Pseudocannabinoid H4CBD improves glucose response during advanced metabolic syndrome in OLETF rats independent of increase in insulin signaling proteins.

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.

Cannabidiol Does Not Impair Anabolic Signaling Following Eccentric Contractions in Rats.

Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle (n = 7) or 100 mg/kg CBD (n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group (p < .05). Simultaneously, anabolic signaling through ribosomal protein S6 kinase beta-1 (S6K1) (Thr389) increased after eccentric contractions in both groups with no difference between vehicle and CBD (p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation (p < .001) and tended to be higher in the CBD group (p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation (p = .6), but they were 46% greater in the CBD compared with the vehicle group (p = .01). Although liver weight did not differ between the groups (p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.

In Silico Design of Cylindrophanes: The Role of Functional Groups in a Fluoride Selective Host.

Molecular recognition is the key driver in the formation of supramolecular complexes, enabling the selective encapsulation of specific guests. Here, we explore the delicate balance between different energetic terms in the formation of an efficient host for fluoride anions based on a cylindrophane structure, which can be achieved by the incorporation of ligand sites into a cyanuric acid based cyclophane framework, resulting a close proximity between the ammonium hydrogens and the anion. This study describes the character and contribution of different energetic and repulsive terms that favor the efficient inclusion of fluoride. Our findings are useful for further rational design and synthesis of efficient and highly selective fluoride hosts, which have been generally less well described than complexing agents for other halides.

Butenolide Derivatives of Biobased Furans: Sustainable Synthetic Dyes.

The dye and pigment manufacturing industry is one of the most polluting in the world. Each year, over one million tons of petrochemical colorants are produced globally, the synthesis of which generates a large amount of waste. Naturally occurring, plant-based dyes, on the other hand, are resource intensive to produce (land, water, energy), and are generally less effective as colorants. Between these two extremes would be synthetic dyes that are fully sourced from biomass-derived intermediates. The present work describes the synthesis of such compounds, containing strong chromophores that lead to bright colors in the yellow to red region of the visible spectrum. The study was originally motivated by an early report of an unidentified halomethylfurfural derivative which resulted from hydrolysis in the presence of barium carbonate, now characterized as a butenolide of 5-(hydroxymethyl)furfural (HMF). The method has been generalized for the synthesis of dyes from other biobased platform molecules, and a mechanism is proposed.

New bio-based monomers: tuneable polyester properties using branched diols from biomass.

A family of monomers, including 2,5-hexandiol, 2,7-octandiol, 2,5-furandicarboxylic acid (FDCA), terephthalic acid (TA), and branched-chain adipic and pimelic acid derivatives, all find a common derivation in the biomass-derived platform molecule 5-(chloromethyl)furfural (CMF). The diol monomers, previously little known to polymer chemistry, have been combined with FDCA and TA derivatives to produce a range of novel polyesters. It is shown that the use of secondary diols leads to polymers with higher glass transition temperatures (Tg) than those prepared from their primary diol equivalents. Two methods of polymerisation were investigated, the first employing activation of the aromatic diacids via the corresponding diacid chlorides and the second using a transesterification procedure. Longer chain diols were found to be more reactive than the shorter chain alternatives, generally giving rise to higher molecular weight polymers, an effect shown to be most pronounced when using the transesterification route. Finally, novel diesters with high degrees of branching in their hydrocarbon chains are introduced as potential monomers for possible low surface energy materials applications.

A Zwitterionic, 10 π Aromatic Hemisphere.

A new concept in anionic 10 π aromaticity is described by the embedding of a compensating charge within an aromatic cyclononatetraenide ring by the symmetric superposition of an alkyl ammonium bridge. This is accomplished by the methylation of azatriquinacene to give a quaternary ammonium salt, followed by oxidation to the tetraene and final deprotonation. The resulting zwitterion is a stable [9]annulene with strong aromaticity as shown by its degree of C-C bond equalization and a nucleus-independent chemical shift value lower than that of benzene. The solid-state structure shows an eclipsed stacking motif with the electron-poor ammonium methyl groups occupying the electron-rich cavity of the aromatic bowl.

Chemical-catalytic approaches to the production of furfurals and levulinates from biomass.

The synthesis and chemistry of 5-(hydroxymethyl)furfural (HMF), 5-(chloromethyl)furfural (CMF), and levulinic acid (LA), three carbohydrate-derived platform molecules produced by the chemical-catalytic processing of lignocellulosic biomass, is reviewed. Starting from the historical derivation of these molecules and progressing through modern approaches to their production from biomass feedstocks, this review will then survey their principal derivative chemistries, with particular attention to aspects of commercial relevance, and discuss the relative merits of each molecule in the future of biorefining.

Top chemical opportunities from carbohydrate biomass: a chemist's view of the Biorefinery.

Cheap fossil oil resources are becoming depleted and crude oil prices are rising. In this context, alternatives to fossil fuel-derived carbon are examined in an effort to improve the security of carbon resources through the development of novel technologies for the production of chemicals, fuels, and materials from renewable feedstocks such as biomass. The general concept unifying the conversion processes for raw biomass is that of the biorefinery, which integrates biofuels with a selection of pivot points towards value-added chemical end products via so-called "platform chemicals". While the concept of biorefining is not new, now more than ever there is the motivation to investigate its true potential for the production of carbon-based products. A variety of renewable chemicals have been proposed by many research groups, many of them being categorized as drop-ins, while others are novel chemicals with the potential to displace petrochemicals across several markets. To be competitive with petrochemicals, carbohydrate-derived products should have advantageous chemical properties that can be profitably exploited, and/or their production should offer cost-effective benefits. The production of drop-ins will likely proceed in short term since the markets are familiar, while the commercial introduction of novel chemicals takes longer and demands more technological and marketing effort.Rather than describing elaborate catalytic routes and giving exhaustive lists of reactions, a large part of this review is devoted to creating a guideline for the selection of the most promising (platform) chemicals derived via chemical-catalytic reaction routes from lignocellulosic biomass. The major rationale behind our recommendations is a maximum conservation of functionality, alongside a high atom economy. Nature provides us with complex molecules like cellulose and hemicellulose, and it should be possible to transform them into chemical products while maintaining aspects of their original structure, rather than taking them completely apart only to put them back together again in a different order, or turning them into metabolites and CO2. Thus, rather than merely pursuing energy content as in the case of biofuels, the chemist sees atom efficiency, functional versatility, and reactivity as the key criteria for the successful valorization of biomass into chemicals.To guide the choice of renewable chemicals and their production, this review adopts the original van Krevelen plots and develops alternative diagrams by introducing a functionality parameter F and a functionality index F:C (rather than O:C). This index is more powerful than the O index to describe the importance of functional groups. Such plots are ideal to assess the effect of several reaction types on the overall functionality in biomass conversion. The atom economy is an additional arbitrator in the evaluation of the reaction types. The assessment is illustrated in detail for the case of carbohydrate resources, and about 25 chemicals, including drop-ins as well as novel chemicals, are selected.Most of these chemicals would be difficult to synthesize from petrochemicals feeds, and this highlights the unique potential of carbohydrates as feedstocks, but, importantly, the products should have a strong applied dimension in existing or rising markets. Ultimately, the production scales of those markets must be harmonized to the biomass availability and its collection and storage logistics.

Comment on Gao, W., et al. "Efficient one-pot synthesis of 5-chloromethyl-furfural (CMF) from carbohydrates in mild biphasic systems", Molecules 2013, 18, 7675-7685.

In a recent paper entitled "Efficient One-Pot Synthesis of 5-Chloromethyl-furfural (CMF) from Carbohydrates in Mild Biphasic Systems," published in Molecules [1], Gao and coworkers describe the use of a biphasic aq. HCl-H3PO4/CHCl3 reagent for the preparation of CMF from various feedstocks. The maximum yield (46.8%) was obtained from fructose by reaction at 45 °C for 20 h. While sucrose gave a similar yield, the same reaction with glucose and cellulose gave 7.3% and 7.8% yields, respectively. Remarkably, the same process applied to Kraft pulp and powdered wood samples gave between 16.0% and 31.4% CMF, based on sugar content. Looking to the Experimental section for insight into this unusual outcome, the statement, "the procedure of treating lignocellulose sample (Table 6) was almost the same as the carbohydrate, except adding the selected simple 1.0 mg each trial " [sic] appears, which is difficult to interpret.

Hydrodeoxygenation of the angelica lactone dimer, a cellulose-based feedstock: simple, high-yield synthesis of branched C7 -C10 gasoline-like hydrocarbons.

Dehydration of biomass-derived levulinic acid under solid acid catalysis and treatment of the resulting angelica lactone with catalytic K2 CO3 produces the angelica lactone dimer in excellent yield. This dimer serves as a novel feedstock for hydrodeoxygenation, which proceeds under relatively mild conditions with a combination of oxophilic metal and noble metal catalysts to yield branched C7 -C10 hydrocarbons in the gasoline volatility range. Considering that levulinic acid is available in >80 % conversion from raw biomass, a field-to-tank yield of drop-in, cellulosic gasoline of >60 % is possible.

Industrial Routes from Sugars and Biomass to CMF and other 5-(Halomethyl)furfurals.

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.

Extreme oxatriquinanes: structural characterization of α-oxyoxonium species with extraordinarily long carbon-oxygen bonds.

The first stable α-oxyoxonium species have been synthesized and characterized. Strong donation of nonbonding electrons on oxygen into the adjacent σ*(C-O(+)) orbital was predicted by modeling to result in unheard of carbon-oxygen bond lengths. The kinetic stability of the triquinane ring system provides a platform upon which to study these otherwise elusive species, which are evocative of intermediates on the acetalization reaction pathway. Crystallographic analysis of the α-hydroxy and α-methoxy oxatriquinane triflates reveals 1.658 and 1.619 Å C-O(+) bond lengths, respectively, the former of which is a new record for the C-O bond.

Extraordinary modes of bonding enabled by the triquinane framework.

Incorporation of triquinane ring systems into a macrobicyclic framework enables the stabilization of unusual bonding arrangements, including 3-center-2-electron cation, 3-center-3-electron radical, and 3-center-4-electron anion systems, linear divalent fluorine, triplet carbenes, record short C-C bonds, a powerful proton sponge effect, and oxadionium (R4O(2+)) ions. The means to stabilize and conceivably isolate such species derives from the rigid, convex nature of the triquinane ring system, as well as the substitution of positions adjacent to the bridgeheads atoms which would otherwise be vulnerable to elimination. The potential realization of hitherto undescribed bonding outcomes makes these macrocycles provocative synthetic targets.

Synthesis of N-substituted pyrido[4,3-d]pyrimidines for the large-scale production of self-assembled rosettes and nanotubes.

N-substituted pyrido[4,3-d]pyrimidines are heterocycles which exhibit the asymmetric hydrogen bonding codes of both guanine and cytosine at 60° angles to each other, such that the molecules self-organize unambiguously into a cyclic hexamer, assembled via 18 intermolecular hydrogen bonds. The synthesis is straightforward and can be concluded in six steps from the commercially available malononitrile dimer. X-ray crystallographic analysis of the supermacrocyclic structure shows an undulating disk with a ca. 10.5 Å cavity, the centers of which do not overlap sufficiently to describe a channel in the solid state. However, AFM, SEM, and TEM imaging in solution reveals the formation of 1D nanostructures in agreement with their self-assembly into rosette supermacrocycles, which then stack linearly to form rosette nanotubes.

Electrochemical Incorporation of Electrophiles into the Biomass-Derived Platform Molecule 5-(Chloromethyl)furfural.

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.

The R3O+···H+ hydrogen bond: toward a tetracoordinate oxadionium(2+) ion.

Oxatriquinanes are tricyclic oxonium ions which are known to possess remarkable solvolytic stability compared to simple alkyl oxonium salts. Their rigid, hemispherical structure presents an oxygen at the apex of three fused five-membered rings. While trivalent oxygen species like these have been well described in the literature, the ability of oxygen to enter into a fourth covalent bonding relationship has been visited in theory and suggested by the outcome of certain reactions conducted in superacidic media, but has never been established by the characterization of a stable, persistent R(3)OH(2+) or R(4)O(2+) ion. In this study, the nucleophilicity of the oxatriquinane oxygen was evaluated first by a series of protonation studies using the Brønsted superacid H(CHB(11)Cl(11)) both in the solid state and in liquid HCl solution. The interaction of the oxatriquinane oxygen with a bridging carbocation was also examined. A strong case could be made for the occurrence of hydrogen bonding between H(CHB(11)Cl(11)) and oxatriquinane using IR spectroscopy. Under the most forcing protonation conditions, the oxatriquinane ring is cleaved to give a bridged, dicationic, protonated tetrahydrofuran-carbenium ion.