Practical Synthesis of 7-Bromo-4-chloro-1H-indazol-3-amine: An Important Intermediate to Lenacapavir.

7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38-45%. The new protocol has been successfully demonstrated on hundred-gram scales without the need for column chromatography purification. This new synthesis provides a potential economical route to the large-scale production of this heterocyclic fragment of Lenacapavir.

Association of air pollutants and hospital admissions for respiratory diseases in Lanzhou, China, 2014-2019.

The aim of this study was to assess the effects of air pollutants on hospital admissions for respiratory disease (RD) by using distributed lag nonlinear model (DLNM) in Lanzhou during 2014-2019. In this study, the dataset of air pollutants, meteorological, and daily hospital admissions for RD in Lanzhou, from January 1st, 2014 to December 31st, 2019, were collected from three national environmental monitoring stations, China meteorological data service center, and three large general hospitals, respectively. A time-series analysis with DLNM was used to estimate the associations between air pollutants and hospital admissions for RD including the stratified analysis of age, gender, and season. The key findings were expressed as the relative risk (RR) with a 95% confidence interval (CI) for single-day and cumulative lag effects (0-7). A total of 90, 942 RD hospitalization cases were identified during the study period. The highest association (RR, 95% CI) of hospital admissions for RD and PM2.5 (1.030, 1.012-1.049), and PM10 (1.009, 1.001-1.015), and NO2 (1.047, 1.024-1.071) were observed at lag 07 for an increase of 10 µg/m3 in the concentrations, and CO at lag07 (1.140, 1.052-1.236) for an increase of 1 mg/m3 in the concentration. We observed that the RR estimates for gaseous pollutants (e.g., CO and NO2) were larger than those of particulate matter (e.g., PM2.5 and PM10). The harmful effects of PM2.5, PM10, NO2, and CO were greater in male, people aged 0-14 group and in the cold season. However, no significant association was observed for SO2, O38h, and total hospital admissions for RD. Therefore, some effective intervention strategies should be taken to strengthen the treatment of the ambient air pollutants, especially gaseous pollutants (e.g., CO and NO2), thereby, reducing the burden of respiratory diseases.

Enantioselective Intermolecular Radical C-H Amination.

Radical reactions hold a number of inherent advantages in organic synthesis that may potentially impact the planning and practice for construction of organic molecules. However, the control of enantioselectivity in radical processes remains one of the longstanding challenges. While significant advances have recently been achieved in intramolecular radical reactions, the governing of asymmetric induction in intermolecular radical reactions still poses challenging issues. We herein report a catalytic approach that is highly effective for controlling enantioselectivity as well as reactivity of the intermolecular radical C-H amination of carboxylic acid esters with organic azides via Co(II)-based metalloradical catalysis (MRC). The key to the success lies in the catalyst development to maximize noncovalent attractive interactions through fine-tuning of the remote substituents of the D2-symmetric chiral amidoporphyrin ligand. This noncovalent interaction strategy presents a solution that may be generally applicable in controlling reactivity and enantioselectivity in intermolecular radical reactions. The Co(II)-catalyzed intermolecular C-H amination, which operates under mild conditions with the C-H substrate as the limiting reagent, exhibits a broad substrate scope with high chemoselectivity, providing effective access to valuable chiral amino acid derivatives with high enantioselectivities. Systematic mechanistic studies shed light into the working details of the underlying stepwise radical pathway for the Co(II)-based C-H amination.

Critical flux investigation in treating o/w emulsion by TiO2/Al2O3-PVDF UF membrane.

A standard transmembrane pressure (TMP) step method has been used in membrane fouling assessment in tube ultrafiltration (UF) membrane system treating oil water (o/w) emulsion operated at constant TMP. Three flux reduction curve with different o/w concentration based on TMP variation were concluded by experiment, then, to describe fouling behavior and identify the occurrence of fouling in the so-called critical flux. Furthermore, sub-critical and super-critical flux experiment with a long time was determined, and zero rate of flux reduction (dF/dt) was never found during the whole trial period, indicating that critical flux in o/w UF process with its strict definition could not be defined in this paper. However, quasi-critical flux exists, under which the pollution rate was very slow. Moreover, a high-efficiency four steps cleaning method: mechanic scraping, pure water wash, pure water reverse wash, and dosing cleaning, was explored. It concluded that critical flux in real o/w UF system determined by TMP-step method can be used to predict long-term critical behavior with useful data on fouling propensity.

Room Temperature Activation of Aryloxysulfonyl Azides by [Co(II)(TPP)] for Selective Radical Aziridination of Alkenes via Metalloradical Catalysis.

Aryloxysulfonyl azides can be effectively activated by commercially available cobalt(II) complex of meso-tetraphenylporphyrin ([Co(TPP)]) at room temperature under neutral and nonoxidative conditions for selective radical aziridination of alkenes via metalloradical catalysis. The [Co(TPP)]-catalyzed radical aziridination system is suitable for different combinations of olefin substrates and aryloxysulfonyl azides, producing various N-aryloxysulfonyl aziridine derivatives in good to excellent yields. In addition to generating the environmentally benign N2 as the only byproduct, this Co(II)-based metalloradical aziridination process features mild reaction conditions and operational simplicity.

Synthesis of chiral N-phosphoryl aziridines through enantioselective aziridination of alkenes with phosphoryl azide via Co(II)-based metalloradical catalysis.

The Co(II) complex of a new D 2-symmetric chiral porphyrin 3,5-DiMes-QingPhyrin, [Co(P6)], can catalyze asymmetric aziridination of alkenes with bis(2,2,2-trichloroethyl)phosphoryl azide (TcepN3) as a nitrene source. This new Co(II)-based metalloradical aziridination is suitable for different aromatic olefins, producing the corresponding N-phosphorylaziridines in good to excellent yields (up to 99%) with moderate to high enantioselectivities (up to 85% ee). In addition to mild reaction conditions and generation of N2 as the only byproduct, this new metalloradical catalytic system is highlighted with a practical protocol that operates under neutral and non-oxidative conditions.

Highly Regioselective Protecting-Group-Free Synthesis of the Antimalarial Drug MMV693183.

MMV693183 is a promising antimalarial drug candidate that works for uncomplicated malaria treatment and resistance management. Herein, we report an efficient and highly regioselective synthesis of MMV693183. This novel synthetic method highlights a three-step route with an overall yield of 46% from readily available starting materials. The key to the success lies in (1) utilizing the subtle difference of the two amino groups in the starting material (S)-propane-1,2-diamine dihydrochloride without amino protection and (2) identifying the L-(+)-tartaric acid as the counter acid for the organic salt formation, yielding the desired regioisomer up to 100:0. The efficient and scalable three-step protocol operates under mild conditions with a high chemo/regioselectivity, providing effective access to MMV693183.

Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148.

Visceral leishmaniasis (VL), a parasitic, poverty-linked, neglected disease, is endemic across multiple regions of the world and fatal if untreated. There is an urgent need for a better and more affordable treatment for VL. DNDI-6148 is a promising drug candidate being evaluated for the treatment of VL; however, the current process for producing the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane, is expensive and difficult to scale up. Herein, we describe two practical approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from inexpensive and readily available raw materials. Starting with 4-tolunitrile, the first approach is a five-step sequence involving a Hofmann rearrangement, resulting in an overall yield of 40%. The second approach utilizes 2-methyl-5-nitroaniline as the starting material and features borylation of aniline and continuous flow hydrogenation as the key steps, with an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane, which is challenging and expensive to scale. In particular, the second approach is more practical and scalable because of the mild operating conditions and facile isolation process.

Effects of oriented surface dipole on photoconversion efficiency in an alkane/lipid-hybrid-bilayer-based photovoltaic model system.

When a phospholipid monolayer containing a zinc-coordinated porphyrin species formed atop a self-assembled monolayer of heptadecafluoro-1-decanethiol (CF3(CF2)7(CH2)2SH) is subjected to photoelectrochemical current generation, a significant modulation effect is observed. Compared with devices that contain similar photoactive lipid monolayers but formed on 1-dodecanethiol SAMs, these fluorinated hybrid bilayers produce a >60% increase in cathodic currents and a similar decrease in anodic currents. Photovoltages recorded from these hybrid bilayers are found to vary in the same fashion. The modulation of photovoltaic responses in these hybrid-bilayer-based devices is explained by the opposite surface dipoles associated with the thiols employed in this study, which in one case (fluorothiol) increase and in another (alkanethiol) decrease the work function of the underlying gold substrates. A similar trend of photovoltage/photocurrent modulation is also observed if fullerene is used as the photoagent in these devices. Our results reveal the intricacy of orientated surface dipole in influencing the photovoltaic processes, and its subtle interplay with other factors related to the photoagents, such as their location and orientation within the organic matrix.

Physical and chemical characterization of ashes from a municipal solid waste incinerator in China.

In this study we analyzed the characteristics of bottom and fly ashes from a municipal solid waste incinerator in China. The physical properties of particle size distribution and morphology were evaluated. At the chemical level, the chemical composition, heavy metal leaching behavior and BCR sequential extraction procedure (the Community Bureau of Reference, now the European Union 'Measurement and Testing Programme') were determined. The main mineralogical crystalline phases in raw and leached bottom and fly ashes were also identified. For the bottom ashes, the concentration of heavy metals showed a slight decrease with an increase in particle size, and most of the heavy metal concentrations in fly ashes were higher than those in bottom ashes. The results of the toxicity characteristic leaching procedure indicated that, among the metals, the concentrations of lead (Pb) and copper (Cu) in fly ash leachate exceeded thresholds, while the concentrations of studied heavy metals in bottom ash leachate were all below the regulatory limit. The BCR results indicated that more easily mobilized forms (acid exchangeable) were predominant for cadmium and zinc; in contrast, the largest amount of Pb, Cu and manganese were associated with iron/manganese oxide, organic matter/sulfide fractions, or were residual.

Association between salt sensitivity of blood pressure and the risk of hypertension in a Chinese Tibetan population.

Epidemiological studies have confirmed salt sensitivity as a crucial risk factor for the development of hypertension. However, few studies have investigated the association between salt sensitivity of blood pressure (SSBP) and hypertension in Chinese Tibetan population. Therefore, we conducted a cross-sectional study based on a Tibetan population to evaluate the association between SSBP and the risk of hypertension. Seven hundred and eighty-four participants with hypertension and 645 participants without hypertension were included from five villages in Tibetan Autonomous Region of Gannan during 2013-2014. The assessment of salt sensitivity (SS) and non-salt sensitivity (NSS) was performed according to mean arterial pressure (MAP) changes by the modified Sullivan's acute oral saline load and diuresis shrinkage test (MSAOSL-DST). Logistic regression models and restricted cubic models were used to examine the association between SSBP and hypertension. There were 554 (70.5%) salt-sensitive participants with hypertension and 412 (63.9%) salt-sensitive participants without hypertension in this study. Compared with individuals with NSS, individuals with SS had a significantly increased risk of hypertension, and the multiple-adjusted odds ratios were 2.582 with 95% confidence interval of 1.357-4.912. Furthermore, a significant linear trend was found between MAP changes and hypertension. Subgroup analyses showed significant and stronger associations between SSBP and the risk of hypertension in the older (age ≥ 55 years old), males and participants who took exercise less than 1 time per week. Our results suggest that SS is associated with an increased risk of hypertension in Tibetan population, indicating a need for clinicians dealing with SSBP to decrease the risk of hypertension.

Thermal processing as a means to prepare durable, submicron thickness ionomer films for study by transmission infrared spectroscopy.

A high temperature solution processing method was adapted to prepare durable, freestanding, submicrometer thickness films for transmission infrared spectroscopy studies of ionomer membrane. The materials retain structural integrity following cleaning and ion-exchange steps in boiling solutions, similar to a commercial fuel cell membrane. Unlike commercial membrane, which typically has thicknesses of >25 µm, the structural properties of the submicrometer thickness materials can be probed in mid-infrared spectral measurements with the use of transmission sampling. Relative to the infrared attenuated total reflection (ATR) technique, transmission measurements can sample ionomer membrane materials more uniformly and suffer less distortion from optical effects. Spectra are reported for thermally processed Nafion and related perfluoroalkyl ionomer materials containing phosphonate and phosphinate moieties substituted for the sulfonate end group on the side chain. Band assignments for complex or unexpected features are aided by density functional theory (DFT) calculations.

Associations of nickel exposure and kidney function in U.S. adults, NHANES 2017-2018.

BACKGROUNDS: Nickel (Ni) is a ubiquitous heavy metal, but epidemiological studies on the association between Ni and kidney function are limited and controversial. AIM: We aimed to explore the relationship between urinary Ni concentrations and kidney function in U.S. adults. METHODS: This was a cross-sectional study based on the 2017-2018 National Health and Nutrition Examination Survey (NHANES) (n = 1588). Multiple linear regression models, logistic regression models, and restricted cubic spline models (RCS) were fitted to explore the associations between urinary Ni and estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and the odds of impaired kidney function, which was defined as an eGFR ≤ 60 mL/min per 1.73 m2, or UACR ≥ 30.0 mg/g. Bayesian kernel machine regression (BKMR) was used to account for joint-metal effects. RESULTS: Compared with the lowest quartile, urinary Ni at the third quartile was associated with increased eGFR (ß = 2.42, 95 % CI: 0.23-4.19); the highest quartile of urinary Ni was correlated with increased UACR (ß = 0.10, 95 % CI: 0.02-0.18), as well as higher odds of impaired kidney function (OR=1.65, 95 % CI:1.08-2.54). Urinary Ni had a nonlinear inverted U-shape relationship with eGFR (Pnonlinear = 0.007), and linear J-shape associations with UACR (Pnonlinear = 0.063) and impaired kidney function (Pnonlinear= 0.215). Metal interaction of urinary Ni with cadmium (Cd) on eGFR was observed. CONCLUSIONS: Our findings provided evidence that Ni exposure linked with declined kidney function and might interact with Cd exposure. Considering the cross-sectional design of the NHANES study, further prospective studies are necessary.

Metalloradical activation of carbonyl azides for enantioselective radical aziridination.

Organic azides have been increasingly employed as nitrogen sources for catalytic olefine aziridination due to their ease of preparation and generation of benign N2 as the only byproduct. Among common organic azides, carbonyl azides have not been previously demonstrated as effective nitrogen sources for intermolecular olefin aziridination despite the synthetic utilities of N-carbonyl aziridines. As a new application of metalloradical catalysis, we have developed a catalytic system that can effectively employ the carbonyl azide TrocN3 for highly asymmetric aziridination of alkenes at room temperature. The resulting enantioenriched N-Trocaziridines have been shown as valuable chiral synthons for stereoselective synthesis of other chiral aziridines and various chiral amines. The Co(II)-based metalloradical system, which proceeds with distinctive stepwise radical mechanism, may provide a general method for asymmetric synthesis of chiral aziridines from alkenes with organic azides.

Facile and potent synthesis of carbon bridged fullerene dimers (HC60-CR2-C60H type).

Novel carbon bridged fullerene dimers (HC60-CR2-C60H type) are obtained in high yield by the reaction of aminomethylenebis(phosphonate) anions with [60]fullerene.

Removal of toxic and alkali/alkaline earth metals during co-thermal treatment of two types of MSWI fly ashes in China.

This study aims to vaporize heavy metals and alkali/alkaline earth metals from two different types of fly ashes by thermal treatment method. Fly ash from a fluidized bed incinerator (HK fly ash) was mixed with one from a grate incinerator (HS fly ash) in various proportions and thermally treated under different temperatures. The melting of HS fly ash was avoided when treated with HK fly ash. Alkali/alkaline earth metals in HS fly ash served as Cl-donors to promote the vaporization of heavy metals during thermal treatment. With temperature increasing from 800 to 900°C, significant amounts of Cl, Na and K were vaporized. Up to 1000°C in air, less than 3% of Cl and Na and less than 5% of K were retained in ash. Under all conditions, Cd can be vaporized effectively. The vaporization of Pb was mildly improved when treated with HS fly ash, while the effect became less pronounced above 900°C. Alkali/alkaline earth metals can promote Cu vaporization by forming copper chlorides. Comparatively, Zn vaporization was low and only slightly improved by HS fly ash. The low vaporization of Zn could be caused by the formation of Zn2SiO4, ZnFe2O4 and ZnAl2O4. Under all conditions, less than 20% of Cr was vaporized. In a reductive atmosphere, the vaporization of Cd and Pb were as high as that in oxidative atmosphere. However, the vaporization of Zn was accelerated and that of Cu was hindered because the formation of Zn2SiO4, ZnFe2O4 and ZnAl2O4 and copper chloride was depressed in reductive atmosphere.

Detoxification of ashes from a fluidized bed waste incinerator.

This paper was to test and control the toxicity of bottom and fly ashes from a circulated fluidized bed (CFB) incinerator. Bottom and fly ashes were firstly subject to TCLP test. Even though leachates of most particle size of bottom ash were below regulatory limit, the leachates of finer bottom ash may exceed the regulatory limit. Therefore, finer bottom ash should be separated and treated before landfilled directly or used as cement replacement. Due to high amounts of leached heavy metals, thermal treatment of fly ash was carried out to remove heavy metals. The influence of temperature, residence time, metal chloride and gas velocity were studied. In all conditions, Cd can be well removed. Pb can be almost completely removed with MgCl2 addition at 1000°C in 1h. The removal of Zn and Cu was accelerated significantly by MgCl2 and higher temperature separately. At optimum conditions, more than 90% of Cu and 95% of Zn could be removed, while a maximum 20% of Cr was removed due to the existence or formation of CaCr2O4, MgCr2O4 and K2Cr2O4 in raw or treated fly ashes.

Stereoselective Radical C-H Alkylation with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis.

Co(II)-based metalloradical catalysis has been, for the first time, successfully applied for asymmetric intramolecular C-H alkylation of acceptor/acceptor-substituted diazo reagents. Through the design and synthesis of a new D2-symmetric chiral amidoporphyrin as the supporting ligand, the Co(II)-based metalloradical system, which operates at room temperature, is capable of 1,5-C-H alkylation of α-methoxycarbonyl-α-diazosulfones with a broad range of electronic properties, providing the 5-membered sulfolane derivatives in high yields with excellent diastereoselectivity and enantioselectivity. In addition to complete chemoselectivity toward allylic and allenic C-H bonds, the Co(II)-based metalloradical catalysis for asymmetric C-H alkylation features a remarkable degree of functional group tolerance.

Selective Radical Amination of Aldehydic C(sp2)-H Bonds with Fluoroaryl Azides via Co(II)-Based Metalloradical Catalysis: Synthesis of N-Fluoroaryl Amides from Aldehydes under Neutral and Nonoxidative Conditions.

The Co(II) complex of the D2h-symmetric amidoporphyrin 3,5-Di t Bu-IbuPhyrin, [Co(P1)], has proven to be an effective metalloradical catalyst for intermolecular amination of C(sp2)-H bonds of aldehydes with fluoroaryl azides. The [Co(P1)]-catalyzed process can employ aldehydes as the limiting reagents and operate under neutral and non-oxidative conditions, generating nitrogen gas as the only byproduct. The metalloradical aldehydic C-H amination is suitable for different combinations of aldehydes and fluoroaryl azides, producing the corresponding N-fluoroaryl amides in good to excellent yields. A series of mechanistic studies support a stepwise radical mechanism for the Co(II)-catalyzed intermolecular C-H amination.