Regioselective Pyridine to Benzene Edit Inspired by Water-Displacement.

Late-stage derivatization of drug-like functional groups can accelerate drug discovery efforts by swiftly exchanging hydrogen-bond donors with acceptors, or by modulating key physicochemical properties like logP, solubility, or polar surface area. A proven derivatization strategy to improve ligand potency is to extend the ligand to displace water molecules that are mediating the interactions with a receptor. Inspired by this application, we developed a method to regioselectively transmute the nitrogen atom from pyridine into carbon bearing an ester, a flexible functional group handle. We applied this method to a variety of substituted pyridines, as well as late-stage transformation of FDA-approved drugs.

A Metal-Free Cyclobutadiene Reagent for Intermolecular [4 + 2] Cycloadditions.

Cyclobutadiene is a highly reactive antiaromatic hydrocarbon that has fascinated chemists for over 60 years. However, its preparation and uses in chemical synthesis are sparing, in part due to its lengthy synthesis that generates hazardous byproducts including excess heavy metals. Herein, we report a scalable, metal-free cyclobutadiene reagent, diethyldiazabicyclohexene dicarboxylate, and explore its intermolecular [4 + 2] cycloaddition with various electron-deficient alkenes. We also demonstrate its utility in a three-step synthesis of dipiperamide G and a diverse array of product derivatizations including bromocyclobutadiene.

Emergency Medicine Resident-Driven Point of Care Ultrasound for Suspected Shoulder Dislocation.

OBJECTIVE: To determine the impact of implementing a musculoskeletal in-service educational intervention for emergency medicine (EM) residents on the use of point-of-care ultrasound (POCUS) to diagnose and manage shoulder dislocations in the emergency department (ED). METHODS: This study was conducted in the ED of an academic teaching hospital in Miami, Florida. It consisted of a short in-service educational intervention on how to perform and interpret POCUS, followed by an open, prospective convenience sample study in patients with clinical suspicion of shoulder dislocation. Twenty EM residents, with no prior shoulder scanning training, participated in the study. In all of the cases, the findings of the shoulder US were compared with radiographs, which were considered the reference standard. EM residents enrolled patients, and obtained and interpreted the shoulder US images. RESULTS: Seventy-eight patients were evaluated to rule out shoulder dislocation and/or fracture. Diagnosis of the dislocated shoulder was made in 55 of 78 patients, 53 of whom had anterior dislocations. Resident-driven POCUS had a sensitivity and specificity of 100% to diagnose and rule out, respectively, shoulder dislocations and relocations. There were no differences in the number of dislocations diagnosed and relocated by early and advanced EM residents. Results from a POCUS were available 22 ± 2.8 minutes sooner than x-ray for initial diagnosis and 27 ± 2.9 minutes (P < 0.0001) sooner than x-ray for assessment of reduction. CONCLUSIONS: EM resident physicians, with no previous training in shoulder US imaging, exposed to a brief in-service musculoskeletal education intervention, were able to diagnose shoulder dislocations via POCUS with high sensitivity and specificity. Shoulder US for dislocation should be a core component in EM training.

Transient Quadriplegia: A Case-Based Approach to Cervical Trauma.

INTRODUCTION: Spinal cord injuries are a common reason for presentation to the emergency department (ED). Sports-related spinal injuries are one of the least common spinal injuries, falling behind vehicular accidents, acts of violence, and falls. CASE REPORT: This case report describes a case of transient quadriplegia in a 17-year-old male who presented to the ED after a helmet-to-helmet collision while participating in football. CONCLUSION: Emergency physicians should be cognizant of potential spinal cord injury using clinical decision tools and radiologic imaging to properly disposition a patient presenting with cervical spine injury.

Automatic discovery of photoisomerization mechanisms with nanosecond machine learning photodynamics simulations.

Photochemical reactions are widely used by academic and industrial researchers to construct complex molecular architectures via mechanisms that often require harsh reaction conditions. Photodynamics simulations provide time-resolved snapshots of molecular excited-state structures required to understand and predict reactivities and chemoselectivities. Molecular excited-states are often nearly degenerate and require computationally intensive multiconfigurational quantum mechanical methods, especially at conical intersections. Non-adiabatic molecular dynamics require thousands of these computations per trajectory, which limits simulations to ∼1 picosecond for most organic photochemical reactions. Westermayr et al. recently introduced a neural-network-based method to accelerate the predictions of electronic properties and pushed the simulation limit to 1 ns for the model system, methylenimmonium cation (CH2NH2 +). We have adapted this methodology to develop the Python-based, Python Rapid Artificial Intelligence Ab Initio Molecular Dynamics (PyRAI2MD) software for the cis-trans isomerization of trans-hexafluoro-2-butene and the 4π-electrocyclic ring-closing of a norbornyl hexacyclodiene. We performed a 10 ns simulation for trans-hexafluoro-2-butene in just 2 days. The same simulation would take approximately 58 years with traditional multiconfigurational photodynamics simulations. We generated training data by combining Wigner sampling, geometrical interpolations, and short-time quantum chemical trajectories to adaptively sample sparse data regions along reaction coordinates. The final data set of the cis-trans isomerization and the 4π-electrocyclic ring-closing model has 6207 and 6267 data points, respectively. The training errors in energy using feedforward neural networks achieved chemical accuracy (0.023-0.032 eV). The neural network photodynamics simulations of trans-hexafluoro-2-butene agree with the quantum chemical calculations showing the formation of the cis-product and reactive carbene intermediate. The neural network trajectories of the norbornyl cyclohexadiene corroborate the low-yielding syn-product, which was absent in the quantum chemical trajectories, and revealed subsequent thermal reactions in 1 ns.

Mechanochemical synthesis of an elusive fluorinated polyacetylene.

Polymer mechanochemistry has traditionally been employed to study the effects of mechanical force on chemical bonds within a polymer backbone or to generate force-responsive materials. It is under-exploited for the scalable synthesis of wholly new materials by chemically transforming the polymers, especially products inaccessible by other means. Here we utilize polymer mechanochemistry to synthesize a fluorinated polyacetylene, a long-sought-after air-stable polyacetylene that has eluded synthesis by conventional means. We construct the monomer in four chemical steps on gram scale, which involves a rapid incorporation of fluorine atoms in an exotic photochemical cascade whose mechanism and exquisite stereoselectivity were informed by computation. After polymerization, force activation by ultrasonication produces a gold-coloured, semiconducting fluoropolymer. This work demonstrates that polymer mechanochemistry is a valuable synthetic tool for accessing materials on a preparative scale.

Neck Injuries.

Neck injuries are relatively uncommon but have the potential to cause serious and permanent disability. In athletes, injuries are most common in contact sports, and occur with direct axial loading with a forward-flexed neck. Soft tissue and peripheral nerve injuries are typically minor and self-limiting, with excellent recovery potential and return to activities based on symptoms. Concern for devastating spinal cord injuries has led to routine immobilization using spine boards and hard cervical collars. This approach may provide more harm than benefit when applied universally, and a more commonsense protocol can be used to better address potential neck injuries.

Xenon Difluoride Mediated Fluorodecarboxylations for the Syntheses of Di- and Trifluoromethoxyarenes.

XeF2 is demonstrated to be a more proficient fluorine-transfer reagent than either NFSI or Selectfluor in fluorodecarboxylations of both mono- and difluoroaryloxy acetic acid derivatives. This method efficiently converts a wide range of neutral and electron-poor substrates to afford the desired di- and trifluoromethyl aryl ethers in good to excellent yields. The purifications are facile, and the reaction times are less than 5 min, which makes these fluorodecarboxylations promising for future PET-imaging applications.