Epilepsy affects over 70 million people worldwide, nearly 20% of whom experience pharmacoresistant forms, particularly in pediatric populations. Cannabidiol (CBD) shows promise for the treatment of neurological disorders, including refractory epilepsy, but its low potency necessitates high dosing, leading to side effects that include drowsiness, gastric issues, and potential hepatotoxicity. Regulatory barriers, high cost, abuse liability, and the poor sustainability of hemp cultivation are further drawbacks to CBD use. In an effort to circumvent these issues, a series of structurally related, synthetic “pseudocannabinoids” have been evaluated for antiseizure activity. A high-throughput zebrafish model was employed using pentylenetetrazole (PTZ) and strobing light stimuli to induce seizures, with drug efficacy assessed by automated behavioral analysis and whole-brain imaging. Several of the tested analogs significantly suppressed PTZ-induced seizures, with some outperforming CBD. Imaging revealed corresponding reductions in neural hyperactivity. This study highlights both the promise of safer, more effective cannabinoids for seizure mitigation and the potential of phenotypic, target-agnostic zebrafish screening as a powerful tool for drug discovery.

A novel methodology, Retrosynthetic Network Assessment (ReNA), has been developed to evaluate the environmental sustainability of fine chemical synthetic routes at early development stages. ReNA harnesses automative retrosynthesis tools to quantify a set of metrics that integrate green chemistry with life cycle thinking. A stepwise procedure is presented to construct retrosynthetic networks, tracing synthetic pathways back to a selection of 174 commodity chemicals. The retrosynthetic networks enable the calculation of new sustainability metrics that quantify the network complexity and the carbon footprint of commodity chemicals in the network. The use of averaged carbon footprint values for the commodity chemicals, derived through clustering techniques, is also explored. The method is demonstrated in a case study on the synthesis of rosefuran, an industrially important aroma chemical, for which seven published routes are compared. ReNA indicators are shown to be complementary to traditional green chemistry metrics, providing a more informed comparison of synthetic pathways and revealing optimization opportunities early in the innovation pipeline, at a stage where the detailed process data required for LCA are not yet available. ReNA is therefore intended as an early-stage screening tool that complements, rather than replaces, LCA.

Trialkyl oxonium salts are among the most powerful electrophiles known. They are immediately quenched by nucleophiles like alcohols and halide ions, and are therefore used in unreactive solvents and have non-nucleophilic counterions. Any proposal to incorporate a nucleophilic hydroxy substituent into a trialkyl oxonium species would thus be ill-considered, and pairing an R3O+ cation with an alkoxide counterion would be an abstract notion, at best. Here, we describe how these combinations are made possible within the context of the robust environment of the heterotriquinane ring system. A stable, C3 symmetric oxatriquinanetriol can be simply accessed by reaction of the tris-epoxide of 1,4,7-cyclononatriene with aqueous acid. The three OH groups of this hemispherical cation point into the endo space of the bowl and participate in strong intramolecular hydrogen bonding. A close balance in the dynamics of proton exchange between these hydroxy functions and amine bases is predicted by modeling. In practice, treatment of oxatriquinanetriol with the non-nucleophilic base 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base) leads to a zwitterionic oxonium alkoxide.

Sequential multilayer processing has become increasingly important for the fabrication of semiconducting polymer (SP) devices. For organic light-emitting diodes, photovoltaics (OPVs), and field-effect transistors (OECTs), reducing the energy gap between the transport layer in the SP and the electrode material is critical for optimized devices. Bulk heterojunctions in OPVs suffer from dark charge transport, while planar heterojunctions offer greater control and optimization of interfaces, enabling directional charge transport. Multilayer OPVs are also more mechanically and thermally stable with less dependence on processing conditions. Presented here is a method for preparing multilayers of SPs from solution using sequentially deposited molecular dopants to render the underlayer(s) insoluble. The SP film is temporarily cross-linked by the dopant. Next, a second SP film is deposited from solution. Finally, the doped conjugated polymer undergoes quantitative dedoping, resulting in the complete removal of the dopant from the bilayer. This multi-step processing method can be universally applied to unaltered SPs, resulting in unmixed planar heterojunctions between the SPs. Deposition of p/n, p/p, n/p, and n/n bilayers is demonstrated using multiple different molecular dopants and SPs. The ease, reliability, reproducibility, and materials universality of this processing method will make it valuable for organic electronics research.

The emerging significance of furan fatty acids (FuFAs) is explored at the intersection of food, chemistry, nutrition, and therapeutics. FuFAs, with a distinctive furan ring incorporated into fatty acyl chains, are minor yet bioactive constituents of dietary lipids known for their unique chemical properties. This review examines FuFA biosynthesis in various organisms, highlighting their occurrence in food products. We also address the challenges of FuFA instability, which influence their availability and impact on food science. The chemical synthesis of FuFAs is reviewed, paving the way for future animal and human studies. FuFAs exhibit potent antioxidant and anti-inflammatory effects, with growing evidence of their role in metabolic health. Recent research suggests that FuFAs may extend benefits beyond omega-3 fatty acids in promoting cardiovascular and metabolic health. By consolidating current knowledge and identifying gaps, this review sets the stage for future research to harness the therapeutic potential of FuFAs.

Furylogous active methylene compounds retain the ability to undergo Knoevenagel condensations with aromatic aldehydes, leading to highly conjugated molecules with strong chromophores. In this work, a doubly furylogous malonate diester derived from the renewable platform molecule 5-(chloromethyl)furfural is prepared and evaluated for carbon acidity by H-D exchange and computational modeling. Its Knoevenagel adducts with biomass-derived carbonyl compounds (furfurals, phenolic aldehydes) are delocalized, push-pull systems of 3-5 rings that have intense, bright colors from the yellow-to-red region of the spectrum. The dyeing performance and wash fastness of these novel bio-based colorants are found to be excellent.

Cardiovascular disease (CVD) remains the number one cause of death in the world, with an increasing prevalence in the United States. Metabolic Syndrome (MetS) is a precursor of CVD with its 6 cluster risk factors individually associated with redox imbalance. There is developing knowledge that cannabidiol analogs and pseudocannabinoids such as H2CBD have similar antioxidant properties like those in phytocannabinoids (CBD). Nonetheless, there is little understanding of the impact of CBD or its analogs on MetS related cardiac damage. To better comprehend these effects during early metabolic dysfunction, 15-weeks-old animals were assigned into three groups, (n=8/group): (1) lean-strain control, Long Evans Tokushima Otsuka (LETO) rats, (2) untreated, Otsuka Long Evans Tokushima Fatty (OLETF) rats, and (3) OLETF + H2CBD (200 mg/kg/day x 4 weeks). Our hypothesis is that continuous treatment with H2CBD during MetS reduces indicators of cardiac oxidation (NOX2 and NOX4) and injury (4-hydroxynonenal;4HNE and 3-nitrotyrosine; 3NT). After four-weeks, H2CBD decreased cardiac 4HNE and 3NT expression by 56% (p<0.05) compared to untreated OLETF, indicating that H2CBD reduced cardiac lipid peroxidation and tyrosine oxidation. Continued research on NOX2 and NOX4 will provide additional insight to the mechanisms by which CBD and its analogs modifies redox regulatory pathways. These findings highlight the potential of CBD and its analytes as an emerging therapeutic to mitigate MetS associated CVD. Center Medical Cannabis Research pilot Grant A21-0086 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

A light-induced cyclization via a radical spin-center shift process that results in the direct functionalization of the indole ring at the C4-position is developed into a practical method for the synthesis of medicinally active, ring-constrained tryptamine analogs. Amino acids were coupled to tryptamine and irradiated with UV light to produce a library of lactams bridging the C3- and C4-positions of the indole nucleus. An extension to this method is introduced that employs α-acetoxy- and α-lactone-substituted tryptamides. Using optimized conditions and these easily accessed precursors, C3- to C4-bridged indoles can now be produced in good to excellent yields, free of the C2-regioisomers that are often seen using α-halo tryptamide substrates. Due to the structural similarities of the reduced lactams (azocinoindoles) with known psychoactive tryptamines, their functional activation at the serotonin 5-HT2A receptor was investigated both in silico and in vitro. These azocinoindoles show both full and partial agonist 5-HT2A Gq activation efficacies and suppress the head-twitch response in vivo, suggesting they belong to an emerging class of nonhallucinogenic 5-HT2A agonists. The azocinoindole core and the synthetic advances described here that enable its structural diversification provide a valuable platform for serotonin receptor drug discovery.

Molecular doping of semiconducting polymers has emerged as a prominent research topic in the field of organic electronics, with new dopant molecules introduced regularly. FeCl3 has gained attention as a p-type dopant due to its low cost, availability, ability to dope high ionization energy copolymers, and its use as a dopant that can be used with anion exchange. Here, we use a combination of UV-vis-NIR spectroscopy, four-probe sheet resistance measurements, and X-ray absorption near-edge structure (XANES) spectroscopy to perform lifetime measurements to assess the stability of the doped polymers over time, which is crucial for evaluating the long-term performance and reliability of the doped films. We used gas chromatography-mass spectrometry (GCMS) to prove that FeCl3 can cause radical side reactions that damage the conjugated polymer backbone, leading to the degradation of the electronic properties. The rate of this degradation is orders of magnitude higher when the film is exposed to air. Anion exchange doping can reduce the [FeCl4](-) concentration, but does not necessarily improve the doping lifetime because anion exchange electrolytes can serve as coreactants for the degradation reaction. By comparison, doping with (2,3,5,6-tetrafluoro-2,5-cyclohexadiene-1,4-diylidene)dimalononitrile (F4TCNQ) as the reactive dopant results in lower initial conductivity, but the lifetime of the doped polymer is almost tripled as compared to that of FeCl3 doped polymer films. These findings highlight that the use of FeCl3 as a molecular dopant requires a cost-benefit analysis between higher initial doping levels and lower film stability.

Vaping cannabinoids in electronic (e)-cigarette devices is rapidly increasing in popularity, particularly among adolescents, although the chemistry affecting the composition of the vape aerosol is not well understood. This work investigates the formation of aerosol mass, bioactive hydroxyquinones, and harmful or potentially harmful carbonyls from the e-cigarette vaping of natural and synthetic cannabinoids e-liquids in propylene glycol and vegetable glycerin (PG/VG) solvent at a 50 mg/mL concentration in a commercial fourth-generation vaping device. The following cannabinoids were studied: cannabidiol (CBD), 8,9-dihydrocannabidiol (H2CBD), 1,2,8,9-tetrahydrocannabidiol (H4CBD), cannabigerol (CBG), and cannabidiolic acid (CBDA). Quantification of analytes was performed using liquid chromatography coupled to accurate mass spectrometry. The addition of cannabinoids significantly increased aerosol and carbonyl formation compared with the PG/VG solvent alone. All cannabinoids in the study formed hydroxyquinones during vaping (up to ∼1% mass conversion) except for CBDA, which primarily decarboxylated to CBD. Hydroxyquinone formation increased and carbonyl formation decreased, with a decreasing number of double bonds among CBD and its synthetic analogues (H2CBD and H4CBD). During the vaping process, ∼3-6% of the cannabinoid mass can be observed as carbonyls under the study conditions. Oxidation of the terpene moiety on the cannabinoids is proposed as a major contributor to carbonyl formation. CBD produced significantly higher concentrations of formaldehyde, acetaldehyde, acrolein, diacetyl, and methylglyoxal compared with the other cannabinoid samples. CBG produced significantly higher levels of acetone, methacrolein, and methylglyoxal. Conversion of CBD to tetrahydrocannabinol (THC) was not observed under the study conditions. The chemical mechanism basis for these observations is discussed. Compared with other modalities of use for CBD and other cannabinoids, vaping has the potential to adversely impact human health by producing harmful products during the heated aerosolization process.

Cardiovascular disease (CVD) is a leading cause of death globally and MetS is an associated precursor of CVD. Of the 6 known cluster factor conditions of MetS, obesity, and poor glucose tolerance are known to contribute to high lipid peroxidation, which can contribute to the generation of damaging free radical species and a pro-oxidant system. Cannabidiol (CBD) is a known antioxidant and a growing understanding of CBD analogs and pseudocannabinoids, like H4CBD, implicate similar antioxidant effects. However, little is known about the effects of CBD analogs on MetS-associated cardiac tissue damage. To better understand these effects during extreme metabolic dysfunction, 41-weeks-old animals were assigned into three groups, (n=8/group): (1) one-lean-strain control, Long Evans Tokushima Otsuka (LETO), (2) untreated OLETF, and (3) OLETF + H4CBD (200 mg/kg/day x 4 weeks). Our hypothesis focuses on the prospect that ongoing treatment with H4CBD in a MetS model using Otsuka Long-Evans Tokushima Fatty (OLETF) rats will reduce indicators of lipid peroxidation including 4-hydroxynonenal (4HNE), a toxic end product of lipid peroxidation. After the 4-week treatment, cardiac tissue was analyzed for 4-hydroxynonenal (4HNE) protein expression. We found that H4CBD decreased cardiac 4HNE protein expression in treated OLETF rats by 68% (p<0.05) compared to OLETF control, which indicates H4CBD attenuated cardiac lipid peroxidation overall. Although the 4-week treatment of H4CBD was not suffcient to ameliorate MetS-associated hypertension, the reduction of 4HNE suggests that the attenuation of cardiac damage is independent of arterial pressure. These data indicate that H4CBD and its derivatives hold promise for therapeutic use in managing CVD and related metabolic syndrome-associated pathologies. Undergraduate Research Training Initiative for Student Enhancement (U-RISE), Center for Medical Cannabis Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cannabidiol (CBD) use has grown exponentially more popular in the last two decades, particularly among older adults (>55 yr), though very little is known about the effects of CBD use during age-associated metabolic dysfunction. In addition, synthetic analogues of CBD have generated great interest because they can offer a chemically pure product, which is free of plant-associated contaminants. To assess the effects of a synthetic analogue of CBD (H4CBD) on advanced metabolic dysfunction, a cohort of 41-wk-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered 200 mg H4CBD/kg by oral gavage for 4 wk. Animals were fed ad libitum and monitored alongside vehicle-treated OLETF and Long-Evans Tokushima Otsuka (LETO) rats, the lean-strain controls. An oral glucose-tolerance test (oGTT) was performed after 4 wk of treatment. When compared with vehicle-treated, OLETF rats, H4CBD decreased body mass (BM) by 15%, which was attributed to a significant loss in abdominal fat. H4CBD reduced glucose response (AUCglucose) by 29% (P < 0.001) and insulin resistance index (IRI) by 25% (P < 0.05) compared with OLETF rats. However, H4CBD did not statically reduce fasting blood glucose or plasma insulin, despite compensatory increases in skeletal muscle native insulin receptor (IR) protein expression (54%; P < 0.05). H4CBD reduced circulating adiponectin (40%; P < 0.05) and leptin (47%; P < 0.05) and increased ghrelin (75%; P < 0.01) compared with OLETF. Taken together, a chronic, high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of the profound loss of visceral adiposity.NEW & NOTEWORTHY Cannabis product use has grown in the last two decades despite the lack of research on Cannabidiol (CBD)-mediated effects on metabolism. Here, we provide seminal data on CBD effects during age-associated metabolic dysfunction. We gave 41-wk-old OLETF rats 200 mg H4CBD/kg by mouth for 4 wk and noted a high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of loss of visceral adiposity.

The synthesis of 5-(halomethyl)furfurals (XMFs, X=F, Cl, Br, I), including 5-(chloromethyl)furfural (CMF), 5-(bromomethyl)furfural (BMF), 5-(iodomethyl)furfural (IMF), and 5-(fluoromethyl)furfural (FMF), from biomass represents a pivotal advancement in renewable chemistry and engineering. Harnessing waste biomass as a raw material offers a sustainable alternative to fossil-based resources, mitigating environmental degradation and addressing pressing energy needs. CMF and BMF, characterized by their enhanced stability over the hydroxyl analog, 5-(hydroxymethyl)furfural (HMF), exhibit promise as renewable building blocks for scale-up and commercialization. The surge in research interest, particularly from 2010 to 2024, reflects a growing recognition of XMFs' potential as novel platform chemicals. This review highlights the evolution of XMF synthesis methods, focusing on their transformation from saccharides and lignocellulosic biomass. Mechanistic insights and experimental setups are scrutinized for industrial feasibility and scalability, shedding light on technical challenges and avenues for further research. The analysis underscores the burgeoning significance of XMFs in the transition towards sustainable chemical production, emphasizing the importance of process optimization and mechanistic understanding for commercial deployment.

Highly branched alkanes and cycloalkanes are produced via electrochemical processing of the renewable platform molecule mesityl oxide, which is a dimer of biogenic acetone. The final product is a sustainable, drop-in jet fuel.

The chemistry of furylogous malonic and cyanoacetic esters prepared from 5-(chloromethyl)furfural (CMF), a highly versatile biobased platform molecule, was investigated. Hydrogen isotope exchange data and computational results show a significant degree of remote methylene activation by the furylogy effect. The installation of strong chromophores using Knoevenagel chemistry with natural aldehydes leads to a series of biobased synthetic colorants in good to excellent yields. Fabric dyeing tests showed their potential to serve as alternatives to petrochemical dyes in the textile industry.

The 5-(chloromethyl)furfural (CMF) derivative ethyl 5-(chloromethyl)furan-2-carboxylate undergoes two-electron electrochemical reduction in a simple, undivided cell to give the corresponding furylogous enolate anion, which can either be quenched with carbon dioxide to give a 5-(carboxymethyl)furan-2-carboxylate or with hydrogen ion to give a 5-methylfuran-2-carboxylate, thereby expanding the derivative scope of CMF as a biobased platform molecule.

Conjugated polymers are sequentially doped to control film conductivity and optical properties. (1) Carrier fractions (measured via optical absorbance), (2) polymer site densities, and (3) dopant volumes are used to calculate polaron densities.

While reports of innovations in the production of cellulose nanocrystals (CNCs) are common, strategies for dispersing CNCs in various media, on which many practical applications depend, are limited. Although the suspension of surface-modified cellulose nanoparticles in water and other media has been described, dispersion of native CNCs in common solvents is challenging. Here, we show that trifluoroacetic acid, a volatile liquid which is miscible both with water and organic solvents, can be used to prepare metastable, turbid suspensions of native CNCs that clarify and stabilize over the course of several hours. These suspensions were characterized by imaging (TEM/AFM), thermal analysis (TGA), spectroscopic analysis (FT-IR and NMR), and evolution of crystallinity (XRD). Composite films could be made from these suspensions and waste poly(ethylene terephthalate) (PET) by simple evaporation of the TFA medium and subsequent washing with water. These films were observed to be hydrophilic and porous, and were characterized by SEM and porosimetry.

Molecular doping of conjugated polymers causes bleaching of the neutral absorbance and results in new polaron absorbance transitions in the mid and near infrared. Here, the concentration dependent changes in the spectra for a series of molecularly doped diketopyrrolopyrrole (DPP) co‐polymers with a series of ultra‐high electron affinity cyanotrimethylenecyclopropane‐based dopants is analyzed. With these strong dopants the polaron mole fraction (Θ) reaches saturation. Analysis of the full spectrum enables separation of neutral and polaron signals and quantification of the polaron mole fraction using a simple noninteracting site model. The peak ratios for both neutral and polaron peaks change systematically with increasing polaron mole fraction for all measured polymers. Analysis of the spectral changes indicates that the polaron mole fraction can be quantified to within 5%. While the total change in the absorbance spectrum with increasing polaron mole fraction is linear, the lowest energy polaron peak (P1) grows nonlinearly, which indicates increased polarization/delocalization. Molecular doping of polymers that form either H‐ or J‐aggregates shows systematically different spectral changes in the vibronic peak ratios of the neutral spectra and provides insights into the polymer configuration at undoped sites in the film.