants and algae. Lab experiments showed that aluminum sulfate, compared with iron and calcium salts, most effectively binds phosphorus at low concentrations (5 to 15 mg/L). To test the feasibility of using aluminum sulfate on cranberry farms, the scientists dispersed 15 mg/L aluminum sulfate into an irrigation pond and a former cranberry bog. Aluminum sulfate treatment worked best in the shallow waters of the former cranberry bog, removing 94% of the phosphorus from the water compared with 78% from the irrigation pond.—EMMA HIOLSKI

Farmers harvest cranberries by flooding fields, but the water can carry excess phosphorus downstream and pollute waterways. DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

11

Business Concentrates START-UPS

FTC seeks to block Tronox’s purchase of Cristal Regulator says the combined firm will have too much power in the titanium dioxide market The U.S. Federal Trade Commission is attempting to block Tronox’s purchase of the Saudi Arabian titanium dioxide maker Cristal, maintaining that the transaction will diminish competition in a market that is already an oligopoly. Tronox agreed to purchase Cristal in February for $1.7 billion in cash, plus stock. The purchase would create the world’s largest producer of the white pigment—ubiquitous in paints, plastics, and other products—edging out perennial leader Chemours. Cristal had $1.7 billion in 2016 sales; Tronox had $1.3 billion. The FTC has issued a complaint against the deal and is seeking a restraining order and a court injunction. The regulator is worried about concentration in the business of making TiO2 by the chloride process. The process yields a high-quality, potent pigment that generally commands a premium over pigment made with the sulfate process. Should the deal go through as is, FTC asserts, Chemours and Tronox would control more than 80% of the North American market for chloride-process TiO2. Tronox operates three plants around the world, one of which is in Hamilton, Miss.; Cristal runs eight plants globally, including a site in Ashtabula, Ohio. “The market is already dominated by a few large players with a history of seeking to support higher prices by restricting pro-

Regulators say Tronox’s purchase of Cristal would make for too hefty a player in the white pigment market. duction,” FTC said in a statement. Tronox CEO Jeffry N. Quinn told analysts on a conference call that he disagrees with FTC’s assessment. “We believe the appropriate geographic market is the global TiO2 market, and we believe the relevant product market includes TiO2 produced from both the chloride and the sulfate processes,” he said. Quinn moreover maintained that the aim of the transaction is integration between white pigment production and TiO2 ore extraction, not to cut capacity to boost prices. Quinn vowed to fight the FTC, though he also promised to engage in discussions. “We are always willing to consider appropriate action to address the commission’s concerns,” he said.—ALEX TULLO

BY THE NUMBERS

$32.8 billion Total sales of Pfizer’s sildenafil, more commonly known as Viagra, since 1998. Generic versions of the drug hit the U.S. market last week. The ground-breaking erectile dysfunction treatment was discovered in 1993 after unusual side effects were reported in clinical studies of sildenafil to treat high blood pressure and chest pain. Viagra works by blocking an enzyme that interferes with nitric oxide’s ability to dilate blood vessels.

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Obsidian launches to tune CAR-Ts Armed with $49.5 million in its first formal round of funding, Obsidian Therapeutics has launched to finetune the activity of cellular and gene therapies. The Boston-based biotech firm aims to make the treatments safer and more effective across a broader range of diseases. Ever since early clinical trials suggested chimeric antigen receptor (CAR) T cells could quickly obliterate blood cancer in some patients, companies have been racing to harness the technology, in which a patient’s own T cells are genetically engineered to include a protein receptor that helps them see and attack cancer cells. The problem is that CAR T cells “are sort of on a therapeutic knife edge: They can either be profoundly effective or terribly toxic,” says Obsidian CEO Michael Gilman. When CAR T cells home in on cancer cells, they can prompt a rapid—and potentially deadly—release of cytokines, proteins involved in immune system response. Moreover, CAR T cells don’t always produce lasting responses. Obsidian hopes its technology, which was discovered in the labs of Stanford University professor Thomas Wandless, can address those limitations. Wandless found a way to add a region on a protein, what he calls a “destabilizing domain,” that allows expression of the protein to be controlled based on exposure to a small molecule. Without the small molecule around, the protein is tagged for disposal in the cellular trash bin; when the small molecule—an already-approved drug—is given, the protein is stabilized. By giving proteins something like a volume knob that can be tuned by small molecules, Obsidian expects to avoid the sometimes-deadly cytokine storms, while also giving CAR T cells “entirely new functionalities,” Gilman says.—LISA JARVIS

C R E D I T: TRO N OX ( P L A N T ) ; S H UT TE RSTOC K ( P I LL)

MERGERS & ACQUISITIONS

NANOMATERIALS

Nobel Prize winner introduces skin care line J. Fraser Stoddart is behind new firm that will sell high-priced antiaging cosmetics In 2016, J. Fraser Stoddart won the Nobel Prize in Chemistry for his part in designing a molecular machine. Now as chief technology officer and cofounder of nanotechnology firm PanaceaNano, he has introduced the “Noble” line of antiaging cosmetics, including a $524 formula described as an “anti-wrinkle repair” night cream. The firm says the cream contains Nobel Prize-winning “organic nano-cubes” loaded with ingredients that reverse skin damage and reduce the appearance of wrinkles. Other prize-winning chemists have founded companies, but Stoddart’s backing of the antiaging cosmetic line takes the promotion of a new company by an award-winning scientist to the next level. The nano-cubes are made of carbohydrate molecules known as cyclodextrins. The cubes, of various sizes and shapes, release ingredients such as vitamins and

peptides onto the skin “at predefined times with molecular precision,” according to the Noble skin care website. PanaceaNano cofounder Youssry Botros, former nanotechnology research director at Intel, contends that the metering technology makes the product line “far superior to comparable products in the market today.” However, the nanocubes aren’t molecular machines, for which Stoddart won his Nobel prize. While acknowledging the product line trades on his Nobel prize, Stoddart points out to C&EN that “we’re not spelling our product name, Noble, the way the Swedish Nobel Foundation does.” Ethicist Michael Kalichman has a different perspective. Use of the word Noble,

even though spelled differently than the prize, is “unseemly but not illegal,” he says. Kalichman, who is director of the Research Ethics Program at the University of California, San Diego, adds, “If his goal is to make money, this may work. But if his goal is to retain credibility and pursue other more laudable goals, maybe he should stay focused on those goals.” Botros says PanaceaNano is also developing nanotechnology materials for markets including hydrogen storage, flexible batteries, and molecular memory based on technology from Stoddart’s lab and licensed from Northwestern University. But PanaceaNano chose to make its first commercial product a line of cosmetics because of the high margins and the ease of market entry.—MARC REISCH

ENVIRONMENT

EU’s chlorine makers end mercury-based production

C R E D I T: PA N AC EA N A N O ( CR EA M) ; K EM O N E ( P LA N T )

Europe’s Dec. 11 ban brings 21 mercury cell production plants to a halt European Union regulations requiring companies to stop making chlorine via a process that involves mercury came into effect last week. Of the 21 mercury technology plants that were operating at the start of 2017, seven have closed and 14 have been converted—or are about to be converted—to the less environmentally harmful membrane technology. The seven closed plants had a combined capacity of 665,000 metric tons per year of chlorine, or 5.5% of Europe’s chlorine production capacity. The 14 plants being converted have a combined capacity of 1.4 million metric tons per year of chlorine. Six of the 21 mercury cell plants are located in Spain, with the rest spread across the bloc. In the U.S., where no equivalent regulation exists, only one plant still uses the toxic element.

EuroChlor, a trade association, estimates that since 2001 the conversion of mercury plants to cleaner technology will have cost the industry about $3.5 billion. In 2016 European chlorine producers released a total of 1.4 metric tons of mercury into the atmosphere. At the end of 2016 they were still using about 5,400 metric tons of mercury in the cells, which electrolyze sodium chloride into chlorine and sodium hydroxide. In one of the final closures, Hydrochem Italia shut down its mercury cell chlorine plant just last week with the loss of 30 jobs, according to the Italian newspaper La Stampa. The firm plans to convert its plant and reinstate staff when the facility reopens at the end of 2019. A major clean-up of mercury-based hazardous waste is now set to take place

Kem One began converting this chloralkali plant in Lavéra, France, in 2015. at the 21 sites. EU regulations allow for liquid mercury to be stored temporarily for up to five years with a possible extension of three years. Liquid mercury must be converted to mercury sulfide before its permanent disposal. “Issues such as the demolition of buildings and the treatment and follow-up of contaminated sites will continue to keep the chlor-alkali industry busy for several more years,” EuroChlor says.—ALEX

SCOTT DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

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Business Concentrates ECONOMY

▸ ICL’s phosphorus specialties go to SK Israel’s ICL is selling two phosphorus chemical businesses to the private equity firm SK Capital for about $1 billion. One business makes phosphorus pentasulfide, used in lubricants, mining chemicals, and pesticides. The other business makes firefighting mixtures, based on ammonium phosphate and other ingredients, that are air-dropped onto forest fires. In the past 12 months, the businesses generated $112 million in operating profits on $294 million in sales. ICL says it is selling them because they have limited fit with its other phosphorus-related businesses such as phosphoric acid. —ALEX TULLO

GREEN CHEMISTRY

▸ Partners convert waste to ethanol Sekisui Chemical and LanzaTech are using fermentation to convert municipal solid waste into ethanol at a demonstration facility at a Japanese landfill. In traditional fermentation, yeast

Sekisui and LanzaTech converted waste to ethanol in this demonstration facility. converts sugar into products. LanzaTech uses bacteria to convert carbon-containing gases from waste incineration and other industrial sources into chemicals such as ethanol.—JEAN-FRANÇOIS TREMBLAY

PETROCHEMICALS

▸ Nova advances Canadian polyethylene Nova Chemicals is going ahead with plans to build a polyethylene plant in Sarnia, Ontario, and to expand its ethylene cracker there. Nova will invest more than $1.3 billion in the projects. The poly-

14


Clear vista for chemicals The U.S. chemical industry is on the cusp of a strong 2018, while its counterparts in Europe, including Germany, are expecting a good but not spectacular year. The American Chemistry Council (ACC) trade association is calling for an increase in U.S. chemical production of 3.7% in 2018 after an estimated 0.8% increase this year, when Hurricane Harvey hampered production along the Gulf Coast. “Manufacturing has turned a corner, business investment is on the rise, and domestic oil and gas production is on the rebound,” notes Kevin Swift, ACC’s chief economist. Cheap and abundant feedstocks and energy give U.S. chemical makers an edge, he points out. The European Chemical Industry Council and Germany’s Chemical Industry Association each predict a 2.0% rise in chemical output in the regions they represent. The groups say they are enjoying robust demand from the European Union as well as Asia and Russia. However, both note that high energy and feedstock prices as well as carbon costs under the EU Emissions Trading System will put them at a disadvantage to North America and China in 2018.—MARC REISCH

ethylene plant will use the company’s Advanced Sclairtech process and have a capacity of 450,000 metric tons per year. To feed the plant, Nova is expanding the cracker by 50%. Earlier this year the Canadian firm opened a polyethylene plant in Alberta, bought a controlling interest in a Williams Cos. cracker in Louisiana, and announced plans to build a cracker in Texas with Total and Borealis.—ALEX TULLO

on his promise to launch a major restructuring of the indebted generic-drug giant. Schultz aims to reduce Teva’s costs around the globe by $3 billion by 2019. To do that, Teva will slash 25% of its workforce, about 14,000 employees, and shutter many of its R&D facilities, manufacturing plants, and offices worldwide next year. The Israeli firm’s stock spiked 16% upon the news.—RYAN CROSS

INVESTMENT

CONSUMER PRODUCTS

▸ Covestro adds MDI, chlorine in Spain

▸ DuPont launches microbiome venture

Covestro will spend about $235 million to increase its production capacity for methylene diphenyl diisocyanate (MDI) in Tarragona, Spain, by about 30% to 220,000 metric tons per year. Covestro also plans to establish its own facilities for making chlorine, a raw material for the polyurethane intermediate, in Tarragona. The new MDI capacity is due online in 2022 and the chlorine by the end of 2020. Covestro had considered closing the Tarragona plant in 2015 when chlorine supply became uncertain.—ALEX SCOTT

DuPont Nutrition & Health has launched a microbiome venture that will partner with scientists in academia and industry to develop new products. DuPont says it currently offers microbiome-enhancing probiotics and prebiotics, including human milk oligosaccharides. The firm’s first partner is the APC Microbiome Institute, a collaboration of three Irish institutions. The partners will focus on products that establish healthy microbiomes in infants.—MELODY

EMPLOYMENT

▸ Teva will cut 14,000 jobs worldwide Kåre Schultz, the new CEO of Teva Pharmaceutical Industries, is making good

BOMGARDNER

BIOLOGICS

▸ WuXi throws switch on biologics expansion WuXi Biologics says its new biologics manufacturing plant, which it claims is the world’s largest such facility using dispos-

C R E D I T: LA N Z AT EC H

INORGANIC CHEMISTRY

it has a new partnership with Synlogic, a drug discovery firm, to find so-called living medicines to treat neurological and liver disorders.—MELODY BOMGARDNER

O H2N

O N S

FINE CHEMICALS

▸ PMC bests Axyntis in quest for Isochem WuXi says it began construction of this facility in April 2015.

able bioreactors, is now in full operation. The $150 million, 45,000-m2 plant in Wuxi, China, has a total capacity of 30,000 L. The facility quintuples biologics capacity for the firm, which opened its first such plant in Wuxi in 2012.—RICK MULLIN

SYNTHETIC BIOLOGY

▸ Ginkgo raises funds, forms partnership

C R E D I T: WUX I BI O LO GI CS

Synthetic biology start-up Ginkgo Bioworks raised $275 million in its fourth round of venture capital funding, led by Viking Global Investors, the Y Combinator Continuity fund, and Bill Gates’s Cascade Investment. Ginkgo will use the money to open its third facility to develop microbes altered with synthetic DNA. Ginkgo sells the microbes to firms that use them to produce flavors, fragrances, and other molecules. Separately,

PMC has prevailed over Axyntis, a French manufacturer of active pharmaceutical ingredients, in its bid to acquire Isochem, the former drug chemical operation of France’s SNPE. The acquisition, for an undisclosed sum, takes a company with little experience supplying complex chemistries to the drug industry into what it perceives as a lucrative market. It follows PMC’s purchase of Yegna Manojavam Drugs & Chemicals, an Indian fluoroquinolone drug maker, in October.—RICK MULLIN

PHARMACEUTICALS

▸ Janssen buys into Idorsia drug Janssen, the research arm of Johnson & Johnson, has opted into the development of Idorsia’s blood pressure drug aprocitentan. The decision, which grants Janssen global rights to the compound and its derivatives, triggers a payment of $230 million to the Swiss biotech firm.

N

O N

Br

Aprocitentan, a small-molecule dual endothelin receptor antagonist, is for people whose high blood pressure can’t be sufficiently lowered by other medicines. Idorsia is developing a Phase III study of the drug, set to begin next year.—LISA JARVIS

BIOTECHNOLOGY

▸ Gilead to acquire Cell Design Labs Gilead Sciences is expanding its cell therapy program by acquiring Emeryville, Calif.-based Cell Design Labs for up to $567 million. Cell Design Labs focuses on improving CAR T-cell immunotherapies, in which a person’s T cells are removed, edited, and reinjected to kill tumors. The firm’s technologies include an “on-off” switch for CAR T cells and novel receptors that could help T cells target cancerous cells while ignoring healthy ones. The buyout comes just two months after FDA approved a CAR T-cell therapy from Kite Pharma, which Gilead acquired in August for $11.9 billion.—RYAN CROSS

▸ Hanwha Total Petrochemical will spend $300 million to expand polyethylene capacity in Daesan, South Korea, by 50% to 1.1 million metric tons per year. Set to be completed in 2019, the expansion will complement an ongoing project at the site to start using propane feedstock.

▸ Asilomar Bio, a start-up developing crop yield-enhancing chemicals, has raised $12 million in a second round of funding from the venture arms of Syngenta and Wilbur-Ellis. Asilomar’s first product is intended to help plants better use water and nutrients in the soil.

▸ Mitsui Chemicals and BASF will commercialize broflanilide, a broad-use insecticide with a new mode of action. The chemical, discovered and developed by the two firms, interrupts a GA-

O

Aprocitentan

BA-gated chloride channel in the motor neurons of insects.

▸ Cornerstone Chemical is licensing hydrogen cyanide technology from Chemours. Cornerstone will decide next year whether to use the technology to build another hydrogen cyanide plant in Waggaman, La.

N H

Br

Business Roundup ▸ Lubrizol and the University of Pittsburgh’s department of chemical and petroleum engineering have received a U.S. Department of Energy grant to develop energy efficiency and productivity improvement methods. The $7.5 million project includes financial contributions from Lubrizol and the school.

N

▸ Solvay will increase its production of natural vanillin, made from rice bran, by 60 metric tons per year. While most vanillin is made from petroleum precursors, companies are increasingly seeking out natural vanillin.

▸ NorthSea Therapeutics has launched with nearly $30 million in funding to develop icosabutate for nonalcoholic steatohepatitis, a liver disease. NorthSea licensed icosabutate, which has already completed Phase II studies as a treatment for high levels of triglycerides, from Pronova BioPharma Norge. ▸ Amgen has tapped Berkeley, Calif.-based Carmot Therapeutics for a Parkinson’s disease drug discovery partnership potentially worth $240 million in milestones. Carmot’s technology, chemotype evolution, is a type of fragment-based drug discovery.


15

Policy Concentrates INDUSTRIAL SAFETY

CSB sued for lack of reporting rule

First responders have sued Arkema for alleged exposure to toxic fumes after tailers of organic peroxides ignited at the company’s Crosby, Texas, site after flooding from Tropical Storm Harvey.

Regulation proposed in 2009 was dropped because of cost, industry opposition Several nonprofit organizations sued the U.S. Chemical Safety Board earlier this month for failing to establish a national reporting system to collect data on air pollution emissions from accidents by U.S. companies. The CSB reporting system is required by the Clean Air Act of 1990, which created the board. CSB is an independent federal agency responsible for investigating industrial, chemically related accidents and determining their root cause. Several hundred accidents annually meet the criteria for CSB investigations—a fatality among workers or the public, serious injuries, or substantial property damage—although the agency only has the resources to investigate a few. CSB has in the past recognized the importance of the reporting requirement

and proposed a regulation in 2009. In that proposal, the board identified a host of improvements that would come from the regulation. It noted, for instance, that timeliness, completeness, and accuracy of chemical incident reports would be improved. Also, required reporting would better help the agency assess issues and trends and further the cause of accident prevention, the proposal said. But CSB dropped the proposal due to a combination of implementation costs, lack of funding, and industry opposition to new reporting requirements, according to sources familiar with the proposal. The arguments in the lawsuit pushing for the reporting regulation largely echo those that CSB identified in its proposal. CSB currently tracks incidents using me-

dia reports in combination with data collected by the U.S. Coast Guard National Response Center and a mix of other sources of accident information. Adam Carlesco, a lawyer with Public Employees for Environmental Responsibility, which is leading the litigation, compares that current system to a “news clipping service” and calls it an inadequate safeguard for the health of communities, workers, and first responders. CSB did not respond to questions. Aside from the suit, the agency has been hammered for more than a decade by reports from the Government Accountability Office and the EPA Office of Inspector General for its failure to comply with the Air Act’s accident reporting provisions.—JEFF JOHNSON, special to C&EN

CHEMICAL REGULATION

Brazil asbestos ban impacts U.S. imports The U.S. chlor-alkali industry is feeling the hit from a Nov. 29 ruling of the Brazil Supreme Federal Court that bans the mining, use, and commercialization of asbestos in Brazil. About 95% of the asbestos used in the U.S. in 2016 was imported from Brazil, with the rest coming from Russia. The chlor-alkali industry used nearly all of the material, or about 340 metric tons, according to estimates by the U.S. Geological Survey. Much of the U.S. chlor-alkali industry still uses asbestos diaphragms to produce chlorine. The industry is phasing out such diaphragms and replacing them with more expensive ion-exchange membranes as has been done in Europe to replace mercury cells (see page 12), but not all companies have made the switch. Some members of Congress are raising concerns about having Russia as the sole

16


supplier of asbestos to the U.S. By continuing to allow industrial use of asbestos, a known carcinogen, the Environmental Protection Agency “is protecting Russian mining at the expense of American workers,” Rep. Frank Pallone (D-N.J.) said during a Dec. 7 subcommittee hearing of the House of Representatives Energy & Commerce Committee. Pallone and other Democrats are urging EPA to use its new authorities under the revised Toxic Substances Control Act to ban the use of asbestos in the U.S. EPA announced in June that it would evaluate asbestos manufacturing, processing, and distribution as part of an upcoming risk assessment. Pallone asked EPA Admin-

Chrysotile, shown here, is the most commonly used form of asbestos.

istrator Scott Pruitt why the agency is not also considering the use and disposal of the mineral. “The use and disposal of asbestos is the main source of risk from asbestos,” Pallone said. “If you ignore those things, you will produce a risk assessment that fails to capture the risks to workers and ordinary Americans and, in my opinion, will not be scientifically valid and will not be protective of public health.” Pruitt agreed, saying disposal of asbestos is a “very important factor that we need to consider.” The Asbestos Disease Awareness Organization (ADAO), an advocacy group, welcomes the Brazil court ruling. “This decision sounds a clarion call reaffirming there is no safe or controlled use of asbestos,” says ADAO cofounder Linda Reinstein.—BRITT ERICKSON

C R E D I T: A P ( A R K E MA ) ; S H U TT E RSTOC K ( AS BESTOS )

Russia is now the sole source of carcinogenic mineral for the U.S.

POLLUTION

▸ World officials set goal for contaminationfree planet Top environmental officials from around the globe pledged on Dec. 6 to improve people’s lives by cutting contamination of land, air, freshwater, and oceans. Meeting as the United Nations Environment Assembly in Nairobi, Kenya, the officials set an international goal of a pollution-free planet. They did not establish a time frame for reaching this lofty objective, calling it “a long-term endeavor.” One activity that must be improved to eliminate pollution

is use of commercial Delegates at the chemicals, the asUnited Nations sembly determined. Environment “We believe that it is Assembly committed to a both inexcusable and pollution-free preventable that tens planet. of thousands of chemicals are used in everyday objects and applied in the field without proper testing, labelling or tracking,” the environment ministers say in a declaration. The assembly also called for action to curb the amount of plastic in the world’s oceans as global plastic production and use continue to increase. The assembly called for the United Nations Environment Programme to create a global experts group to study options for reducing marine plastic litter, including microplastics.—CHERYL HOGUE

ENERGY

C R E D I T: UN E P

▸ Climate change may impact future wind energy generation Wind energy is a growing renewable energy source with great potential, but greenhouse gas emissions and climate change may

EDUCATION

Research institutions agree to share data about science careers Ten major research institutions have come together to create more openness about Data to be released by research institutions: career outcomes for graduate students ▸ Admissions and and postdocs in life sciences departments. matriculation data of Calling themselves the Coalition for Next Ph.D. students Generation Life Sciences, the institutions ▸ Median time to plan to publish data, such as median time degree and completion to degree and where alumni are working, to data for Ph.D. programs help graduate students and postdocs make ▸ Median time as more informed career choices. In the past, a postdoc at the universities have been reluctant to share institution data for fear that releasing the information ▸ Demographics would slow recruitment and retention of of Ph.D. students graduate students and postdocs. That lack and postdoctoral of information has hurt science trainees, scholars by gender, many of whom enter graduate school underrepresented hoping to become professors; however, minority status, and only 10% of Ph.D. biomedical trainees get citizenship tenure-track positions. While releasing ▸ Career outcomes for data won’t fix the problem, it does “reflect Ph.D. and postdoctoral an essential step in acknowledging our alumni, classified by job shared obligation to protect and enhance sector and career type the vibrancy, humanity, and fairness of this system. We hope that in due course other institutions will join our efforts,” the coalition says in a Science paper announcing its plan (2017, DOI: 10.1126/science. aar4638). The institutions will begin releasing some data in February 2018, with data in all areas available within 18 months.—ANDREA WIDENER

influence wind energy’s future availability across the globe. In the next century, because of climate change, wind resources may decrease in the Northern Hemisphere and sharply increase in hot spots in southern latitudes and the tropics, according to a study by University of Colorado, Boulder, researchers (Nat. Geosci. 2017, DOI: 10.1038/s41561-017-0029-9). Wind energy resources are an integral part of many nations’ strategies to meet carbon dioxide emissions reduction targets. Globally, installed wind power capacity has grown by some 22% per year since 2006, and wind power now provides about 3.7% of energy worldwide. However, assessments of future wind energy resources are usually based on today’s climate without considering that anthropogenic greenhouse gas emissions will continue to modify global atmospheric circulation and temperature. In the new work, the researchers combined wind industry power calculations with an ensemble of 10 global climate models under high and low greenhouse gas emissions scenarios.—JEFF JOHNSON, special to C&EN

RESEARCH FUNDING

▸ DOE illegally withheld ARPA-E funds U.S. Department of Energy officials instructed the Advanced Research Projects Agency-Energy (ARPA-E) not to spend $91 million in funds allocated by Congress, according to the Government Accountability Office (GAO), Congress’s investigative arm. In its fiscal 2018 budget proposal, the Donald J. Trump Administration said it wanted to close down ARPA-E, which received $307 million from Congress in fiscal 2017. DOE withheld the $91 million in anticipation of Congress going along with the plan, GAO says. However, the executive branch is required by law to spend money allocated by Congress unless it asks for an exception. GAO received a report about the withheld funding in September and asked DOE for more information. In November, DOE said that the funds had been returned to ARPA-E.—ANDREA WIDENER DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

17

Cover story

18


c&en’s

YEAR

IN

CR E DI T: YAN G H . KU/C &E N/ S H UT TE RSTOCK

CHEMISTRY C&EN’s writers and editors look at the science that shone brightest in 2017: The biggest headlines. The most thrilling research findings. The coolest new molecules. And much more.

In brief ▸ Research of the year P.20 ▸ Headlines of the year P.30 ▸ What to watch for in 2018 P.40 ▸ Look back at 2007 P.42

More online ▸ Find more of C&EN’s Year in Chemistry at cenm.ag/yic2017.


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YEAR IN CHEMISTRY RESEARCH

RESEARCH OF

THE YEAR C&EN reviews notable chemistry research advances from 2017

C

Computerdriven research reached new milestones Machine learning and quantum computing tackled complex problems

20


IBM researchers used the seven qubits (dark squares in center) in this processor to achieve a quantum-computing milestone this year.

ally intense aspects of density functional theory (Nat. Commun. 2017, DOI: 10.1038/ s41467-017-00839-3). As some researchers pushed the chemistry-predicting capabilities of traditional computers, scientists at IBM, Microsoft, and Google pushed forward with quantum computers. Unlike conventional machines, which use transistors and memory cells to process ones and zeros that approximate electron wave functions, quantum computers use magnetic elements or other types of two-state quantum systems, known as qubits, to represent wave functions as superpositions of electron energies and states. That strategy should enable quantum computers to calculate properties of complex molecules that conventional computers are not powerful enough to address. This feat has not yet been demonstrated. Nonetheless, researchers at IBM reached a milestone this year by using a 7-qubit quantum computer to calculate the ground-state energies of lithium hydride and beryllium hydride. These were the first calculations of molecules containing atoms larger than hydrogen and helium using quantum computing (Nature 2017, DOI: 10.1038/nature23879).—MITCH JACOBY

C R E D I T: I BM

omputers have been powering scientific discovery for decades. But this year, several developments in machine learning and quantum computing raised the bar substantially. As academic researchers exploited the advances to tackle problems in basic science, chemical companies including BASF and COMPUTATIONAL CHEMISTRY Dow Chemical formed alliances with computer giants such as IBM and Hewlett Packard Enterprise to capitalize on the advances for commercial applications. Machine learning refers to algorithms that enable computers to go beyond rigid programming instructions and “learn” from and implement decisions and make predictions on the basis of large sets of data. Programs for voice and face recognition, spam email filtration, and weather forecasting use such algorithms. On the chemistry front, David Baker of the University of Washington and coworkers reported using this technique to determine the three-dimensional conformations of 600 families of proteins for which structures had been unknown (Science 2017, DOI: 10.1126/science.aah4043). And an international team used the method to enable computers to predict a compound’s scent on the basis of its molecular structure. That advance broadens understanding of olfaction and one day may benefit the fragrance industry (Science 2017, DOI: 10.1126/science.aal2014). Machine-learning strategies also made headway in calculating molecular electronic structures in a manner that bypasses the most computation-

Waldvogel’s lab uses a variety of divided and undivided batch-type electrochemical cells (colored solutions added for visualization) for small-scale screening reactions and for prep-scale electrosynthesis.

GREEN CHEMISTRY

W

hen it comes to electrochemistry, the first things that pop into mind might be batteries and solar cells, or industrial processes like electroplating. Organic synthesis is not usually part of the conversation. Although electrochemical synthesis is well established, chemists have been reluctant to adopt the approach for common organic reactions, such as C–H activation or arene cross-couplings, believing it is too cumbersome or expensive. But the technology has been trending since 2015 and fully emerged this year. “Synthetic chemists have long viewed electrochemistry as an area where a few people do interesting reactions that are difficult for everyone else to repeat,” commented Kevin D. Moeller of Washington University in St. Louis. “That view is changing: The field is undergoing a dramatic uptick in popularity.” Electric current, when used as a surrogate reagent, offers the ability to avoid toxic or dangerous reagents, protecting groups, and catalysts typically used in organic synthesis. Moreover, electrosynthesis can reduce or eliminate the need to heat and cool reaction vessels, cutting energy consumption. Those advantages play right into the

C R E D I T: V E R BA N D D E R C H E MI S C H E I N D U STR I E /G E RA LD FU EST

Electrosynthesis got chemists charged up Using electrons as a reagent helped streamline organic reactions

hands of today’s synthetic organic chemist, who is faced with the challenge of creating increasingly complex molecules, but doing so in a greener, more sustainable, safer, and more cost-effective manner than before. In one example, Siegfried R. Waldvogel of Johannes Gutenberg University Mainz and his group in collaboration with researchers at Evonik Industries created a one-step electrochemical protocol for cross-coupling reactions to make biaryl diols and diamines, which are important chemical intermediates (C&EN, March 13, page 23). “This stuff is extraordinary,” Waldvogel told C&EN. “Electrosynthesis represents a disruptive technology and will be a game changer for industry.” Besides pushing to develop new electrochemically enabled reactions, academic research groups are helping develop user-friendly instrumentation specifically for the organic synthesis community. Last year, Waldvogel helped launch IKA’s labscale continuous-flow electrosynthesis system, called ElectraSyn Flow. And this year, Phil S. Baran of Scripps Research Institute California, whose group is turning more often to electrosynthesis for difficult steps in preparing terpene natural products, helped IKA launch ElectraSyn 2.0, a modernized version of the company’s electrochemical synthesis system. “This is incredibly impactful research,” Baran said. “The reemergence of electrochemistry deserves our attention.”—STEVE RITTER DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

21

YEAR IN CHEMISTRY RESEARCH BIOCATALYSIS

ENZYMES SPARKED INNOVATIVE CHEMISTRY Advances this year included improved oxidations, decarboxylations, and alkylations

E

nzymes play a key role in chemistry research and in the chemical and food processing industries. Evidence comes from the pages of C&EN: A search shows that enzymes were covered in about 200 articles this year, roughly four articles per issue. Among those were many tales of cutting-edge discoveries. For example, researchers hunted down new enzymes capable of catalyzing syntheses useful to the biotech industry, and they artificially evolved known enzymes to orchestrate tough organic reactions. “I believe we are entering a new era of enzyme discovery,” says Emily P. Balskus of Harvard University. “Expanding the types of molecules we can access using biocatalysis and synthetic biology requires that we identify enzymes that perform new chemical transformations, either through discovery or engineering.” Here are three of C&EN’s favorite enzyme feats of 2017.—STU BORMAN

Friedel-Crafty bacteria Balskus’s group at Harvard pinpointed the enzymes that cyanobacteria use to synthesize aromatic natural products called cylindrocyclophanes. In 1877, Charles Friedel and James Crafts discovered that a Lewis acid could add an alkyl halide’s alkyl group to an aromatic ring. Balskus and coworkers showed that cyanobacteria developed the same type of reaction first (Nat. Chem. Biol. 2017, DOI: 10.1038/nchembio.2421). One enzyme they found, CylK, decorates aromatic rings with alkyl groups from alkyl halides. Another, CylC, generates the alkyl chlorides that the cyanobacteria need to run the CylK reaction (shown in scheme). The researchers are currently trying to solve CylK’s crystal structure and hope to engineer the enzyme to accept a wider variety of building blocks as substrates. CylC halogenase

O ACP

Cl –

S

O ACP

S Cl

ACP = Acyl carrier protein

HO HO

OH

OH

CylK alkylating enzyme

2x HO

Cylindrocyclophane F

Cl OH

Evolved oxidizer To oxidize the end carbon of a terminal alkene to form an aldehyde—an anti-Markovnikov alkene oxidation— chemists typically have had to use nonenantioselective and fairly unproductive methods. Frances H. Arnold of Caltech and coworkers employed a technique called directed evolution to develop an anti-Markovnikov enzyme that works better. Directed evolution is an iterative protein-mutation and screening process that endows enzymes with abilities they weren’t born with. Arnold’s team identified 12 amino acid substitutions (red circles) that convert a conventional alkene oxidation enzyme called P450LA1 into a predominantly stereoselective anti-Markovnikov catalyst called aMOx (Science 2017, DOI: 10.1126/science.aao1482). The productivity of aMOx (heme group is black, blue, and red stick structure) is nearly 400 times that of some existing commercial alkene oxidation catalysts.

A team led by Fred Beisson of the French Alternative Energies & Atomic Energy Commission found that microalgae possess an unusual enzyme that harnesses light to decarboxylate fatty acids to alkanes or alkenes (Science 2017, DOI: 10.1126/science.aan6349). The researchers investigated microalgae that synthesize hydrocarbons but don’t have genes for the enzymes that typically perform that task. By purifying enzymes from the microalgae, they identified fatty acid photodecarboxylase (shown with the cofactor flavin adenine dinucleotide and a palmitic acid substrate as stick structures), a photoenzyme with unprecedented activity: converting fatty acids into 14- to 18-carbon alkanes or alkenes. The new photoenzyme could be useful for producing biobased hydrocarbons.

22


C R E D I T: S CI E NC E ( BOTH )

Enlightening discovery

PROCESS CHEMISTRY

Flow chemistry advanced in industry Lilly chemists capitalized on continuous chemical manufacturing to make a chemotherapy drug candidate

F

by regulatory agencies for drug produclow chemistry has been steadily tion (Science 2017, DOI: 10.1126/science. gaining ground in academia in reaan0745). cent years, and in 2017 the continuKevin P. Cole, the report’s lead ous chemical synthesis method—in N author, explained in June that which tubes HN CN the group decided to go for H3C and T-junction mixers N O replace the flasks and O a flow approach because N Lilly needed only 24 kg stir bars used for batch reN H O– of the drug candidate. actions—managed to make H2O O OH Making prexasertib inroads in the pharmaceuin batch equipment tical industry. One mileNH3+ stone: Chemists at Eli Prexasertib monolactate monohydrate would have required an extensive cleanup Lilly & Co. used continafterward because the compound is pouous-flow chemistry as a safer, faster, and A walk-in fume hood contains newly tent and cytotoxic, so any residue could cheaper way to make the chemotherapy designed continuous-flow equipment at Eli potentially contaminate future reactions. drug candidate prexasertib monolactate Lilly’s facility in Kinsale, Ireland. The small flow setup the team used could monohydrate. Flow chemistry was popular elsebe dedicated to making this single comThe Lilly team set up eight continuous where this year. Flow chemistry company process steps to make the compound. One pound and then discarded, if necessary, Snapdragon partnered step used hydrazine, a O with Pfizer to prepare component of rocket H O N O Li H H the highly reactive fuel, which would have H n-Hexyllithium O reagent allenyllithium been too dangerous to O N Chiral zinc complex H en route to making an use in a batch process. H H OH important drug interBut perhaps the most Allene Allenyllithium Chiral homopropargyl 𝛍-amino alcohol mediate. Snapdragon notable part of this synat no great cost, Cole said. The success of also formed a pact with Johnson Matthey, thesis is that the Lilly chemists linked the a leading supplier of bulk pharmaceutical using flow to make prexasertib prompted final stages in the continuous manufacchemicals, to collaborate on flow chemLilly to build a continuous-flow facilituring process to quality-control systems istry for drug manufacturing.—BETHANY ty in Kinsale, Ireland, which opened in to achieve current Good Manufacturing October. Practices (cGMPs) standards required HALFORD

CR E DI T: E L I L I L LY & CO.

•


23


MOLECULAR MACHINES

BIG MOVES FOR LITTLE DEVICES Geared up after last year’s Nobel nod, researchers put rotors, drills, pulleys, and more into action

S

ince the 1980s, chemists have been creating molecular machines—single molecules that resemble and function like motors, rotors, and even tiny cars. When three molecular machine pioneers won the 2016 Nobel Prize in Chemistry, the field gained a certain gravitas: The whirligig molecules being created were certified as more than mere chemical curiosities. It’s not a surprise that molecular machines continued to make headlines this year, including a souped-up motor-rotor combo, polymer pulleys designed to boost battery performance, and the world’s first nanocar race. “It is fascinating to see the current acceleration in the field,” says Ben L. Feringa, one of the 2016 Nobel laureates. “The recent ingenious designs, ranging from molecular pumps to reshaping polymers, reflect how molecular machines will bring responsive and adaptive behavior, enabling numerous potential applications.” Here C&EN revisits some favorite molecular machine stories of 2017.—BETHANY HALFORD O

O H

N H N N

O

O

N HN (CH3CH2)3SiO Ph Ph = phenyl

(S)

N N N

N N N

Ph

Chiral construction by molecular machines

Substrate

NH OSi(CH2CH3)3 Ph Ph Arm

(R)

Rotary switch

David A. Leigh and coworkers S R Chiral activating sites at the University of Manchester built a programmable molecular machine that creates four different products by adding thiol and alkene substituents asymmetrically to an α,β-unsaturated aldehyde substrate. The machine features an arm and rotatory switch that moves between a site for R stereochemistry and a site for S stereochemistry depending on pH (Nature 2017, DOI: 10.1038/nature23677).

24


C R E D I T: TO UR GRO UP/ R IC E UN I V E RS I T Y ( D R I LL) ; N AT UR E ( MAC H I N E A R M)

Drilling holes in cells Scientists led by Rice University’s James M. Tour turned ultraviolet light-activated molecular motors into tiny drills that can bore through cellular membranes. The idea is to get enough motors drilling into cancer cells in order to destroy the cells’ integrity in a matter of minutes. Cancer cells can’t develop a resistance to the molecular motor’s motion the way they do for many chemotherapy treatments, Tour says (Nature 2017, DOI: 10.1038/nature23657).

O

O

Nanocars zoomed into action Move over, NASCAR. Nanocars have taken to the racing stage. Actually, real race car drivers probably won’t need to move at all, because these little racers are measured in nanometers, and their racetracks have to be viewed with scanning tunneling microscopes. In April, six international teams participated in the world’s first nanocar race, which resulted in a tie. Top honors went to the Nanoprix Team, led by Rice University’s James M. Tour and the University of Graz’s Leonhard Grill. Their Dipolar Racer featured low-adhesion molecular wheels, alkynyl axles, an aryl chassis, and dipolar functionalities in the nanocar’s front and rear. Top honors also went to the makers of the Swiss Nano Dragster, a triangular molecule designed to glide and helmed by the University of Basel’s Rémy Pawlak and Ernst Meyer.

Polymer ‘pulleys’ for boosting battery performance

C R E D I T: TU D R ES D EN / MA N A- N I MS /OH IO UN I V E RS I T Y/U N I V E RS I T Y O F BASE L / R I CE U N I VE RSI T Y/G . RAP E N N E / P. A BE I LH O U/C EM ES -C N RS CN RS /C & E N ( RAC E ) ; A DA PTE D F RO M JA N G WO OK CH O I A N D CO L L EAGU ES (P U L L E YS ); A DA PTE D F RO M S CI E NC E ( MOTOR-ROTO R )

Researchers led by Ali Coskun and Jang Wook Choi at Korea Advanced Institute of Science & Technology developed polymers that, when added to a silicon anode, can relieve the stress the anode undergoes when charging and discharging so that it will last longer. The secret to the polymer’s success: a network made of the linear polymer polyacrylic acid covalently linked to polyrotaxanes containing mechanical bonds. During battery charging, as the silicon anode expands, the polyrotaxanes’ rings freely slide along the chain to dissipate stress, operating like a pulley system (Science 2017, DOI: 10.1126/science.aal4373).

F F

Motor-rotor combo on the move The University of Groningen’s Ben L. Feringa upped the complexity of the classic light-activated molecular motor his group is known for by attaching a rotor to it. The two components turn with synchronized movement thanks to the assembly’s complex stereochemical design (Science 2017, DOI: 10.1126/science.aam8808).

F F

S

F F

Visible UV

F F

S

S

F F

F F

S

Modulator Ring closing UV

Motor

Unwound

O O

Vis

UV

S

Winding

Visible Ring opening

Unwinding

Winding and unwinding By combining two types of light-activated molecular machines, a team led by the University of Strasbourg’s Nicolas Giuseppone created a twisting system that winds and unwinds polymer chains, resulting in a material that contracts and expands depending on the wavelength of light shining on it. The system could lead to new types of actuators—for example, in artificial muscles (Nat. Nanotechnol. 2017, DOI: 10.1038/nnano.2017.28). DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

25


Each compartment in Evatar contains a functioning model of different parts of the female reproductive tract.

Artificial female reproductive systems debuted A menstrual cycle mimic and artificial ovary topped new developments

26


C R E D I T: NAT. CO M MU N. ( EVATA R ) ; N O RTH WESTE R N ME D I C I N E ( D I AG RAM)

T

he female reproductive system is complicated. Its multiple organs, tissues, and hormones all have to work in concert to function properly. Imagine trying to replicate that in an artificial device. That’s what Teresa K. Woodruff of Northwestern University and coworkers did this year, reporting multiple advances in TISSUE ENGINEERING making engineered versions of this system. First, Woodruff ’s Ovarian, fallopian tube, uterine, team reported a miand cervical tissues are grown crofluidic device called in the Evatar device. the Evatar that reproduces the hormone profiles of the 28-day menstrual cycle (Nat. Commun. 2017, DOI: 10.1038/ ncomms14584). Evatar contains modules with cultured tissue from mouse ovary and human fallopian tube, uterus, cervix, and reproductive system. Her team plans to liver connected by microfluidic add modules with other types of tissues to channels and pumps. The reinvestigate how hormones such as estrogen searchers initiate the menstrual affect other systems in the body. Currently cycle by adding follicle-stimuthe researchers have pancreas organoids lating hormone. In response, the producing insulin to provide on-device ovary module produces estrogen. metabolism, and they are using testis and At day 14, they add luteinizing prostate cultures to study the toxicity of hormone to trigger ovulation. drugs on male testosterone production. In response, the ovary module In other work, Woodruff teamed up stops producing estrogen and with Ramille N. Shah of Northwestern to starts producing progesterone. make artificial ovaries (Nat. Commun. 2017, Woodruff and her coworkers are receiv- DOI: 10.1038/ncomms15261). They seeded ing funding from the U.S. National Instithree-dimensionally printed gelatin scaftutes of Health to adapt the technology to folds with ovarian follicles, which are the create models of diseases that affect restructures that house immature eggs. When productive-age women, such as polycystic the researchers implanted seeded scaffolds ovary syndrome, fibroids, and endometriin mice whose ovaries had been surgically osis. They also have a grant from the Bill & removed, the mice were able to mate and Melinda Gates Foundation to further debear young naturally. Prosthetic ovaries invelop the technology to find new methods corporating human follicles are more chalof contraception. lenging to build, Woodruff admits, but she Woodruff doesn’t expect to stop at the sees them on the horizon.—CELIA ARNAUD

REACTION DYNAMICS

Polymer growth spurts discovered Researchers got the first detailed look at how catalysts crank out polymer chains

C

ornell University researchers achieved the first real-time visualization of single polymer chain growth this year. What they saw came as a big surprise to them and the polymer research community. Using a pair of magnetic tweezers, optical microscopy, and spectroscopic techniques, the team discovered that individual polymer chains don’t grow smoothly and continuously from a catalyst as chemists had envisioned, but undergo consecutive wait and jump steps (Science 2017, DOI: 10.1126/science.aan6837). The view of how polymer growth unfolds had been murky because of the limitations of analytical techniques. Researchers typically use methods such as dynamic light scattering to observe all the molecules in a polymer sample at once, then extract information about size distributions of the chains and other polymer parameters from the data. But those data are a challenge to

interpret without corroborating spectroscopic methods. The Cornell team led by Peng Chen, Geoffrey W. Coates, and Fernando A. Escobedo coupled its experimental approach with molecular dynamics computer simulations to get an unobscured view of polymer growth. The researchers attribute the jerky mechanism to formation of polymer tangles, which they call hair balls, that form around the catalyst as thousands of new monomer units are added to the growing chain. The hair balls randomly unravel after a couple of minutes, and a new hair ball starts to form. Besides helping researchers better understand polymerization processes, the growth spurt discovery may be relevant to how cells produce proteins, nucleic acids, and polysaccharides, the team suggests. “The ability to see dynamics in an important reaction like polymerization and to

Researchers are able to watch the wait-andjump dynamics of ring-opening polymerization by attaching a polymer chain to a glass slide and to a ruthenium catalyst bound to a magnetic particle and then pulling the chain with a pair of magnetic tweezers.

understand them through modeling is an exciting technological advance,” commented reaction dynamics expert Suzanne A. Blum of the University of California, Irvine. “The Cornell team’s tantalizing view of how polymer chains grow sheds light on many synthetic challenges dating from the earliest days of polymer chemistry,” added polymer chemist Craig J. Hawker of the University of California, Santa Barbara.—STEVE RITTER

MICROBIOME

C R E D I T: A DA PT E D FRO M S CI E NC E ( G RA P H I C ) ; COU RTESY OF P I N A KI PAN I G RA H I (FAM I LY )

Probiotics found success in large trial Combination of probiotic strain and prebiotic sugar prevented sepsis in infants

S

cientists continue to uncover ways in which microbes living in our bodies interact with and influence our biology. And some researchers hope to apply that growing knowledge to develop probiotic bacteria to treat or prevent disease. This year, scientists reported a major demonstration of the probiotic field’s promise. In a trial involving more than 4,500 infants in rural India, a probiotic bacterium combined with a prebiotic sugar prevented sepsis, a potentially fatal inflammatory condition triggered by a bacterial infection in the blood (Nature 2017, DOI: 10.1038/nature23480). Study leader Pinaki Panigrahi of the University of Nebraska Medical Center thinks the combination, called a synbiotic, could

provide an inexpensive way to tackle early-infant mortality in the developing world. In the multiyear trial, the synbiotic reduced cases of sepsis and death by 40%. The results were so good that the board overseeing the trial ended it early because it was no longer ethical to give infants the placebo. These are landmark results, says Barbara B. Warner, who studies the neonatal microbiome at Washington University School of Medicine in St. Louis. She thinks one of the major lessons from the study is that probiotic researchers need to do their homework to find bacterial strains that will stably colonize the gut. Before the trial began, Panigrahi’s team screened more than 200 strains of bacteria in cell culture and in rabbit studies to find microbes that could adhere to the

Panigrahi (foreground, left) visits a family in rural India during the probiotic trial.

intestines and block harmful bacteria from attaching to and slipping out of the gut and into the bloodstream. They also found that the prebiotic sugar fructooligosaccharide helps the optimal strain, Lactobacillus plantarum, colonize the gut. This kind of preliminary research on probiotic strains “is not frequently seen in the probiotic literature,” Warner says. The study overall reinforces the idea that we can design ways to modify our gut microbiomes, Warner adds.—MICHAEL TORRICE DECEMBER 11/18, 2017 | CEN.ACS.ORG | C&EN

27

YEAR IN CHEMISTRY RESEARCH SYNTHESIS

MOLECULES OF THE YEAR Braiding a molecular knot

C&EN highlights some of the coolest compounds reported in 2017

Chemists built on norbornane’s structural complexity Two research teams completed challenging syntheses of new bridged polycyclic hydrocarbons this year, engineering complex derivatives of norbornane, which itself is a complex molecule. A team led by Marcel Mayor of the University of Basel prepared trinorbornane, a symmetrical saturated C11H16 OH molecule consisting of two norbornane units that share a pair of neighboring edges, an HO arrangement that coincidentally results in a C3 axis third norbornane subunit. This approach helps OH expand on techniques for the total synthesis Nortricyclene triol of natural products (Chem. Commun. 2017, DOI: 10.1039/ c7cc06273g). And a team led by Volodymyr Kozel and Trinorbornane Günter Haufe of the University of Münster synthesized a nortricyclene triol, the smallest known molecule to display threefold molecular symmetry in a chiral polycyclic compound. The researchers are using pure enantiomers of the nortricyclene to prepare liquid crystals (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201709279).

David A. Leigh and coworkers at the University of Manchester wove together three helical strands to construct the first braided molecular knot this year. The new chiral, 192-atom knot has eight crossing points and is considerably more complex than previous examples of molecular knots, which were based on just two twisted strands. Leigh’s group first used iron atoms to guide assembly of bipyridine-based ligands into the braided structure. The researchers then linked olefins at the ends of the ligand strands together using metathesis chemistry (shown, Fe is purple, Cl is green) and removed the iron ions and the counterions to produce the continuous, entwined structure. The researchers hope to create more complex braided knots and possibly even woven polymers (Science 2017, DOI: 10.1126/science.aal1619).

Chemists over the years have combined boron, carbon, nitrogen, and oxygen in various ways to create a variety of six-membered heterocyclic ring systems. One of the goals is to create new polycyclic aromatic compounds containing electron-deficient boron atoms, which are useful for N making optoelectronic devices. But B B O O incorporating both nitrogen and oxygen along B with boron in heterocyclic rings has remained elusive. A research team led by Masakatsu Shibasaki and Naoya Kumagai at Japan’s Institute of Microbial Chemistry designed and synthesized a dioxaazatriborinane (B3NO2), which had been a missing link between borazines (B3N3) and boroxines (B3O3). The team found that the dioxaazatriborinane can function as an organocatalyst for S amidation reactions, outperforming S previously known boron-based amidation organocatalysts (Nat. Chem. 2017, DOI: 10.1038/nchem.2708). S S

28

A new ‘sulflower’ bloomed A persulfurated coronene, a molecule dubbed a “sulflower” for its resemblance to a sunflower, bloomed this year. It’s the first fully sulfur-substituted polycyclic aromatic hydrocarbon and only the second member of a new class of circular S S heterocyclic carbon sulfide compounds, after the synthesis of octathio[8] S circulene a decade ago. Chemists hope to create other class S members, including the simplest one, persulfurated benzene, for use in battery cathodes and other electronic materials. A team led by Xinliang Feng of Dresden University of Technology and Klaus Müllen S of the Max Planck Institute for Polymer Research created the S sulflower (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.6b12630). S S


C R E D I T: RO B ERT W. MCG R EGO R ( K N OT)

Chemists constructed a heterocycle missing link

O

Trinitrogen compounds display unique electronic structures

O

O HO O O

HO HO

O

OH

O

OH

OH

O OH

C&EN polled readers online about which of these is truly the molecule of the year. This complex polysaccharide received the most votes. To see the full results, go to cenm.ag/moy.

Pd N N

HO

O

OH O HO O O O

OH

O

OH

OH

OH O

OH

O

O

Chemists designed this truncated pentagram-shaped palladium coordination complex this year. It’s unique not just because it has an interesting shape—a pentagon ringed by isosceles trapezoids—but also because it’s the first pentanuclear self-assembling multicompartment molecule containing two different nonchelating ligands. Self-assembled coordination complexes are typically built from metals linked by one type of ligand. On top of that, the ligands often are chelating, meaning each ligand binds one metal through two or more atoms. Dillip Kumar Chand of the Indian Institute of Technology Madras and colleagues believe their molecular star could inspire the synthesis of cell-like cages for biomedical applications (Chem.– Eur. J. 2017, DOI: 10.1002/chem.201702264).

O

HO

O

O OH

OH

O

O

O O

O

OH

O

OH

O

O

OH

OH

O

OH O

HO

OH

HO

HO HO

O

O

O

OC8H17

O O

HO

HO

OH

OH

OH

O

O O

HO

OH 3

OH

OH O

O

O

OH

HO

OH

O

OH

O

O OH

OH

O

HO

O

Galactan

O OH

HO HO

O

O

HO

OH

O

O

HO O

O OH

OH

O

OH O

O

OH

The largest, most complex polysaccharide

OH

A record in carbohydrate synthesis was broken this year: Xin-Shan Ye of Peking University and coworkers synthesized HO O OH a glycan nearly twice as large and more complex than any made HO HO 9 before. The polysaccharide, called an arabinogalactan, contains 92 OH OH HO sugar units and is an essential cell-wall component in Mycobacterium tuberculosis, the bacterium that causes tuberculosis. The tuberculosis drug ethambutol blocks the polysaccharide’s biosynthesis. The tendency for natural glycans to have different structural forms and their low abundance make them hard to isolate and study as drug targets or for vaccine development. Trying to synthesize them from scratch is equally challenging. In a one-pot reaction, Ye’s group combined sets of short glycans into one 30-sugar galactan (blue) and two identical 31-sugar arabinans (black), then joined the three fragments into the 92-sugar arabinogalactan (Nat. Commun. 2017, DOI: 10.1038/ncomms14851). HO

C R E D I T: C HE M. –E UR . J . ( STA R )

O

OH O

O

OH

13

Arabinan

HO

OH

OH

O

O

O HO

O

HO

OH

OH

O O

O

A new molecular star was born

OH O

OH

O O

O O

OH

OH

O

HO O

HO O

HO

O

O

HO

O

O

O

HO

O

HO OH

OH

O

OH

OH

O O

N

O

13

Arabinan

O HO

N Pd

N

OH O

OH

N

O O

O

HO

HO HO

O OH

OH

O

N N Pd N N

OH

OH

O

HO O

HO

O

O

O

HO

OH

O

O O

O N N

O

O

N N Pd N N

O O

OH

READERS’ CHOICE

10 BF4–

O

O

N N Pd N N

O

Chemists this year added to the varied ways three nitrogens can bond. Electron-rich nitrogen-centered molecules CH3 : Base normally function as Lewis bases, donating an electron N pair to create a bond with an acceptor partner. Mark + N : Gandelman of Technion—Israel Institute of Technology N and his group discovered a triazolium salt in which they CH3 could turn that donor-acceptor reactivity around so that the nitrogen center functions as a Lewis acid and accepts Triazolium Lewis acid electrons. Nitrogen-based Lewis acids could serve in reactive frustrated Lewis pairs or other types of catalysts R R (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.6b12360). On another front, nitrogen-containing triazenyl radicals N N N N N had previously been detected spectroscopically and are N N known to serve as ligands in transition-metal complexes. But they’ve been challenging to stabilize and isolate. ReR R searchers led by Eunsung Lee of the Institute for Basic R = aryl Science and Pohang University of Science & Technology Triazenyl radical found a way to do it using N-heterocyclic carbenes as stabilizing substituents. The researchers used the triazenyl radical as a cathode material in a lithium-ion battery (J. Am. Chem. Soc. 2017, DOI: 10.1021/ jacs.7b08753).

O

O

HO O

O

OH

OH

OH

HO

HO

O

O

O


29

Molecules of the year - C&EN Global Enterprise (ACS Publications)

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