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Noteworthy Chemistry

August 3, 2015


In utero DDT exposure is linked to higher breast cancer rates.  Diethylstilbestrol (DES) was the first synthetic estrogen to be identified as a transplacental carcinogen. In utero exposure to DES causes clear-cell carcinoma of the vagina and cervix and predicts a higher risk of breast cancer. It also raises questions about the effects of other synthetic chemicals that disrupt estrogen-related functions and increase the risk of breast cancer. As with other estrogenic chemicals, the timing of the carcinogenic exposure determines its effects.

B. A. Cohn and her collaborators at the Public Health Institute (Berkeley and Oakland, CA); the University of California, Davis; and the California Department of Toxic Substances Control (Berkeley) looked specifically at exposure to the pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT, 1 in the figure) and the incidence of breast cancer. With regard to breast cancer and DDT, there are developmental windows when breast tissue is more susceptible to the xenoestrogen.

Cohn and her coauthors used data that were collected between 1959 and 1967 (which coincided with the peak use of DDT in the United States) as part of the Child Health and Development Studies (CHDS) in California. During that time 20,754 mothers agreed to the collection of blood samples during pregnancy and 1–3 days after delivery specifically to examine prenatal exposures with health and development of parents and children. 

DDT structure

The authors then investigated the correlation of in utero exposure. They identified 9300 living female offspring of the CHDS mothers. Using records from the California Cancer Registry and self-reports to identify breast cancer, they found 137 CHDS daughters with incident invasive or noninvasive breast cancer diagnosed by the age of 52. Among these individuals, the maternal blood samples for 118 women showed exposure to DDT. The final study comprised 103 cases of breast cancer and 315 controls.

The authors confirmed that in utero exposure to DDT is linked to breast cancer. Maternal exposure to the minor DDT isomer o,p′-DDT (2) correlated with diagnosis in ways that could not be explained by breast cancer history, weight, age, race, or lipid levels. Elevated maternal serum levels of o,p′-DDT predicted a statistically significant, almost 4-fold, increase in breast cancer risk for the daughter.

DDT activates the HER2 protein, which is expressed in certain breast cancers. Maternal serum o,p′-DDT was positively associated with the occurrence of HER2-positive tumors in the daughters and with advanced cancer stages at diagnosis, suggesting a strong effect of in utero o,p′-DDT on breast cancer stage and HER2 status. (J. Clin. Endocrinol. Metab. DOI: 10.1210/jc.2015-1841; Abigail Druck Shudofsky)

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Biofuel cultivation affects more than greenhouse gases. Biogenic volatile organic compounds (VOCs) account for >90% of non-methane hydrocarbon emissions in the atmosphere. Isoprene is emitted in the largest amounts and has the greatest effect on atmospheric composition. Photochemical oxidation of isoprene in the presence of nitrogen oxides governs the production rate of ground-level ozone. It also forms aerosol-phase reaction products that damage plant and animal health.

O. Wild and coauthors at Lancaster University (UK) and the University of Colorado, Boulder, produced a lower-bound estimate of increases in ground-level ozone that would occur by planting poplar trees, a high-isoprene emitting species, to use as a biofuel feedstock.

Few grasses and conventional food crops emit detectable amounts of isoprene. Various types of poplars emit different levels of isoprene, but they also produce different biomass yields. Genetically modified poplars that do not emit isoprene have been developed but are not commercially available.

The researchers studied relationships between biomass yield and isoprene emissions by using experimental data for 29 commercially available poplar hybrids. They predict that increases in poplar plantings across Europe will increase ground-level ozone enough to cause substantial wheat and maize crop losses (3–9 Mt/year) and increase the annual number of premature human deaths that are attributable to ozone pollution by as much as 6%.

The impact of poplar plantings depends on their location, which determines the prevailing weather, population density, and dominant crop type. To meet EU biomass targets, medium-yielding poplar cultivars would require 33 Mha of land. Planting this area in commercially available poplar trees would increase isoprene emissions from 12 to 36%. The highest increase in emissions would occur in hot, sunny Mediterranean regions; the lowest would occur in northwestern Europe.

Because isoprene has an atmospheric lifetime of ≈90 min, increases in its atmospheric concentration would be confined to near its origin. Boundary-layer nitrogen oxide concentrations, however, are moderately high across Europe, but VOC emissions are relatively low. Thus, even a small increase in VOC emissions could have a significant effect on ozone production. Background levels of ground-level ozone are rising across Europe, so a small increase could raise levels above the threshold of observable health effects. (Environ. Sci. Technol. DOI: 10.1021/acs.est.5b00266; Nancy McGuire)

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Use silver salts to prepare 18F-labeled drugs. Positron emission tomography (PET) is a noninvasive, quantitative imaging technology that is used to study biological processes. Labeling tracer molecules with radioactive 18F would augment the utility of PET, but incorporating 18F currently requires harsh reaction conditions. V. Gouverneur and coauthors at the University of Oxford (UK), Advion BioSystems (Ithaca, NY), and GlaxoSmithKline R&D (Stevenage, UK) developed an improved process for preparing the labeled tracers.

The authors used silver salts to promote halogen exchange between aryl bromides or chlorides (1 in the figure) and 18F-fluoride. They found that catalytic silver trifluoromethanesulfonate [Ag(OTf)] was the best catalyst. They used [18F]KF as the 18F source and the cryptand Kryptofix 222 (EMD Millipore, Billerica, MA) to activate the fluorination under mild conditions. 

Preparation of 18F-labeled compounds

Using this method, the authors prepared monolabeled ArSCF3, ArOCF3, and ArOCHF2 molecules in moderate-to-good yields. The reactivity order of substrates is ArOCHCFCl > ArCF2Br ≈ ArCHFCl > ArSCF2Br > ArOCF2Br, which, together with the observation that electron-withdrawing groups reduce radiochemical yields, suggests the presence of cationic intermediates.

The authors used their technique to produce medicinally relevant 18F-riluzole (2), a drug used to treat amyotrophic lateral sclerosis. They obtained a 29% radiochemical yield without having to protect the molecule’s nitrogen atom. (Angew. Chem., Int. Ed. DOI: 10.1002/anie.201206566; José C. Barros)

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Which solvents are used in pharmaceutical process R&D? A. S. Wells at Charnwood Technical Consulting (Quorn, UK) and coauthors at Pfizer (Sandwich, UK) and GlaxoSmithKline (Stevenage, UK) present the results of a survey of solvent usage in pharmaceutical process development. On the basis of certain keywords, they selected 388 papers published in Organic Process Research & Development from 1997 to 2012 for the survey.

The authors discuss in detail changes in the use of three main solvent types: solvents of health, safety, or environmental concern; dipolar aprotic solvents (many of which are also hazardous); and neoteric (“green”) solvents. Some key findings:

  • With respect to solvents of concern, chloroform and n-hexane use has been reduced since 2001; but the use of some other solvents, such as 1,4-dioxane, increased slightly during that time.
  • Dipolar aprotic solvents such as N,N-dimethylformamide and dimethyl sulfoxide are still widely used, but the authors give some notable examples in which acetone or ethanol is used in their place.
  • Of all of the neoteric solvents considered, only 2-methyltetrahydrofuran has been accepted to any degree by the pharmaceutical industry.

(Org. Process Res. Dev. DOI: 10.1021/op500276u; Will Watson)

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Thin, flexible device generates electricity from waves. Converting water-wave kinetic energy to electricity could provide power for corrosion protection devices, pollution degradation, water desalination, and wireless sensing for marine surveillance. Triboelectrification, electricity generated from two surfaces in contact, has been used on a small scale to harvest wave energy, but scale-up has proven difficult.

G. Zhu and coauthors at the Chinese Academy of Sciences (Beijing) and Georgia Tech (Atlanta) developed a flexible thin-film triboelectric generator. As water waves hit the device, they generate a triboelectric charge at the nanostructured solid–liquid interface that induces a flow of free electrons in an external circuit. The thin, flexible device can be applied to the surfaces of objects placed in rivers, lakes, or oceans without adding much in the way of size and weight. The figure shows a wave splashing on the device (scale bar = 25 mm).

Thin-film triboelectric generator interacting with a water wave

The device uses an array of surface-mounted bridge rectifiers to link an array of electrodes together in parallel. The authors linked 11 electrodes to create a 100 mm x 60 mm device with optimum output power of 1.1 mW, an order of magnitude higher than a previously reported device. The generated electricity can power small electronic devices or LED arrays, or it can provide cathodic protection for carbon steel.

The device consists of a polyimide film substrate that supports a parallel array of strip-shaped copper electrodes. A thin top film consists of a dense uniform array of 200-nm diameter poly(tetrafluoroethylene) spheres. This hydrophobic surface protects the electrodes beneath it and provides a rough surface for greater contact area with the water waves. The bridge rectifiers ensure that the current in the external circuit always flows in one direction to produce a single current peak for all the linked electrodes.

The authors measured up to 230 V for a pulsed current of 13 µA. The maximum power of 1.1 mW was reached at an optimal load of 25 MΩ. The charge carried by a single current peak scales linearly with the number of electrodes. If more than six electrodes are linked, however, the voltage amplitude starts to saturate, possibly because the diodes begin to break down.

Faster-propagating waves induce a larger current amplitude and a faster charge flow. Salt water, with its higher conductivity, generates less triboelectric charge than fresh water, but even a saturated salt solution produces 40% of the current that fresh water does. (ACS Nano DOI: 10.1021/acsnano.5b03093; Nancy McGuire)

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