Nature Of Substituents Research Articles

Potential Induced Protonation of the Second Coordination Sphere in a Hangman-type Iron Porphyrin Complex Promotes HER: Insights via in Situ Raman Spectroelectrochemistry.

The iron-based porphyrin complex containing a bispyridine-based hanging unit termed Py2XPFe was previously used as an effective catalyst for the reduction of protons to molecular hydrogen in solution. Here, the molecular compound was immobilized on a modified gold electrode surface and investigated by spectroelectrochemical methods under catalytic conditions. Immobilization of the Py2XPFe was facilitated using a pyridine-based amine linker molecule grafted to the gold electrode by electrochemical amine oxidation. The linker molecule denoted in this report as Pyr-1 allows for effective coordination of the iron porphyrin compound to the modified gold surface through axial coordination of the pyridine component to the Fe center. Resonance Raman spectroelectrochemistry was performed on the immobilized catalyst in pH 7 buffer at increasing cathodic potentials. This facilitates the electrochemical hydrogen evolution reaction (HER) while concurrently allowing for the observation of the v4, v3, and v2 porphyrin marker bands, which are sensitive to oxidation and spin state changes at the metal center. The observed changes in these bands at decreasing potential indicate that the immobilized Py2XPFe exists in the formal high-spin FeIII state before being reduced to the low-spin FeII state resulting from axial interaction with the linker moiety. This FeII state likely acts as the precatalyst for the HER reaction. Surfaced enhanced Raman spectroelectrochemistry was also conducted on the system as the gold electrode provides a sufficient surface enhancement effect so as to observe the bonding nature of the pyridine substituents within the second coordination sphere. As the potential is lowered cathodically, the pyridine ring breathing modes at 999 cm-1 are shown to increase in intensity due to protonation, which reach an intensity saturated limit whereat HER is conducted. This suggests that in pH 7 buffer, the increase in cathodic potentials facilitates protonation of the pyridine-based second coordination sphere. The extent to which protonation occurs can be viewed as a function of decreasing potential due to an increase in proton flux at the immobilized catalyst which, at the required onset potential for catalysis, aids in the reduction of protons to molecular hydrogen.

Bromination of indazoles enhanced by organic-dye, visible-light photoredox catalysis

A variety of functionalized indazoles are brominated in moderate to excellent yields using N-bromosuccinimide (NBS) under visible-light activated conditions. A screening of organic dye catalysts resulted in the identification of rose bengal as the most efficient catalyst to use with NBS toward indazoles. According to mechanistic studies, the reaction is speculated to proceed via a single electron oxidation of NBS that amplifies the electrophilicity of the bromine atom, thus leading to enhanced reactivity as a brominating reagent. Differing intermediate indazole species have been observed depending upon the electronic nature of the indazole substituents. The indazole-containing pharmaceutical Benzydamine has been brominated in good yield using the optimized reaction conditions as a demonstration of the bromination method.

Microwave-Assisted Synthesis of E-Aldimines, N-Heterocycles, and H2 by Dehydrogenative Coupling of Benzyl Alcohol and Aniline Derivatives Using CoCl2 as a Catalyst.

The acceptorless dehydrogenative coupling (ADC) between alcohols and amines to produce imines has been achieved mostly by employing precious-metal-based complexes or complexes of earth-abundant metal ions with sensitive and complicated ligand systems as catalysts mostly under harsh reaction conditions. Methodologies using readily available earth-abundant metal salts as catalysts without the requirement of ligand, oxidant, or any external additives are not explored. We report an unprecedented microwave-assisted CoCl2-catalyzed acceptorless dehydrogenative coupling of benzyl alcohol and amine for the synthesis of E-aldimines, N-heterocycles, and H2 under mild condition, without any complicated exogenous ligand template, oxidant, or other additives. This environmentally benign methodology exhibits broad substrate scope (43 including 7 new products) with fair functional-group tolerance on the aniline ring. Detection of metal-associated intermediate by gas chromatography (GC) and HRMS, H2 detection by GC, and kinetic isotope effect reveal the mechanism of this CoCl2-catalyzed reaction to be via ADC. Furthermore, kinetic experiments and Hammett analysis with variation in the nature of substituents over the aniline ring reveal the insight into the reaction mechanism with different substituents.

Theoretical calculation of the adiabatic electron affinities of the monosubstituted benzaldehyde derivatives

In the current study, several computational models were examined to calculate accurate adiabatic electron affinity (AEA) of twelve m- and p-monosubstituted benzaldehyde derivatives. The examined models are as follows: (i) composite high-level ab initio (G3B3, G4, CBS-Q, and CBS-QB3), (ii) Three hybrid DFT approaches (B3LYP, CAM-B3LYP, and wB97XD) with two basis sets (6–31 + G(d,p) and 6–311++G(2df,2p)) and (iii) single point calculation using fifteen DFT approaches with 6–311++G(2df,2p) at the B3LYP/6–31 + G(d,p) geometry. Several statistical descriptors were computed to validate the calculated AEAs based on the available experimental results. Results revealed that G3B3 and CBS-QB3 are the most accurate result, while G4 and CBS-Q methods yield less accurate ones. Also, the wB97XD and CAM-B3LYP in combination with 6–311++G(2df,2p) able to calculate accurate AEAs. Low CPU time single point calculation strategy by using wb97 and wb97X approaches can compute AEAs value as accurately as G3B3 and CBS-QB3 methods. The AEAs of other several monosubstituted benzaldehydes were also predicted by using the wb97, wb97X, and wb97XD. The effect of the nature and position of substituents on the natural spin density and natural charge is also studied and discussed.

Development of the P-Arylation of Dithieno[3,2-b : 2',3'-d]phosphole with Aryl Iodonium Salts.

P-Arylation of dithieno[3,2-b : 2',3'-d]phosphole toward cationic phenyl phospholium species using diaryliodonium reagents was explored. Multiple conditions were tested to optimize the reaction, including variation of solvent, temperature, stoichiometry, time, and aryliodonium species employed. Initial use of diphenyliodonium chloride led to an unexpected dithienophosphole Cu(I) chloride complex that was characterized crystallographically. Alternatively, the use of diphenyliodonium hexafluorophosphate in ethanol under microwave conditions led to the successful isolation of the P-arylated target. The phenyl dithienophospholium species exhibits blue luminescence with a quantum yield of 100 % in solution that is considerably red-shifted in the solid state. The photophysics and solid-state organization of the new species were compared with those of a related methyl congener, showing distinct differences that are assigned to the nature of the carbon-based substituent at the phosphorus center, which was also confirmed by DFT calculations, and the supramolecular organization in the solid state.

Synthesis, spectroscopic, and structural studies of substituent effect on the solvatochromic, tautomeric, and halochromic behavior of 2-methylated arylazoquinoline dyes along with DFT calculations

Six methylated heteroarylazo quinoline dyes with different electron-withdrawing/donating substituents, namely 5-(4-substituted arylazo)-8-hydroxy-2-methyl quinoline dyes, were synthesized by coupling reaction and their chemical structures were elucidated by conventional spectroscopic methods. The photophysical properties of the dyes were examined and systematically compared in a range of solvents of various solvatochromic parameters and at various pH values through UV–Vis spectroscopy. 2-methylated arylazoquinoline dye (the unsubstituted dye) was prepared and chosen for comparison purposes. The dyes show different chromic behavior including tautomerism, solvatochromism, ionochromism, and halochromism. The chromic and azo/hydrazone tautomeric properties of the dyes were found to depend on the substituent nature, solvent polarity/polarizability, and the acidity/basicity of the solvent environment. The Kamlet-Abboud-Taft, Katritzky, and Catalán linear solvation energy relationships (LSER) were used to correlate the dye spectral data. The acid-base equilibria between neutral and anionic forms of the dyes were studied in buffer solutions in a range of pH 1.0–13.0 and the ionization constants,pKa, were determined. Finally, the DFT calculations on the studied compounds provide an overall supportive and complementary picture of the spectral measurements of representative structure of the azo model.

ProDOT-Based Polymers: From Energy Storage to Smart Window Applications

Nowadays, electroactive materials based on conjugated polymers for energy storage and electrochromic window applications attract large interest due to their low cost, accessible synthetic procedures, and interesting electrochemical properties. Herein, we report on the performance of two propylenedioxythiophene (ProDOT)-based polymers having varying length and functionality side chains, which were explored to assess their potential for these applications. The polymers were obtained by oxidative chemical polymerization and processed from organic solvents into thin coatings with different molecular assemblies. Preliminary studies on their chemical structure and optical and electrochemical characteristics were performed to evidence how these are influenced by the side chain substituent nature. When tested as electrode material in the three-electrode cell configuration, the synthesized ProDOT-based polymers provided the highest specific areal capacitance of 1.059 mF/cm2 at a scan rate of 10 mV/s and 0.538 mF/cm2 at 0.01 mA/cm2 in cyclic voltammetry and galvanostatic charge–discharge measurements, respectively. One of the polymers showed electrochromic response, with ultrafast color change from deep purple to highly transmissive green/blue. A coloration efficiency of 123 cm2/C and a maximum CE decay of 9.9% after 100 cycles was achieved for this material, which is also able to efficiently store electrical charge, thus demonstrating potential for use in energy storage smart window applications where the energy level can be estimated by simple visual observation.

Structural effects of benzene-centered tripodal diglycolamides on extraction of trivalent f-cations into a room temperature ionic liquid

A series of three benzene functionalized tripodal diglycolamide (DGA) extractants (abbreviated as Bz-T-DGA, and termed as LI, LII and LIII) were studied for their extraction abilities for Eu3+ and Am3+ ions. Extraction efficiencies of these ligands are distinctly dependent on: (i) the nature of alkyl substituents on amidic N atoms of DGA, (ii) alkyl chain length that connects the DGA moeties with the benzene ring, and (iii) the medium of extraction. Substitution of protons with iso-pentyl groups on DGA nitrogen atoms enhanced the ligand extraction efficiency many folds. At the same time, increasing the spacer atoms between the benzene platform and the DGA units reduced the ligand extraction efficiency. The distribution ratio of Eu3+ was higher than that of Am3+ with all the three ligands, but the separation factor between the two elements was less than 2. Solvent extraction mechanism was entirely different when the organic solvent changed from n-dodecane (a molecular solvent) to ionic liquid. DFT calculations revealed that the solvent extraction abilities of these ligands were primarily goverened by their complexation abilities for trivalent f-cations.

Spectrophotometric study of basic properties of glycosylated tetraphenylporphin derivatives

The paper presents the results of spectrophotometric study of the basic properties of glycosylated substituted derivatives of 5,10,15,20-tetraphenylporphyrin, namely 5-(4′- O -galactosylphenyl)-10,15,20-tris( N -methylpyridin-3-yl)porphine, 5,15-bis(4′- O -galactosylphenyl)-10,20-bis( N -methylpyridin-3-yl)porphine, 5,10,15,20-tetra( N -methylpyridin-3-yl)porphin, 5,10,15,20-tetra(4- O -galactosylphenyl)porphin. The basic properties of the studied ligands in acetonitrile at 298 K were studied by spectrophotometric method. The effect of glycosylated fragments, as constituents of a macromolecule, on protolytic equilibria during acid-base interactions of the ligand in basic media and the change in the reactivity of porphyrin ligands depending on the nature of the peripheral substituent was analyzed.

Protocol for structure determination of unknowns by EI mass spectrometry. II. Diagnostic ions in one ring alicyclic, heterocyclic, and aromatic compounds

Electron ionization (EI) mass spectra of saturated carbocyclic hydrocarbons containing a single ring with three or more members are discussed followed by the examination of their unsaturated analogs, including aromatic hydrocarbons. Mass spectrometry characteristics of heterocyclic compounds for each cycle size with one, two, three, and more hetero-atoms in a ring are considered along with their mono- and polyunsaturated analogs. An effect of the (a) size of a cycle; (b) number, nature, and location of elements in a ring; (c) position and nature of ring substituents; and (d) nature and location of unsaturation on the dissociation is revealed. Characteristic dissociation directions of these compounds and diagnostically important ions in their spectra are identified. Basic dissociation rules for alicyclic, heterocyclic, and aromatic compounds under EI are established for further use in the analysis of complex chemicals containing these structural elements.

The substituent effect on CW laser beam self-action manifestation under UV irradiation of azo-azomethine PMMA composites thin films

We report synthesis and study of E→Z→E photoswitching transformations of methyl-substituted azo-aldehyde and six novel corresponding azo-azomethines containing electron withdrawing/donating substituents in para-position to – CHN– bond, being analyzed by UV–Vis and 1H NMR spectroscopy techniques. Impact of donor/acceptor substituent nature on isomerization kinetics was studied in THF solutions by light activation at 390 nm. We obtained high optical quality of PMMA thin films doped with mentioned dyes. It was characterized with both angularly resolved optical elastic scattering data and nonlinear refractive/absorptive optical responses analysis via CW laser beam self-action effects manifestation at wavelength 532 nm. Pronounced self-focusing effect contribution was shown for electron donating substituents (-CH3, -OCH3) and self-defocusing one for electron withdrawing -NO2 group. UV irradiation at 254 nm provides switching from self-defocusing to self-focusing mode of -NO2 substituted dye-doped film with refractive nonlinear optical response efficiency Re(χ(3)) ≈10−2 esu on background of moderate photoinduced absorption effects manifestation.

Synthesis of Spirolactones and Functionalized Benzofurans via Addition of 3-Sulfonylphthalides to 2-Formylaryl Triflates and Conversion to Benzofuroisocoumarins.

A convenient protocol for the synthesis of spirobenzofuran-isobenzofurans and substituted benzofurans via a modified Hauser-Kraus reaction of 3-sulfonylphthalide with 2-formylaryl triflates is reported here. The initial reaction involved 1,2-addition of phthalide to the formyl group and intramolecular cyclization via substitution of triflate followed by a cascade of rearrangements leading to spirolactone or benzofuran derivatives. The electronic nature of substituents on aryl triflates affected the course and outcome of the reaction. The mechanism was supported by successful characterization of one of the intermediates by mass spectrometry. A medicinally relevant influenza virus type B inhibitor, benzofuroisocoumarin, was synthesized in a single step from the spiro compound, thus demonstrating the synthetic utility of our methodology.

Interaction of Copper(II) Complexes of Bidentate Benzaldehyde Nicotinic Acid Hydrazones with BSA: Spectrofluorimetric and Molecular Docking Approach.

Two copper(II) complexes of 4-chloro- and 4-dimethylaminobenzaldehyde nicotinic acid hydrazones were prepared and characterized by elemental analysis, mass spectrometry, infrared and electron spectroscopy and conductometry. These rare examples of bis(hydrazonato)copper(II) complexes are neutral complex species with copper(II) center coordinated with two monoanionic bidentate O,N-donor hydrazone ligands coordinated in enol-imine form. The interaction of hydrazone ligands and corresponding copper(II) complexes with CT DNA and BSA was investigated. Copper(II) complexes are slightly effective in binding the DNA than pristine hydrazones. The results indicate groove binding or moderate intercalation which are not significantly affected by the nature of substituent at hydrazone ligands. On contrary, affinities of two copper(II) complexes toward BSA significantly differs and depends on the nature of the substituent, however in absence of thermodynamic data difference in nature of binding forces cannot be excluded. The complex bearing electron-withdrawing 4-chloro substituent has larger affinity toward BSA compared to 4-dimethyamino analogue. These findings were theoretically supported by molecular docking study.

3D-QSAR, design, docking and in silico ADME studies of indole-glyoxylamides and indolyl oxoacetamides as potential pancreatic lipase inhibitors

The versatility of indole heterocyclic led to the understanding of their structural requirements to develop new potential derivatives. The indole derivatives estimated to be active against pancreatic lipase have been chosen to develop 3D-QSAR field and atom-based models, validated using the Schrodinger suite. Designing of new agents through QSAR based predictions and performing docking on these compounds helped in defining the binding pattern and pharmacophoric features like π–π stacking interactions, hydrogen bonding, and π-cation interactions with the amino acid residues. The protein-ligand complex displayed good binding energies. In silico ADMET properties have been generated using the Quick-prop module of the Schrodinger suite. The 3D-QSAR model is found to be statistically significant and evaluated using various parameters like R2, R2CV, stability, F-value, P-value, RMSE, Q2, and Pearson-r by PLS factor of 4. The field fractions and contour maps along with their visualizations have helped in inferring the essential nature and type of substituent that should be incorporated for a compound to display potent pancreatic lipase inhibitory activity. These deductions and evaluations of the synthesized compounds through the generation of models could be further utilized for designing new molecules rationally.

Computational design of the novel building blocks for the metal-organic frameworks based on the organic ligand protected Cu4 cluster

Abstract Metal-organic frameworks (MOFs) are tunable porous network compounds composed of inorganic nodes bound by various organic linkers. Here we report the density functional theory (DFT) study of the MOF novel building blocks made of the Cu4 clusters protected by four organic ligands having two phenyl rings and terminated either with Cl or Br atom (precursors 1 and 2, respectively). The research was performed both in the gas phase and with the implicit effects of acetonitrile included, with two functionals, B3LYP and PBE, both with and without the second-order dispersion correction. We analyzed the structural features of the precursors 1 and 2, their electronic structures, molecular electrostatic potential (MEP) distribution, and global reactivity parameters (GRPs). Both functionals resulted in the singlets of the precursors 1 and 2 as the most stable species. The precursor structures optimized with the hybrid functional were found to be quite similar for both halogens, both containing somewhat distorted from planarity Cu4 cluster, with the outer phenyls of the ligands rotated relative to the inner phenyls. With both halogens and both DFT approaches, the frontier molecular orbitals (FMOs) of the precursors 1 and 2 were shown to have quite similar compositions. The change of the substituent from Br to Cl was found to cause slight stabilizations or destabilizations of the HOMOs and LUMOs. The central parts and especially the inner phenyl ring parts of the precursors 1 and 2 were suggested to play a role of nucleophile in various chemical reactions due to the significant accumulation of negative electrostatic potential. Also, weak intermolecular interactions might exist between the ligands of neighboring precursor molecules. Finally, with both substituents the precursors 1 and 2 should be relatively unreactive and demonstrate thermodynamic stability. Further, the precursors 1 and 2 should be quite stable in oxidation reactions and more active in reduction processes. Generally, the substituent nature was shown not to affect significantly the reactivity of the precursors 1 and 2, as well as their other properties.

Halolactonization of N-Acyl-N-(2-cyclohex-1-en-1-yl-6-methylphenyl)glycines: Towards Production of 4,1-Benzoxazoheterocycles

AbstractA significant influence of the nature of the acyl substituent at the nitrogen atom on the direction of the reaction in the interaction of N-acyl-N-(2-cyclohex-1-en-1-yl-6-methylphenyl)glycines with bromine was found. In the case of the N-benzoyl derivative, along with benzoxazocinone, which is formed through the stages of pseudoallyl halogenation and subsequent lactonization due to the replacement of the bromine atom by the oxygen atom of the carboxyl group, a mixture of axially chiral isomers of spiro-fused 2′-bromocyclohexane-benzoxazepin-3-ones was also obtained. The aR*,R*,R*-isomer of benzoxazepinone, which initially is four times predominant in the reaction mixture, upon dissolution in deuterochloroform, slowly transforms into aS*-conformer until a ratio of 2:1 is established. In the case of the N-acetyl analogue of this glycine, the only heterocycle is the product of 7-exo-halogenlactonization, the benzoxazepinone spiro-fused with 2′-bromocyclohexane and an undetermined configuration of the axial chirality.

Boranes Paving the Way to Anionic Cyclic (Alkyl)(amino)carbenes (Ani-cAACs).

First examples of anionic cyclic (alkyl)(amino)carbenes (Ani-cAACs) that contain borane substituents have been synthesized. The nature of the borane substituents allows a modulation of the σ-donor or π-acceptor abilities compared to their neutral analogues. A B(CN)3 -substituted Ani-cAAC has been generated and used in situ. The corresponding C2 F5 BF2 -Ani-cAAC 6 was obtained in high yield on a multigram scale. First reactions of these novel ligands with elemental selenium and chloro(triphenylphosphine)gold(I) led to the anionic selenium adducts 7 and 8 and the Ani-cAAC gold complex 9. The properties of these compounds and data derived from theoretical calculations provide an insight into the electronic and steric properties of these novel anionic cAACs. Especially the ease of synthesis and the combination of properties such as negative charge, large buried volume, and good σ-donor and π-acceptor ability renders Ani-cAACs unique and promising new building blocks.

Impact of Internal Charge Transfer on the Photophysical Properties of Pyridine-Fused Phosphorus-Nitrogen Heterocycles.

The phosphaquinolinone scaffold has been previously studied as a modular core for a variety of fluorescent species where use of substituent effects has focused on increasing or decreasing electron density in the core rings. We now report the synthesis and analysis of several pyridine-containing phosphaquinolinone species exhibiting notable linear conjugation from the aryl-substituent to electron-withdrawing pyridyl nitrogen. Varying the nature of the aryl substituent from electron-withdrawing to electron-donating leads to the generation of an internal charge-transfer (ICT) band in the absorbance spectrum, which becomes the dominant absorbance in terms of intensity in the most electron-rich -NMe2 example. This heterocycle exhibits improved photophysical properties compared to others in the set including high quantum yield and considerably red-shifted emission. The enhanced ICT can be observed in the X-ray data where a rare example of molecule co-planarity is observed. Computational data show increased localization of negative charge on the pyridyl nitrogen as the electron-donating character of the aryl-substituent increases.

Dramatic effect of the nature of R on the intrinsic acidity and basicity of potential astrochemical R–C≡COH and R–C≡CSH compounds

The effect of changing the nature of the R substituent from the first row (H, Li, BeH, BH2, CH3, NH2, OH and F) to second row (Na, MgH, AlH2, SiH3, PH2, SH and Cl) on the intrinsic acidity and basicity of R–C≡COH and R–C≡CSH compounds was investigated through the use of G4 high-level ab initio calculation. The variation of the acidity and basicity of the R–C≡CSH derivatives as a function of R is practically parallel to that found for the corresponding R–C≡COH analogs; though the basicities of the former are 9–14% higher than those of the latter, the acidity gap being very small (~ 2%). When this analysis is extended to the derivatives in which the triple CC bond is replaced by a double or single bond, it is found that the acidity gap increases systematically as the CC bond goes from triple to single; whereas, as expected for the basicity, the trend is the opposite. Quite surprisingly, however, the variation of the basicity of R–C≡CX (X = OH, SH) compounds with the nature of the first-row substituents, R, is remarkably different from that produced by the second-row analogs. The same is observed as far as intrinsic acidities are concerned. These dissimilarities reflect the rather different changes in the strength of the CC and the CX (X = OH, SH) bonds when a first-row substituent is replaced by the second-row analog, as reflected in the atoms in molecules (AIM), natural bond orbital (NBO) and the electron localization function (ELF) analyses of the corresponding species.

Synthesis of New Shogaol Analogues as NRF2 Activators and Evaluation of Their Anti-Inflammatory Activity, Modes of Action and Metabolic Stability

6-shogaol is a natural and the most potent bioactive vanilloid in dried Zingiber officinale rhizomes. Many scientific studies have reported the diverse biological activities of 6-shogaol. However, the major drawback of 6-shogaol is its instability at room temperature. We synthesised new shogaol thiophene compounds (STCs) by replacing the pentyl group in the sidechain with thiophene derivatives. The STCs were tested for their nuclear factor erythroid 2-related factor 2 (NRF2) activation ability in murine hepatoma cells (Hepa1c1c-7) by determining their NAD(P)H quinone oxidoreductase 1 (NQO1) inducing ability and expression of NRF2-associated antioxidant genes. The anti-inflammatory activity of STCs was determined in Escherichia coli lipopolysaccharide (LPSEc)-stimulated NR2-proficient and -silenced mouse microglial cells (BV-2) by measuring the inflammatory markers, cytokines, and mediators. The modes of action (interacting with the Kelch domain of KEAP1, covalent bonding with cysteines of KEAP1, and inhibition of GSK-3β enzyme activity) of NRF2 activation by STCs were determined using commercially available kits. The in vitro metabolic stability of the STCs in liver microsomes (humans, rats, and mice) was also investigated. The molecular docking and molecular dynamics studies were conducted to identify the binding poses, stability, and molecular interactions of the STCs in the binding pockets of Kelch and BTB domains of KEAP1 and GSK-3β enzyme. The new STCs were synthesised in good yields of > 85%, with a purity of about 95%, using a novel synthesis method by employing a reusable proline-proline dipeptide catalyst. The STCs are more potent than 6-shogaol in activating NRF2 and reducing inflammation. The nature of substituents on thiophene has a profound influence on the bioactivity of the STCs. Phenylthiophene STC (STC5) is the most potent, while thiophenes containing electron-withdrawing groups showed weaker bioactivity. The bioactivity of 6-shogaol is in the micromolar range, whereas STC5 showed bioactivity in the sub micromolar range. The STCs showed anti-inflammatory effects via NRF2-dependent and NRF2-independent mechanisms. The STCs improved NRF2 activity through multiple (KEAP1-independent and -dependent) mechanisms. The STCs showed decreased reactivity with thiols than 6-shogaol and thus may possess fewer side-effects than 6-shogaol. The STCs were more metabolically stable than 6-shogaol.