Modular preparation of cationic bipyridines and azaarenes via C-H activation.

Bipyridines are ubiquitous in organic and inorganic chemistry because of their redox and photochemical properties and their utility as ligands to transition metals. Cationic substituents on bipyridines and azaarenes are valuable as powerful electron-withdrawing functionalities that also enhance solubility in polar solvents, but there are no general methods for direct functionalization. A versatile method for the preparation of trimethylammonium- and triarylphosphonium-substituted bipyridines and azaheterocycles is disclosed. This methodology showcases a C-H activation of pyridine N-oxides that enables a highly modular and scalable synthesis of a diverse array of cationically charged azaarenes. The addition of trimethylammonium functionalities on bipyridine derivatives resulted in more anodic reduction potentials (up to 700 mV) and increased electrochemical reversibility compared to the neutral unfunctionalized bipyridine. Additonally, metallation of 4-triphenylphosphinated biquinoline to make the corresponding Re(CO)3Cl complex resulted in reduction potentials 400 mV more anodic than the neutral derivative.

Studying Regioisomer Formation in the Pd-Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification.

Pd-catalyzed nucleophilic fluorination reactions are important methods for the synthesis of fluoroarenes and fluoroalkenes. However, these reactions can generate a mixture of regioisomeric products that are often difficult to separate. While investigating the Pd-catalyzed fluorination of cyclic vinyl triflates, we observed that the addition of a substoichiometric quantity of TESCF3 significantly improved the regioselectivity of the reaction. Herein, we report a combined experimental and computational study on the mechanism of this transformation focusing on the role of TESCF3 . The poor regioselectivity of the reaction in the absence of additives results from the formation of LPd-cyclohexyne complexes (L=biaryl monophosphine ligand). When TESCF3 is added to the reaction mixture, the generation of the Pd-cyclohexyne complexes is diminished by an unexpected pathway involving the dearomatization of the ligand by nucleophilic attack from a trifluoromethyl anion (CF3 - ).

A Neophyl Palladacycle as an Air- and Thermally Stable Precursor to Oxidative Addition Complexes.

The utilization of isolated Palladium Oxidative Addition Complexes (OACs) has had a significant impact on Pd-catalyzed and Pd-mediated cross-coupling reactions. Despite their importance, widespread utility of OACs has been limited by the instability of their precursor complexes. Herein, we report the use of Cámpora's palladacycle as a new, more stable precursor to Pd OACs. Using this palladacycle, a series of biarylphosphine ligated OACs, including those with pharmaceutical-derived aryl halides and relevance to bioconjugation, were prepared.

Rural youth's exposure to firearm violence and their attitudes regarding firearm safety measures.

BACKGROUND: In the wake of an epidemic in firearm-related deaths and injuries, youth have become leading voices of concern. This study's objective was to investigate rural youth's personal experiences with firearm-related violence, and their attitudes towards firearms and gun violence prevention strategies. METHODS: Attendees of the 2019 Iowa FFA Leadership Conference were surveyed about personal experiences with firearm-associated deaths and injuries, and their attitudes regarding firearm-related issues. Descriptive (frequencies), bivariate (chi square, Fisher's exact test) and multivariable logistic regression analyses were performed utilizing Stata 15.1 (StataCorp, College Station, Texas). RESULTS: Responses from 1382 FFA members 13-18 years of age were analyzed. About 5% had personally seen someone threatened with a firearm. Over one-third (36%) stated they knew someone who had been killed or injured by gunfire. Of these, over two-thirds knew of someone who had died or was injured unintentionally and 30% knew of someone killed or injured intentionally (e.g. suicide). Nearly all agreed or strongly agreed that the right to use firearms for hunting and shooting sports should be legal (94%), that a firearm safety course should be required to get a hunting license (89%), and that there should be a required background check before purchasing a firearm (89%). Over three-fifths (61%) agreed or strongly agreed that there should be laws requiring safe storage of firearms in homes. Although still high, lesser support for firearm safety policies was seen among males, older youth, participants living on farms or in the country, and youth who hunted, had firearms in their homes, and/or were in homes with unsafe firearm storage. CONCLUSIONS: The majority of youth in this study supported firearm safety measures including required training, background checks, and safe firearm storage in homes. These findings are consistent with the national youth-led call for firearm safety. Additionally, over one-third of respondents personally knew someone who was killed or injured by a firearm and 5% had seen someone or been personally threatened with firearm violence. Our study did not investigate the effects of firearm violence on participants' mental health and wellbeing, but future studies addressing this question seem highly justified.

Live cell tagging tracking and isolation for spatial transcriptomics using photoactivatable cell dyes.

A cell's phenotype and function are influenced by dynamic interactions with its microenvironment. To examine cellular spatiotemporal activity, we developed SPACECAT-Spatially PhotoActivatable Color Encoded Cell Address Tags-to annotate, track, and isolate cells while preserving viability. In SPACECAT, samples are stained with photocaged fluorescent molecules, and cells are labeled by uncaging those molecules with user-patterned near-UV light. SPACECAT offers single-cell precision and temporal stability across diverse cell and tissue types. Illustratively, we target crypt-like regions in patient-derived intestinal organoids to enrich for stem-like and actively mitotic cells, matching literature expectations. Moreover, we apply SPACECAT to ex vivo tissue sections from four healthy organs and an autochthonous lung tumor model. Lastly, we provide a computational framework to identify spatially-biased transcriptome patterns and enriched phenotypes. This minimally perturbative and broadly applicable method links cellular spatiotemporal and/or behavioral phenotypes with diverse downstream assays, enabling insights into the connections between tissue microenvironments and (dys)function.

A Ligand Exchange Process for the Diversification of Palladium Oxidative Addition Complexes.

Palladium oxidative addition complexes (OACs) have recently emerged as useful tools to enable challenging bond connections. However, each OAC can only be formed with one dative ligand at a time. As no one ligand is optimal for every cross-coupling reaction, we herein disclose a ligand exchange protocol for the preparation of a series of OACs bearing a variety of ancillary ligands from one common complex. These complexes were further applied to cross-coupling transformations.

Pharmaceutical diversification via palladium oxidative addition complexes.

Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addition complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of benchtop storage under ambient conditions. We demonstrated the utility of OACs in a variety of experiments including automated nanomole-scale couplings between an OAC derived from rivaroxaban and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.

Nanomole-Scale Assignment and One-Use Kits for Determining the Absolute Configuration of Secondary Alcohols.

Two different protocols were developed and optimized to address the need for (1) high sensitivity or (2) convenient utilization in the determination of the absolute configuration of secondary alcohols. The first protocol uses the competing enantioselective conversion (CEC) method to determine configuration on nanomole scale. Reactions were conducted with 145 nmol of the substrate using a 50 µL microsyringe as the reaction vessel, and the absolute configuration was assigned via qualitative determination of the fast reaction by thin-layer chromatography. This protocol resulted in a 50-fold reduction in material required from previous CEC method studies. The approach was evaluated with benzylic and ß-aryl systems. The second protocol was optimized to address the needs of practicing medicinal chemists. A one-use CEC kit was developed, where the fast reaction was identified by (1)H NMR spectroscopy and thin-layer chromatography. The CEC reaction conditions developed for the microsyringe protocol and the one-use kit both displayed data consistent with pseudo-first-order kinetics in substrate. Therefore, the lower limit of sensitivity for the substrate is limited only by the ability to effectively detect the reaction conversions between alcohol substrate and ester product.