The Versatile and Strategic O-Carbamate Directed Metalation Group in the Synthesis of Aromatic Molecules: An Update.

The aryl O-carbamate (ArOAm) group is among the strongest of the directed metalation groups (DMGs) in directed ortho metalation (DoM) chemistry, especially in the form Ar-OCONEt2. Since the last comprehensive review of metalation chemistry involving ArOAms (published more than 30 years ago), the field has expanded significantly. For example, it now encompasses new substrates, solvent systems, and metalating agents, while conditions have been developed enabling metalation of ArOAm to be conducted in a green and sustainable manner. The ArOAm group has also proven to be effective in the anionic ortho-Fries (AoF) rearrangement, Directed remote metalation (DreM), iterative DoM sequences, and DoM-halogen dance (HalD) synthetic strategies and has been transformed into a diverse range of functionalities and coupled with various groups through a range of cross-coupling (CC) strategies. Of ultimate value, the ArOAm group has demonstrated utility in the synthesis of a diverse range of bioactive and polycyclic aromatic compounds for various applications.

Probing Alzheimer's pathology: Exploring the next generation of FDDNP analogues for amyloid ß detection.

Fluorescent probes are a powerful tool for imaging amyloid ß (Aß) plaques, the hallmark of Alzheimer's disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aß fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aß- and Tau-aggregates. First, 1Ae had large Stokes shifts (138-213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aß fibrils in vitro (Kd = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aß1-42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aß plaques. The intermolecular interactions of fluorophores with Aß were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aß1-42 in cerebrospinal fluid or blood.

Towards structurally versatile mesoionic N-heterocyclic olefin ligands and their coordination to palladium, gold, and boron hydride.

We have developed an efficient and versatile approach for the synthesis of a family of 1,2,3-triazole-based mesoionic N-heterocyclic olefin (mNHO) ligands and investigated their coordination to palladium, gold, and boron hydride experimentally and computationally. We reacted mNHOs obtained through deprotonation of the corresponding methylated and ethylated 1,3,4-triaryl-1,2,3-triazolium salts with [Pd(allyl)Cl]2 to give the corresponding [Pd(η3-allyl)Cl(mNHO)] coordination complexes. 13C NMR data revealed the strong σ-donor character of the mNHO ligands, consistent with the calculated bond orders and atom-condensed charges. Furthermore, we also synthesized [AuCl(mNHO)] and a BH3-mNHO adduct by reacting the triazolium salts with AuCl(SMe2) and BH3·THF, respectively. The BH3-mNHO adduct was tested in the reduction of select aldehydes and ketones to alcohols.

CO2-responsive gels.

CO2-responsive materials undergo a change in chemical or physical properties in response to the introduction or removal of CO2. The use of CO2 as a stimulus is advantageous as it is abundant, benign, inexpensive, and it does not accumulate in a system. Many CO2-responsive materials have already been explored including polymers, latexes, surfactants, and catalysts. As a sub-set of CO2-responsive polymers, the study of CO2-responsive gels (insoluble, cross-linked polymers) is a unique discipline due to the unique set of changes in the gels brought about by CO2 such as swelling or a transformed morphology. In the past 15 years, CO2-responsive gels and self-assembled gels have been investigated for a variety of emerging potential applications, reported in 90 peer-reviewed publications. The two most widely exploited properties include the control of flow (fluids) via CO2-triggered aggregation and their capacity for reversible CO2 absorption-desorption, leading to applications in Enhanced Oil Recovery (EOR) and CO2 sequestration, respectively. In this paper, we review the preparation, properties, and applications of these CO2-responsive gels, broadly classified by particle size as nanogels, microgels, aerogels, and macrogels. We have included a section on CO2-induced self-assembled gels (including poly(ionic liquid) gels).

Efficacy of Drpitor1a, a Dynamin-Related Protein 1 inhibitor, in Pulmonary Arterial Hypertension.

Rationale: Dynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes pulmonary arterial hypertension (PAH). We developed a Drp1 inhibitor, Drpitor1a, and tested its ability to regress PAH. Objectives: Assess Drpitor1a's efficacy and toxicity in: a)normal and PAH human PASMC (hPASMC); b)normal rats versus rats with established monocrotaline (MCT)-induced PAH. Methods: Drpitor1a's effects on recombinant and endogenous Drp1-GTPase activity, mitochondrial fission, and cell proliferation were studied in hPASMCs (normal=3; PAH=5). Drpitor1a's pharmacokinetics and tissue concentrations were measured (n=3 rats/sex). In a pilot study (n=3-4/sex/dose), Drpitor1a (1mg/kg/48-hours, intravenous) reduced adverse PA remodeling only in females. Consequently, we compared Drpitor1a to vehicle in normal (n=6 versus 8) and MCT-PAH (n=9 and 11) females, respectively. Drpitor1a treatment began 17-days post-MCT with echocardiography and cardiac catheterization performed 28-29 days post-MCT. Results: Drpitor1a inhibited recombinant and endogenous Drp1 GTPase activity, which was increased in PAH hPASMC. Drpitor1a inhibited mitochondrial fission and proliferation and induced apoptosis, in PAH hPASMC but not normal hPASMC. Drpitor1a tissue levels were higher in female versus male RVs. In MCT-PAH females, Drpitor1a regressed PA obstruction, lowered pulmonary vascular resistance, and improved RV function, without hematologic, renal, or hepatic toxicity. Conclusions: Drpitor1a inhibits Drp1 GTPase, reduces mitochondrial fission, and inhibits cell proliferation in PAH hPASMC. Drpitor1a caused no toxicity in MCT-PAH and had no significant effect on normal rats or hPASMCs. Drpitor1a is a potential PAH therapeutic which displays an interesting therapeutic sexual dimorphism.

Deuterated Drugs and Biomarkers in the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially identified in Wuhan (China) in December 2019, COVID-19 rapidly spread globally, resulting in the COVID-19 pandemic. Carriers of the SARS-CoV-2 can experience symptoms ranging from mild to severe (or no symptoms whatsoever). Although vaccination provides extra immunity toward SARS-CoV-2, there has been an urgent need to develop treatments for COVID-19 to alleviate symptoms for carriers of the disease. In seeking a potential treatment, deuterated compounds have played a critical role either as therapeutic agents or as internal MS standards for studying the pharmacological properties of new drugs by quantifying the parent compounds and metabolites. We have identified >70 examples of deuterium-labeled compounds associated with treatment of COVID-19. Of these, we found 9 repurposed drugs and >20 novel drugs studied for potential therapeutic roles along with a total of 38 compounds (drugs, biomarkers, and lipids) explored as internal mass spectrometry standards. This review details the synthetic pathways and modes of action of these compounds (if known), and a brief analysis of each study.

Electrical Response of Poly(N-[3-(dimethylamino)Propyl] Methacrylamide) to CO2 at a Long Exposure Period.

Amine-functionalized polymers (AFPs) are able to react with carbon dioxide (CO2) and are therefore useful in CO2 capture and sensing. To develop AFP-based CO2 sensors, it is critical to examine their electrical responses to CO2 over long periods of time, so that the device can be used consistently for measuring CO2 concentration. To this end, we synthesized poly(N-[3-(dimethylamino)propyl] methacrylamide) (pDMAPMAm) by free radical polymerization and tested its ability to behave as a CO2-responsive polymer in a transducer. The electrical response of this polymer to CO2 upon long exposure times was measured in both the aqueous and solid phases. Direct current resistance measurement tests on pDMAPMAm films printed along with the silver electrodes in the presence of CO2 at various concentrations reveal a two-region electrical response. Upon continuous exposure to different CO2 flow rates (at a constant pressure of 0.2 MPa), the resistance first decreased over time, reaching a minimum, followed by a gradual increase with further exposure to CO2. A similar trend is observed when CO2 is introduced to an aqueous solution of pDMAPMAm. The in situ monitoring of pH suggests that the change in resistance of pDMAPMAm can be attributed to the protonation of tertiary amine groups in the presence of CO2. This two-region response of pDMAPMAm is based on a proton-hopping mechanism and a change in the number of free amines when pDMAPMAm is exposed to various levels of CO2.

Synthesis of [2 H5 ]baricitinib via [2 H5 ]ethanesulfonyl chloride.

Baricitinib, typically applied as a treatment for rheumatoid arthritis, has recently attracted the attention of clinicians and researchers as a potential treatment for COVID-19. Naturally, there has been a need for the preparation of the isotope-labelled analogue of baricitinib to probe the pharmacokinetics of baricitinib in this new role. As such, we have developed a simple synthetic route to deuterated [2 H5 ]baricitinib, facilitating its formation over four steps and in a 29% overall yield based on starting [2 H5 ]ethanethiol (19% if we start with [2 H5 ]bromoethane instead). A critical component of the overall process involves the synthesis of [2 H5 ]ethanesulfonyl chloride, and we describe in detail the two routes that were explored to optimize this step.

Directed ortho and Remote Metalation-Suzuki-Miyaura Cross Coupling Route to Azafluorenol Core Liquid Crystals.

Two new smectic C* mesogens containing a hexyloxy side chain and an azafluorenone (3a) or azafluorenol (3b) core were synthesized using a combined directed ortho metalation-directed remote metalation-Suzuki-Miyaura cross-coupling strategy. 3b was formed in 10 steps and 25% overall yield based on starting benzamide 1a. 3a forms a nematic phase, while 3b forms a smectic A phase. The large temperature range of the smectic phase for the azafluorenol 3b is indicative of mesophase stabilization by intermolecular hydrogen bonding between the hydroxyl group and pyridine nitrogen of neighboring 3b molecules.

Diffusion in Organic Film Stacks Containing Solution-Processed Phosphorescent Poly(dendrimer) Dopants.

Efficient organic light-emitting diodes (OLEDs) consist of an emissive layer comprising a blend of a light-emitting and host material in contact with one or more charge transporting layers. The distribution of the active material in the guest-host emissive layer blend and the changes that may occur upon thermal annealing are two important factors in determining the stability and efficiency of OLEDs. We have combined neutron reflectometry and photoluminescence measurements to investigate the structures of films comprising an emissive layer containing a phosphorescent poly(dendrimer) material blended with 4,4'-N,N'-di(carbazolyl)biphenyl. This combination has been shown to give rise to highly efficient OLEDs. Here, we show that the emissive poly(dendrimer) material was not uniformly distributed in the host, but formed a concentration gradient within the emissive layer. Upon heating, the adjacent electron transport layer was found to intermix with the emissive layer, accompanied by changes in the material distribution in the emissive layer. The intermixing of the materials led to a decrease in the photoluminescence from the poly(dendrimer) within the film. The decrease in the photoluminescence was ascribed to an increase in interchromophore interactions that could arise from a conformational change of the poly(dendrimer) or phase separation leading to aggregation. The results indicate that, while uniform mixing of the guest and host is not essential for efficiency, the thermal stabilities of both host and charge transport materials are important for device durability.

Directed Ortho and Remote Metalation of Naphthalene 1,8-Diamide: Complementing SEAr Reactivity for the Synthesis of Substituted Naphthalenes.

Mono- and dianion species of 1,8-naphthalene diamide 2 were generated under sec-BuLi/TMEDA conditions and trapped with a variety of electrophiles to give 2- and 2,7- substituted products 3 and 4. Using Suzuki-Miyaura cross-coupling, mono- and di-iodinated products were converted into the corresponding 2-aryl (5) and 2,7-diaryl (6) products, respectively. The amide-amide rotation barrier of 2 was established by VT NMR, and the structure of fluorenone structure 9, obtained by remote metalation, was secured.

Morphology of OLED Film Stacks Containing Solution-Processed Phosphorescent Dendrimers.

Organic light-emitting devices containing solution-processed emissive dendrimers can be highly efficient. The most efficient devices contain a blend of the light-emitting dendrimer in a host and one or more charge-transporting layers. Using neutron reflectometry measurements with in situ photoluminescence, we have investigated the structure of the as-formed film as well as the changes in film structure and dendrimer emission under thermal stress. It was found that the as-formed film stacks comprising poly(3,4-ethylenedioxythiophene):polystyrene sulfonate/host:dendrimer/1,3,5-tris(N-phenylbenzimidazol-2-yl)benzene (where the host was deuterated 4,4'-N,N'-di(carbazolyl)biphenyl or tris(4-carbazol-9-ylphenyl)amine, the host:dendrimer layer was solution-processed, and the 1,3,5-tris(N-phenylbenzimidazol-2-yl)benzene evaporated) had well-defined interfaces, indicating good wetting of each of the layers by the subsequently deposited layer. Upon thermal annealing, there was no change in the poly(3,4-ethylenedioxythiophene):polystyrene sulfonate/host:dendrimer interface, but once the temperature reached above the Tg of the host:dendrimer layer, it became a supercooled liquid into which 1,3,5-tris(N-phenylbenzimidazol-2-yl)benzene dissolved. When the film stacks were held at a temperature just above the onset of the diffusion process, they underwent an initial relatively fast diffusion process before reaching a quasi-stable state at that temperature.

Organic Photodiodes: The Future of Full Color Detection and Image Sensing.

Major growth in the image sensor market is largely as a result of the expansion of digital imaging into cameras, whether stand-alone or integrated within smart cellular phones or automotive vehicles. Applications in biomedicine, education, environmental monitoring, optical communications, pharmaceutics and machine vision are also driving the development of imaging technologies. Organic photodiodes (OPDs) are now being investigated for existing imaging technologies, as their properties make them interesting candidates for these applications. OPDs offer cheaper processing methods, devices that are light, flexible and compatible with large (or small) areas, and the ability to tune the photophysical and optoelectronic properties - both at a material and device level. Although the concept of OPDs has been around for some time, it is only relatively recently that significant progress has been made, with their performance now reaching the point that they are beginning to rival their inorganic counterparts in a number of performance criteria including the linear dynamic range, detectivity, and color selectivity. This review covers the progress made in the OPD field, describing their development as well as the challenges and opportunities.

Narrowband light detection via internal quantum efficiency manipulation of organic photodiodes.

Spectrally selective light detection is vital for full-colour and near-infrared (NIR) imaging and machine vision. This is not possible with traditional broadband-absorbing inorganic semiconductors without input filtering, and is yet to be achieved for narrowband absorbing organic semiconductors. We demonstrate the first sub-100 nm full-width-at-half-maximum visible-blind red and NIR photodetectors with state-of-the-art performance across critical response metrics. These devices are based on organic photodiodes with optically thick junctions. Paradoxically, we use broadband-absorbing organic semiconductors and utilize the electro-optical properties of the junction to create the narrowest NIR-band photoresponses yet demonstrated. In this context, these photodiodes outperform the encumbent technology (input filtered inorganic semiconductor diodes) and emerging technologies such as narrow absorber organic semiconductors or quantum nanocrystals. The design concept allows for response tuning and is generic for other spectral windows. Furthermore, it is material-agnostic and applicable to other disordered and polycrystalline semiconductors.