Noteworthy Chemistry

DNA polymerases collaborate to bypass oxidized guanine lesions. Oxidative DNA damage can induce disease-causing mutations. The base guanine has a low oxidation potential and is especially susceptible to oxidative stress. One form of oxidized guanine is hydrolyzed 2,2,4-triamino-5(2H)-oxazolone (Oz, 1 in the figure), which causes G:C–C:G transversions.

Because DNA damage can block the replication activity of DNA polymerases (Pols), eukaryotic cells use translesion synthesis (TLS) polymerases to bypass lesions. K. Kino and co-workers at Tokushima Bunri University (Kagawa, Japan) previously found that

  • replicative polymerases α and ε incorporate deoxyguanosine triphosphate (dGTP) opposite Oz;
  • replicative polymerase γ incorporates dGTP and deoxyadenosine triphosphate (dATP); and
  • the TLS polymerase η incorporates dGTP, dATP, and deoxycytidine triphosphate (dCTP).

The same authors now describe nucleotide insertion and extension of the replicative Pol δ and TLS Pols ι, κ, ζ, and REV1 in the presence of Oz. They found that replicative Pol δ primarily inserts dGTP opposite Oz and causes G:C–C:G transversions. The error-prone TLS Pols ι and κ predominantly mismatch Oz with deoxythymidine triphosphate (dTTP) and dGTP, respectively. Pol δ can extend DNA synthesis past Oz, although not as efficiently as in the presence of G; and the TLS Pols could not extend past Oz.

The TLS Pol REV1 is a deoxycytidyl transferase that inserts dCTPs opposite DNA lesions regardless of the base present in the template. The authors found that REV1 from multiple species incorporates dCTP opposite Oz and plays a key role in preventing G:C–C:G transversions. Replication, however, stalls after REV1 dCTP incorporation.

Conversely, the researchers discovered that, whereas the TLS Pol ζ mainly inserts dGTP opposite Oz, it can elongate full-length DNA products on Oz-containing templates with approximately the same efficiency as occurs beyond G. Their results suggest that together REV1 and Pol ζ can replicate Oz-containing DNA for efficient lesion bypass. (Chem. Res. Toxicol. DOI: 10.1021/acs.chemrestox.5b00114; Abigail Druck Shudofsky)

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Go green with wood-based electronic components. Consumer electronics are increasingly indispensable in everyday life, but the electronics industry faces a twofold hurdle: Conventional electronic chips rely on specialty metals that are currently overexploited; and the high replacement rate of electronic devices produces massive amounts of non-biodegradable, toxic waste.

To circumvent this problem, S. Gong, Z. Ma, and colleagues at the University of Wisconsin–Madison, the USDA Forest Service (Madison), the University of Electronic Science and Technology of China (Chengdu), and the University of Texas–Arlington chose wood as an alternative source of electronic chips. They made microwave and digital electronics devices on wood-derived cellulose nanofibril (CNF) paper.

The authors prepared the film substrate from (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)–oxidized CNFs that were refined in a microfluidizer processor (Microfluidics, Newton, MA) and dried before they were coated with epoxy resin. The mechanical properties of the CNF films are comparable with those of poly(ethylene terephthalate) films, which are common substrates for flexible electronics.

The researchers then prepared two types of electronic devices from CNF films with minimal amounts of conventional semiconducting materials: gallium arsenide–based microwave devices and silicon-based digital circuit devices. Both devices are fully functional. Fungal degradation tests showed that the CNF-based electronic devices are biodegradable.

The biodegradability and renewability of CNF paper should significantly reduce the cost of producing and disposing of electronic chips. Moreover, its usefulness need not be limited to chips. The authors believe that it could be used in other common electronic components, including batteries and displays, launching a “new generation of more ecofriendly electronics”. (Nat. Commun. DOI: 10.1038/ncomms8170; Xin Su)

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The third time’s a charm for making a drug intermediate. 4-Chloromethyl-1-cyclopentyl-2-(trifluoromethyl)benzene (1 in the figure) is a key building block in the synthesis of a developmental autoimmune disease drug. A. G. Montalban and co-workers at Arena Pharmaceuticals (San Diego) describe three routes to 1

Building block 1 and the optimized synthetic route to it

The original route started from 4-hydroxy-3-(trifluoromethyl)benzoic acid (2), which has the correct benzene substitution pattern. But compound 2 requires several steps to get to the required product and uses an expensive cyclopentylzinc reagent.

Two alternative routes started from 1-bromo-2-(trifluoromethyl)benzene (3), which is 7–8 times less expensive than 2. In one of the syntheses, the authors subjected 3 to lithium–bromine exchange and treated the lithiated product with cyclopentanone. This was followed by hydrogenolysis and then bromination. After a second Li–Br exchange, the intermediate reacted with dimethylformamide (DMF) to make an aldehyde that was reduced and chlorinated to make the desired product. But a low yield (30%) in the bromination step and other problems led the authors to develop a third route.

In the final route (shown in the figure), 3 was coupled with cyclopentyl bromide (4) in the presence of magnesium and anhydrous iron(III) chloride in 57% yield to give compound 5. (TMEDA is tetramethylethylenediamine; THF is tetrahydrofuran.) Then 5 was treated with trioxane and thionyl chloride in sulfuric acid to produce the required intermediate in 80% yield after vacuum distillation. (Org. Process Res. Dev. DOI: 10.1021/acs.oprd.5b00038; Will Watson)

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A forest of decision trees “elects” materials candidates. Structural building blocks can be combined in many ways to produce nanoporous materials for gas storage, separation, and sensing, among many other applications. The structural possibilities are so numerous that the Materials Genome Initiative took on the task of developing and using computational tools to produce manageable lists of viable candidates for specific applications.

M. Haranczyk and coauthors at the University of California, Berkeley, the Norwegian University of Science and Technology (Trondheim), the Swiss Federal Institute of Technology in Lausanne (Sion, Switzerland), and Lawrence Berkeley National Laboratory screened the Nanoporous Materials Genome, a database of more than 670,000 structures, for candidate adsorbents for separating mixtures of xenon and krypton at room temperature. The current cryogenic separation methods are expensive and require a large expenditure of energy, which is reflected in the price of about $5,000/kg of high-purity xenon.

The computational resources required for a brute-force screening that uses grand-canonical Monte Carlo simulations of Xe–Kr adsorption are prohibitive. Thus, the authors combined machine learning algorithms with molecular simulations to examine the relationships between pore size and selectivity.

The authors created an ensemble of decision trees that they call a “random forest”. A decision tree is “grown” by using a training set of materials with known selectivities. Test materials are vetted for selectivity by running their vector descriptors through the decision tree. Using the entire training set to train a single decision tree can lead to overfitting errors, so many decision trees (1000 in this study) are trained by using randomly selected subsets of the training set. The resulting selectivity prediction is a product of the average “vote” of each tree in the forest.

This screening study predicts that the two most selective materials in the database are an aluminophosphate zeolite analogue and a calcium-based coordination network. Both have been synthesized but not yet tested for separating xenon and krypton. (Chem. Mater. DOI: 10.1021/acs.chemmater.5b01475; Nancy McGuire)

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Safely prepare aromatic nitriles with acetonitrile. The aromatic nitrile moiety is found in many useful chemicals (e.g., agrochemicals, pharmaceuticals, and dyes); and it is also a precursor to amines, aldehydes, amides, and other important building blocks. The cyanation of arenes, however, usually requires the use of inorganic cyanides, especially metal cyanide salts that are extremely toxic.

In contrast, acetonitrile (MeCN) is a safe, inexpensive, readily available potential cyanating reagent. The only problem is its highly stable C–C bond, which is much stronger than the C–C bonds in alkanes. Z. Shen and co-workers at Shanghai Jiao Tong University found a way to activate this unreactive bond and use the cyano group for preparing aromatic nitriles.

The authors originally planned a two-step process for this transformation: iodination followed by cyanation. They screened a series of Lewis acids for the iodination reaction and the cyanation reaction conditions with toluene as the substrate. They found that copper(II) perchlorate in the presence of N-iodosuccinimide (NIS) and MeCN effectively catalyzed the first step with almost complete conversion (see figure). They then treated the intermediates with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), hexamethyldisilane, and a copper–1,10-phenanthroline catalyst and obtained p- and o-tolunitrile in a ≈1:1 ratio.

Two-step preparation of aromatic nitriles

The researchers then applied this sequential iodination–cyanation strategy to several arene substrates and in most cases obtained cyanated products in high yields and with good regioselectivity. They also verified that the TEMPO–MeCN complex reacts with p-iodotoluene under oxygen to give p-tolunitrile in 90% yield. They thus propose that this complex is a key intermediate in MeCN activation.

This copper-catalyzed sequential cyanation reaction solves the problem of activating the C–C bond in MeCN. In addition, the use of benign MeCN as the cyano source is an appealing alternative for safe preparation of aromatic nitriles. (Org. Lett. DOI: 10.1021/acs.orglett.5b00886; Xin Su)

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Hydrolyzed 2,2,4-triamino-5(2H)-oxazolone