Synthesis and Analysis of (g,g', g'', - Trifluoro)neopentyl (TFNP) Aryl ethers as a Polar Aliphatic Motif.

A route is developed to (g,g',g''''-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl  substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C-F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their tert-butyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.

Conformational Analysis Explores the Role of Electrostatic Nonclassical CF···HC Hydrogen Bonding Interactions in Selectively Halogenated Cyclohexanes.

The conformational equilibria of selectively halogenated cyclohexanes are explored both experimentally (VT-NMR) for 1,1,4,-trifluorocyclohexane 7 and by computational analysis (M06-2X/aug-cc-pVTZ level), with the latter approach extending to a wider range of more highly fluorinated cyclohexanes. Perhaps unexpectedly, 7ax is preferred over the 7eq conformation by ΔG = 1.06 kcal mol-1, contradicting the accepted norm for substituents on cyclohexanes. The axial preference is stronger again in 1,1,3,3,4,5,5,-heptafluorocyclohexane 9 (ΔG = 2.73 kcal mol-1) as the CF2 groups further polarize the isolated CH2 hydrogens. Theoretical decomposition of electrostatic and hyperconjugative effects by natural bond orbital analysis indicated that nonclassical hydrogen bonding (NCHB) between the C-4 fluorine and the diaxial hydrogens at C-2 and C-6 in cyclohexane 7 and 9 largely accounts for the observed bias. The study extended to changing fluorine (F) for chlorine (Cl) and bromine (Br) at the pseudoanomeric position in the cyclohexanes. Although these halogens do not become involved in NCHBs, they polarize the geminal -CHX- hydrogen at the pseudoanomeric position to a greater extent than fluorine, and consequent electrostatic interactions influence conformer stabilities.

Mapping pollution exposure and chemistry during an extreme air quality event (the 2018 Kilauea eruption) using a low-cost sensor network.

Extreme air quality episodes represent a major threat to human health worldwide but are highly dynamic and exceedingly challenging to monitor. The 2018 Kilauea Lower East Rift Zone eruption (May to August 2018) blanketed much of Hawai'i Island in "vog" (volcanic smog), a mixture of primary volcanic sulfur dioxide (SO2) gas and secondary particulate matter (PM). This episode was captured by several monitoring platforms, including a low-cost sensor (LCS) network consisting of 30 nodes designed and deployed specifically to monitor PM and SO2 during the event. Downwind of the eruption, network stations measured peak hourly PM2.5 and SO2 concentrations that exceeded 75 µg m-3 and 1,200 parts per billion (ppb), respectively. The LCS network's high spatial density enabled highly granular estimates of human exposure to both pollutants during the eruption, which was not possible using preexisting air quality measurements. Because of overlaps in population distribution and plume dynamics, a much larger proportion of the island's population was exposed to elevated levels of fine PM than to SO2 Additionally, the spatially distributed network was able to resolve the volcanic plume's chemical evolution downwind of the eruption. Measurements find a mean SO2 conversion time of ∼36 h, demonstrating the ability of distributed LCS networks to observe reaction kinetics and quantify chemical transformations of air pollutants in a real-world setting. This work also highlights the utility of LCS networks for emergency response during extreme episodes to complement existing air quality monitoring approaches.

4'-Fluoro-nucleosides and nucleotides: from nucleocidin to an emerging class of therapeutics.

The history and development of 4'-fluoro-nucleosides is discussed in this review. This is a class of nucleosides which have their origin in the discovery of the rare fluorine containing natural product nucleocidin. Nucleocidin contains a fluorine atom located at the 4'-position of its ribose ring. From its early isolation as an unexpected natural product, to its total synthesis and bioactivity assessment, nucleocidin has played a role in inspiring the exploration of 4'-fluoro-nucleosides as a privileged motif for nucleoside-based therapeutics.

Identification of Genes Essential for Fluorination and Sulfamylation within the Nucleocidin Gene Clusters of Streptomyces calvus and Streptomyces virens.

The gene cluster in Streptomyces calvus associated with the biosynthesis of the fluoro- and sulfamyl-metabolite nucleocidin was interrogated by systematic gene knockouts. Out of the 26 gene deletions, most did not affect fluorometabolite production, nine abolished sulfamylation but not fluorination, and three precluded fluorination, but had no effect on sulfamylation. In addition to nucI, nucG, nucJ, nucK, nucL, nucN, nucO, nucQ and nucP, we identified two genes (nucW, nucA), belonging to a phosphoadenosine phosphosulfate (PAPS) gene cluster, as required for sulfamyl assembly. Three genes (orf(-3), orf2 and orf3) were found to be essential for fluorination, although the activities of their protein products are unknown. These genes as well as nucK, nucN, nucO and nucPNP, whose knockouts produced results differing from those described in a recent report, were also deleted in Streptomyces virens - with confirmatory outcomes. This genetic profile should inform biochemistry aimed at uncovering the enzymology behind nucleocidin biosynthesis.

The Emergence and Properties of Selectively Fluorinated 'Janus' Cyclohexanes.

This account describes the evolution of a research programme that started by linking fluoromethylene (-CHF-) groups along aliphatic chains and then progressing to alicyclic rings with contiguous fluorine atoms. Different stereoisomers of aliphatic chains tend to adopt low polarity conformations. In order to force polar conformations, the programme began to address ring systems and in particular cyclohexanes, to restrain conformational freedom and co-aligned C-F bonds. The flagship molecule, all-cis-1,2,3,4,5,6-hexafluorocyclohexane 7, emerged to be the most polar aliphatic compound recorded. The polarity arises because there are three co-aligned triaxial C-F bonds and the six fluorines occupy one face of the ring. Conversely the electropositive hydrogens occupy the other face. These have been termed Janus face cyclohexanes after the Roman god with two faces. The review outlines progress by our group and others in preparing derivatives of the parent cyclohexane 7, in order to explore properties and potential applications of these Janus cyclohexanes.

Contribution of Hyperconjugation and Inductive Effects to the Pseudo-anomeric Effect in 4-Substituted Methoxycyclohexanes.

The importance of electrostatic nonconventional hydrogen bonds (NCHBs) to the pseudo-anomeric effect of 4-substituted methoxycyclohexanes is evaluated using theory [natural bond orbital (NBO)] to deconvolute electrostatic from other contributing effects. There is an interesting interplay between σCH → σCX* hyperconjugation and the electropositive charge on 3,5-axial hydrogens (Hax). In essence, better σCX* (or πCO*) acceptors increase the charge on 3,5-CHax, which in turn strengthens Cδ+Hax···Î´-OMe NCHB interactions.

3'-O-ß-Glucosyl-4',5'-didehydro-5'-deoxyadenosine Is a Natural Product of the Nucleocidin Producers Streptomyces virens and Streptomyces calvus.

3'-O-ß-Glucosyl-4',5'-didehydro-5'-deoxyadenosine 13 is identified as a natural product of Streptomyces calvus and Streptomyces virens. It is also generated in vitro by direct ß-glucosylation of 4',5'-didehydro-5'-deoxyadenosine 12 with the enzyme NucGT. The intact incorporation of oxygen-18 and deuterium isotopes from (±)[1-18O,1-2H2]-glycerol 14 into C-5' of nucleocidin 1 and its related metabolites precludes 3'-O-ß-glucosyl-4',5'-didehydro-5'-deoxyadenosine 13 as a biosynthetic precursor to nucleocidin 1.

The historical development of zoo elephant survivorship.

In the discussion about zoo elephant husbandry, the report of Clubb et al. (2008, Science 322: 1649) that zoo elephants had a "compromised survivorship" compared to certain non-zoo populations is a grave argument, and was possibly one of the triggers of a large variety of investigations into zoo elephant welfare, and changes in zoo elephant management. A side observation of that report was that whereas survivorship in African elephants (Loxodonta africana) improved since 1960, this was not the case in Asian elephants (Elephas maximus). We used historical data (based on the Species360 database) to revisit this aspect, including recent developments since 2008. Assessing the North American and European populations from 1910 until today, there were significant improvements of adult (≥10 years) survivorship in both species. For the period from 1960 until today, survivorship improvement was significant for African elephants and close to a significant improvement in Asian elephants; Asian elephants generally had a higher survivorship than Africans. Juvenile (<10 years) survivorship did not change significantly since 1960 and was higher in African elephants, most likely due to the effect of elephant herpes virus on Asian elephants. Current zoo elephant survivorship is higher than some, and lower than some other non-zoo populations. We discuss that in our view, the shape of the survivorship curve, and its change over time, are more relevant than comparisons with specific populations. Zoo elephant survivorship should be monitored continuously, and the expectation of a continuous trend towards improvement should be met.

Outcomes of young active patients with displaced clavicle fractures treated with Rockwood pin.

PURPOSE: Various fixation techniques have been described for midshaft clavicle fractures in the literature. We hypothesized that use of the Rockwood pin for fixation of displaced midshaft clavicle fractures would result in favorable outcomes in a young active cohort. METHODS: Patients aged 10-35 years who underwent Rockwood clavicle pin fixation at a single institution were identified. Preoperative and postoperative radiographs were reviewed and assessed for fracture characteristics, postoperative alignment, and radiographic union. Postoperative outcome scores were obtained. RESULTS: A total of 39 patients (age 17.3 ± 3.9 years) with clavicle fracture treated with Rockwood pin were identified. Radiographic review demonstrated that 88% of fractures were 100%, or more, displaced, and surgery achieved near-anatomic reduction in 92% of cases. Average time to radiographic union was 2.3 ± 0.8 months, and average time to clinical union was 2.5 ± 0.3 months. One patient required revision for nonunion (3%). Complete outcome responses were obtained for 24 patients, with an average 40 ± 27.7 months of follow-up. Mean Total Clavicle Functional score was 2.75 ± 3.6 for minor patients. For adult patients, Nottingham Clavicle score was 90.7 ± 10.7, mean American Shoulder and Elbow Society score was 92.4 ± 11.2, and mean Single Assessment Numerical Evaluation score was 88.8 ± 21.5. 77% of adults reported no long-term functional limitation; 54% reported a bump at the prior fracture site, but 100% reported satisfaction with shoulder appearance. CONCLUSIONS: In our cohort of young active patients, treatment with Rockwood pin allowed for anatomic reduction, healing with a low nonunion rate, and favorable patient reported outcomes.

Glenoid component placement accuracy in total shoulder arthroplasty with preoperative planning and standard instrumentation is not influenced by supero-inferior glenoid erosion.

PURPOSE: Accurate glenoid component placement in total shoulder arthroplasty (TSA) remains challenging even with preoperative planning, especially for variable glenoid erosion patterns in the coronal plane. METHODS: We retrospectively reviewed 170 primary TSAs in which preoperative planning software was used. After registration of intraoperative bony landmarks, surgeons were blinded to the navigation screen and attempted to implement their plan by simulating placement of a central-axis guide pin: 230 screenshots of simulated guide pin placement were included (aTSA = 66, rTSA = 164). Displacement, error in version and inclination, and overall malposition from the preoperatively-planned target point were stratified by the Favard classification describing superior-inferior glenoid wear: E0 (n = 89); E1 (n = 81); E2 (n = 29); E3(n = 29); E4(n = 2). Malposition was considered > 10° for version/inclination errors or > 4 mm displacement from the starting point. RESULTS: Mean displacement error was 3.5 ± 2.7 mm (aTSA = 2.7 ± 2.3 mm, rTSA = 3.8 ± 2.9 mm), version error was 5.7 ± 4.7° (aTSA = 5.8 ± 4.4°, rTSA = 5.7 ± 4.8°), inclination error was 7.1 ± 5.6 (aTSA = 4.8 ± 4.8°, rTSA = 8.1 ± 5.7°), and malposition rate was 53% (aTSA = 38%, rTSA = 59%). When compared by Favard classification, there were no differences in any measure; when stratified by TSA type, version error differed for rTSAs (P = .038), with E1 having the greatest version error (6.9 ± 5.2°) and E3 the least (4.2 ± 3.4°). When comparing glenoids without wear (E0) and glenoids with superior wear (E2 and E3), the only difference was greater version error in glenoids without wear (6.0 ± 4.9° vs. 4.6 ± 3.7°, P = .041). CONCLUSIONS: Glenoid malposition did not differ based on coronal glenoid morphology. Although, malposition was relatively high, suggesting surgeons should consider alternate techniques beyond preoperative planning and standard instrumentation in TSA. LEVEL OF EVIDENCE III: Retrospective Cohort Study.

Refraction of space-time wave packets in a dispersive medium.

Space-time (ST) wave packets are a class of pulsed optical beams whose spatiotemporal spectral structure results in propagation invariance, tunable group velocity, and anomalous refractive phenomena. Here, we investigate the refraction of ST wave packets normally incident onto a planar interface between two dispersive, homogeneous, isotropic media. We formulate a new, to the best of our knowledge, refractive invariant for ST wave packets in this configuration, from which we obtain a law of refraction that determines the change in their group velocity across the interface. We verify this new refraction law in ZnSe and CdSe, both of which manifest large chromatic dispersion at near-infrared frequencies in the vicinity of their band edges. ST wave packets can thus be utilized in nonlinear optics for bridging large group-velocity mismatches in highly dispersive scenarios.

Femtosecond Spectroscopy and Nonlinear Optical Properties of aza-BODIPY Derivatives in Solution.

The fast relaxation processes in the excited electronic states of functionalized aza-boron-dipyrromethene (aza-BODIPY) derivatives (1-4) were investigated in liquid media at room temperature, including the linear photophysical, photochemical, and nonlinear optical (NLO) properties. Optical gain was revealed for nonfluorescent derivatives 3 and 4 in the near infrared (NIR) spectral range under femtosecond excitation. The values of two-photon absorption (2PA) and excited-state absorption (ESA) cross-sections were obtained for 1-4 in dichloromethane using femtosecond Z-scans, and the role of bromine substituents in the molecular structures of 2 and 4 is discussed. The nature of the excited states involved in electronic transitions of these dyes was investigated using quantum-chemical TD-DFT calculations, and the obtained spectral parameters are in reasonable agreement with the experimental data. Significant 2PA (maxima cross-sections ∼2000 GM), and large ESA cross-sections ∼10-20  m2 of these new aza-BODIPY derivatives 1-4 along with their measured high photostability reveal their potential for photonic applications in general and optical limiting in particular.

Investigating the Sources of Urban Air Pollution Using Low-Cost Air Quality Sensors at an Urban Atlanta Site.

Advances in low-cost sensors (LCS) for monitoring air quality have opened new opportunities to characterize air quality in finer spatial and temporal resolutions. In this study, we deployed LCS that measure both gas (CO, NO, NO2, and O3) and particle concentrations and co-located research-grade instruments in Atlanta, GA, to investigate the capability of LCS in resolving air pollutant sources using non-negative matrix factorization (NMF) in a moderately polluted urban area. We provide a comparison of applying the NMF technique to both normalized and non-normalized data sets. We identify four factors with different temporal trends and properties for both normalized and non-normalized data sets. Both normalized and non-normalized LCS data sets can resolve primary organic aerosol (POA) factors identified from research-grade instruments. However, applying normalization provides factors with more diverse compositions and can resolve secondary organic aerosol (SOA). Results from this study demonstrate that LCS not only can be used to provide basic mass concentration information but also can be used for in-depth source apportionment studies even in an urban setting with complex pollution mixtures and relatively low aerosol loadings.

Transient mid-IR nonlinear refraction in air.

We use the polarization-sensitive, time-resolved Beam-Deflection technique to measure the nonlinear refraction of air, exciting in both the near and mid-IR and probing in the mid-IR. This gives us the first measurements for air using both excitation and probe in the mid-IR, and we find no dispersion of the bound-electronic nonlinear refractive index, n2,el(λp;λe), assuming, as has been shown earlier, that the nuclear rotational nonlinear refraction is nearly dispersionless. From these data, we can model the pulsewidth dependence of the effective nonlinear refractive index, n2,eff, i.e., as would be measured by a single beam. Interestingly, n2,eff is maximized for a pulsewidth of approximately 0.5 ps. The position of this maximum is nearly independent of pressure while its magnitude decreases with increasing pressure and temperature. From the measurements and modeling, we predict the nonlinear refraction in the atmosphere at different altitudes.

Benzothiadiazole-Substituted Aza-BODIPY Dyes: Two-Photon Absorption Enhancement for Improved Optical Limiting Performances in the Short-Wave IR Range.

Aza-boron dipyrromethenes (aza-BODIPYs) presenting a benzothiadiazole substitution on upper positions are described. The strong electron-withdrawing effect of the benzothiadiazole moiety permits enhancement of the accepting strength and improves the delocalization of the aza-BODIPY core to attain a significant degree of electronic communication between the lower donating groups and the upper accepting groups. The nature of the intramolecular charge transfer is studied both experimentally and theoretically. Linear spectroscopy highlighted the strongly redshifted absorption and emission of the synthesized molecules with recorded fluorescence spectra over 1000 nm. Nonlinear optical properties were also investigated. Strong enhancement of the two-photon absorption of the substituted dyes compared with the unsubstituted one (up to 4520 GM at 1300 nm) results in an approximately 15-20 % improvement of the optical power limiting performances. These dyes are therefore a good starting point for further improvement of optical power limiting in the short-wave IR range.

Janus All-Cis 2,3,4,5,6-Pentafluorocyclohexyl Building Blocks Applied to Medicinal Chemistry and Bioactives Discovery Chemistry.

Monoalkylated derivatives of the unusually polar all-cis 2,3,4,5,6- pentafluorocyclohexyl (Janus face) motif are prepared starting from an aryl hydrogenation of 2,3,4,5,6- pentafluorophenylacetate methyl ester 15. The method used Zeng's Rh(CAAC) carbene catalyst 4 in the hydrogenation following the protocol developed by Glorius. The resultant Janus pentafluorocyclohexylacetate methyl ester 16 was converted to the corresponding alcohol 18, aldehyde 13, bromide 29 and azide 14 through functional group manipulations, and some of these building blocks were used in Ugi-multicomponent and Cu-catalysed click reactions. NBoc protected pentafluoroarylphenylalanine methyl ester 35 was also subject to an aryl hydrogenation, and then deprotection to generate the Janus face ß-pentafluorocyclohexyl-alanine amino acid 15, which was incorporated into representative members of an emerging class of candidate antiviral compounds. Log P measurements demonstrate that the all-cis 2,3,4,5,6-pentafluorocyclohexyl ring system is more polar than a phenyl ring. In overview the paper introduces new building blocks containing this Janus ring and demonstrates their progression to molecules typically used in bioactives discovery programmes.

Osmolyte enhanced aqueous two-phase system for virus purification.

Due to the high variation in viral surface properties, a platform method for virus purification is still lacking. A potential alternative to the high-cost conventional methods is aqueous two-phase systems (ATPSs). However, optimizing virus purification in ATPS requires a large experimental design space, and the optimized systems are generally found to operate at high ATPS component concentrations. The high concentrations capitalize on hydrophobic and electrostatic interactions to obtain high viral particle yields. This study investigated using osmolytes as driving force enhancers to reduce the high concentration of ATPS components while maintaining high yields. The partitioning behavior of porcine parvovirus (PPV), a nonenveloped mammalian virus, and human immunodeficiency virus-like particle (HIV-VLP), a yeast-expressed enveloped VLP, were studied in a polyethylene glycol (PEG) 12 kDa-citrate system. The partitioning of the virus modalities was enhanced by osmoprotectants glycine and betaine, while trimethylamine N-oxide was ineffective for PPV. The increased partitioning to the PEG-rich phase pertained only to viruses, resulting in high virus purification. Recoveries were 100% for infectious PPV and 92% for the HIV-VLP, with high removal of the contaminant proteins and more than 60% DNA removal when glycine was added. The osmolyte-induced ATPS demonstrated a versatile method for virus purification, irrespective of the expression system.

Streptomyces aureorectus DSM 41692 and Streptomyces virens DSM 41465 are producers of the antibiotic nucleocidin and 4'-fluoroadenosine is identified as a co-product.

Genome homology and the presence of a putative biosynthetic gene cluster identified Streptomyces aureorectus DSM 41692 and Streptomyces virens DSM 41465 as candidate producers of the antibiotic nucleocidin 1. Indeed when these bacterial strains were cultured in a medium supplemented with fluoride (4 mM) they each produced nucleocidin 1 and the previously identified 4'-fluoro-3'-O-ß-glucosylated adenosine 2 and its sulfamylated derivative 3. In both of these cases 4'-fluoroadenosine 9 is also identified as a natural product although it has never been observed during fermentations of Streptomyces calvus, the original source of nucleocidin 1. The identity of 4'-fluoroadenosine 9 was confirmed by a total synthesis as well as by its in vitro enzymatic conversion to metabolite 2 using the glucosyl transferase enzyme, NucGT.

The contribution of non-classical CHaxOC hydrogen bonds to the anomeric effect in fluoro and oxa-methoxycyclohexanes.

In this theory study we demonstrate the dominance of non-classical 1,3-diaxial CHaxOC hydrogen bonds (NCHBs) dictating a 'pseudo' anomeric effect in selectively fluorinated methoxycyclohexanes and also influencing the axial preference in the classical anomeric exhibitor 2-methoxytetrahydropyran, a phenomenon which is most often described as a consequence of hyperconjugation. Analogues of methoxycyclohexane where ring CH2's are replaced by CF2 can switch to an axial preference and theory methods (NBO, QTAIM, NCI) indicate the dominance of 1,3-CHaxOMe interactions over hyperconjugation. For 2-methoxytetrahydropyran, it is revealed that the global contribution to the anomeric effect is from electrostatic interactions including NCHBs, not hyperconjugation, although hyperconjugation (nO→σ*CO or nO→σ*CC) remains the main contributor to the exo-anomeric phenomenon. When two and three ether oxygens are introduced into the ring, then both the NCHB interactions and hyperconjugative contributions become weaker, not stronger as might have been anticipated, and the equatorial anomers progressively dominate.