Plasma and urine levels of the potent vasodilator Ang-(1–7) are elevated in mid and late pregnancy and are correlated with elevated placental angiogenesis, fetal blood flow, and rapid fetal growth. We hypothesized that Ang-(1–7), its receptor (Mas1) and the enzymes involved in Ang-(1–7) production  are down regulated in response to glucocorticoid administration contributing to IUGR.n = 6/group). The gene and protein expression of ACE2, MME, Ang-(1–7) and Mas1 receptor in the placental labyrinth (LZ) and basal zones (BZ) were studied. Pregnant female Sprague–Dawley rats were injected with dexamethasone  starting from 14 day gestation (dg) till sacrifice at 19 or 21 dg while control groups were injected with saline (p < 0.001). IUGR, as shown by decreased fetal weights, was evident in DEX treated rats at 21 dg (p < 0.01). ACE2 gene expression was elevated in the LZ of control placentas at 21 dg (p < 0.01) compared to 19 dg and DEX prevented this rise at both gene (p < 0.01) and protein levels (p < 0.05). In addition, Ang-(1–7) protein expression in LZ was significantly reduced in DEX treated rats at 21 dg (p < 0.05). On the other hand, Mas1 and MME were upregulated in LZ at 21 dg in both groups .DEX administration caused a reduction in LZ weight at 19 and 21 dg (The results of this study indicate that a reduced expression of ACE2 and Ang-(1–7) in the placenta by DEX treatment may be responsible for IUGR and consequent disease programming later in life. Administration of glucocorticoids (Betamethasone and/or Dexamethasone) to pregnant women endangered by premature labor is a standard clinical procedure beneficial in terms of maturation of fetal lungs and prevention of serious fetal respiratory problems –4. DespiIn rats, the placenta consists of two discrete zones that differ in both function and morphology; the basal and labyrinth zones. The basal zone is the site of placental hormone production during mid to late pregnancy  with botThe renin angiotensin system (RAS) has various homeostatic functions in the body including control of body sodium and water content and vascular smooth muscle tone. The functions of RAS are achieved through the balance between two main functional peptides the vasoconstrictor Angiotensin II (Ang II) and the vasodilator Angiotensin 1–7 (Ang-(1–7)) as well as the abundance of their receptors; Ang II type 1 and type 2 receptors (AT1 and AT2) and Ang-(1–7) Mas1 receptor  and its receptor Mas1 has not been studied yet in rat placenta and the association with IUGR, if any, is to be identified. We hypothesize that ACE2, MME, Ang-(1–7) and its receptor (Mas1) may be down regulated in response to glucocorticoid administration contributing to reduced blood flow and supply of nutrients to the fetus ultimately resulting in IUGR development and programming of diseases later in life.n = 12) received a daily intraperitoneal (i.p.) injection of dexamethasone (0.4 mg/kg) dissolved in saline from 14 days gestation (dg) until 21 dg. The control group of pregnant rats (n = 12) received daily i.p. injections of the vehicle  on the same gestational days.All procedures used in this study were approved by the Animal Welfare Committee at Kuwait University Health Sciences Center. Male and female Sprague Dawley rats were mated overnight. A vaginal smear was taken the following day and presence of sperm confirmed pregnancy (day 0). Pregnant rats were then housed individually in Plexiglas cages undisturbed until dexamethasone injection regimen. Half the number of pregnant rats (n = 6) and 21 dg (n = 6). Fetuses and placentae were detached and weighed. The placenta was further dissected into the basal and labyrinth zones and samples were snap frozen in liquid nitrogen and subsequently stored at −70 °C. Detection of ACE2, Mas1 and MME mRNAs and ACE2, Ang-(1–7), Mas1 and MME proteins was performed using real time PCR (Ret-PCR) and Western blotting followed by immunodetection, respectively.Pregnant dams were sacrificed by cervical dislocation on 19  and stored at −70 °C . RNA conAll samples were DNase treated before reverse transcription as previously described . DNase-tThe ReT-PCR reaction was run in duplicates in MicroAmp optical 96-well reaction plates . The reaction mix included the following: 12.5 μl of 2× Taqman universal master mix , 1.25 μl target gene primer set , 1.25 μl reference gene primer set (B-actin) in addition to 1 μl of the sample cDNA and the final volume was brought to 25 μl with distilled deionized water. The plate was sealed and cycled in a 7500 ReT-PCR system (Applied Biosystems) as follows: 1 cycle of 2 min at 50 °C; 1 cycle of 10 min at 95 °C, followed by 60 cycles each consists of 15 s at 95 °C to denature the DNA strands and 1 min at 60 °C to allow primer annealing and extension. The gene expression of Ang-(1–7) was not studied because no specific primers exist for Ang-(1–7) as all angiotensin peptides are formed from one common inactive precursor peptide which is angiotensinogen. Studying the gene expression of angiotensinogen does not give a direct conclusion about Ang-(1–7) expression.Protein expression of ACE2, Ang-1–7), Mas1 and MME was studied using Western blotting followed by immunodetection. Placental basal and labyrinth zones were homogenized in ice-cold homogenization buffer containing glycerol and protease inhibitors. Protein concentration was estimated using Versa max microplate reader at a wave length of 562 nm. Loading buffer was added to samples (60 μg protein loaded) and rainbow marker . Tubes were boiled for 5 min, then cooled on ice and centrifuged for 1 min. Electrophoresis was performed using SDS-PAGE gel . Protein was transferred from the gels to PVDF membranes at a stable current of 300 mA overnight at 4 °C. The efficiency of transfer was confirmed by staining the gel with Coomassie blue stain. After transfer was confirmed, membranes were blocked for 1 h at room temperature with 10% non-fat dry milk in TBS-T. They were rinsed twice with TBS-T then washed 2 times for 10 min. The primary antibody  followed by least significant difference (LSD) post hoc analysis using SPSS software as described earlier . A “p” vp < 0.001), however, weights were significantly lower (p < 0.001) at 21 dg in the DEX group compared to control  and labyrinth (p < 0.01) weights in the DEX group compared to the control group at both 19 dg and 21 dg  and only showed significant difference between the control and experimental group at 19 dg  were significantly lower in the DEX group compared to the control group at 21 dg  and Mas1 receptor in the rat placental zones. This study shows that maternal dexamethasone treatment leads to IUGR and reduces the levels of ACE2 and Ang-(1–7) in the rat labyrinth zone in late pregnancy. These findings suggest that a correlation exists between glucocorticoid treatment, ACE2 and Ang-(1–7) levels in the placental labyrinth zone and impaired fetal growth.Our findings confirm the role of Ang-(1–7) in normal pregnancy as the expression of its receptor Mas1 and the enzymes involved in its production (ACE2 and MME) were significantly elevated in control rats at 21 dg. This result is consistent with previous findings , 34, 35 Our results showed that ACE2 and Ang-(1–7) were not expressed in the maternal side of the placenta  late in pregnancy despite their abundance in the fetal side (labyrinth zone). This result is consistent with the previous studies in rats  36] and and36] aDysregulation of the components of the renin angiotensin system was previously reported in pathological pregnancies. In preeclampsia, lower plasma levels of Ang-(1–7) and persistent elevation of plasma Ang II levels were reported possibly causing vasoconstriction resulting in the high blood pressure in preeclamptic subjects . In addiAlthough glucocorticoid administration prevented the rise in Ang-(1–7) and ACE2 levels in the placental labyrinth zone at late gestation (21dg), to our surprise, the protein expression of MME and Mas1 receptor was significantly elevated in the DEX-treated rats. The increase in MME expression may suggest an elevation in the alternative pathway to compensate for the reduced production of Ang-(1–7) through the major production pathway (ACE2 pathway). Similarly, a normal consequence of the reduced ligand availability is the up-regulation of the receptors to enhance the sensitivity of the receptors to the ligand. Therefore, Mas1 receptors were up-regulated in the glucocorticoid treated rats at late gestation but how significant was this increase in terms of reducing the degree of IUGR is a question that cannot be answered by the experimental settings of the current study.This study is the first to find an association between the administration of glucocorticoids and alterations of ACE2 and Ang-(1–7) levels in the labyrinth zone of the placenta in late pregnancy. These results suggest that the drop in ACE2 and/or Ang-(1–7) production may be responsible for a reduced placental blood flow prompting the fetus to compromised nutrient supply and eventually growth restriction.This study opens a wide area of research to further explore the molecular pathways involved in the regulation of placental blood flow in glucocorticoid treated mothers. To confirm the role of ACE2/Ang-(1–7)/Mas1 receptor axis in fetal growth and development, Mas1 receptor antagonists and ACE2 inhibitors could be used. This research may also support the postulated therapeutic role of ACE2/Ang-(1–7)/Mas1 receptor axis where recombinant ACE2, Ang-(1–7) analogue (AVE0991) and the Mas1 receptor agonist (CGEN-856S) may be used alongside with glucocorticoids to recover blood flow and prevent IUGR.


Autophagy is a conserved self‐eating process that delivers cytoplasmic material to the lysosome to allow degradation of intracellular components, including soluble, unfolded and aggregated proteins, damaged organelles, and invading microorganisms. Autophagy provides a homeostatic control mechanism and is essential for balancing sources of energy in response to nutrient stress. Autophagic dysfunction or dysregulation has been implicated in several human pathologies, including cancer and neurodegeneration, and its modulation has substantial potential as a therapeutic strategy. Given the relevant clinical and therapeutic implications of autophagy, there is emerging intense interest in the identification of the key factors regulating the components of the autophagic machinery. Various post‐translational modifications, including ubiquitylation, have been implicated in autophagy control. The list of the E3 ubiquitin protein ligases involved in the regulation of several steps of the autophagic process is continuously growing. In this review, we will focus on recent advances in the understanding of the role of the homologous to the E6AP carboxyl terminus‐type E3 ubiquitin ligases in autophagy control. AMBRA1activating molecule in BECLIN 1‐regulated autophagy protein 1AMLacute myeloid leukemiaATGautophagy‐related proteinsBH3Bcl‐2 homology 3 domainCDLcullin‐dependent ligaseE1E1 activating enzymeE2E2 conjugating enzymeE3E3 ubiquitin ligaseERendoplasmic reticulumHECThomologous to the E6AP carboxyl terminusLC3microtubule‐associated protein light‐chain 3 proteinLIRLC3‐interacting regionLmL. monocytogenesMFN2mitofusin 2MtbM. tuberculosismTORC1mammalian target of rapamycin complex 1NBR1neighbor of BRCA1 geneNEDD4neural precursor cell expressed developmentally down‐regulated protein 4OPTNoptineurinPEphosphatidylethanolaminePI3Pphosphatidylinositol‐3‐phosphatePtdIns3Kclass‐III phosphatidylinositol 3‐kinaseRDLregulator of chromosome condensation 1 (RCC1)‐like domainRINGreally interesting new geneSMURFsSmad ubiquitin regulatory factorsSPRYSPRY/B30.2 domainSQSTM 1sequestosome 1TRIMTRIpartit motifUBAubiquitin‐associated domainULK1Unc‐51‐like kinase 1UPSubiquitin/proteasome systemUVRAGUV resistance‐associated geneWD40W‐D repeat domainWWEWWE domainWWP1WW domain‐containing E3 ubiquitin protein ligase 11et al., et al., et al., et al., Ubiquitylation is an ATP‐dependent and reversible enzymatic process that involves the covalent attachment of the conserved polypeptide ubiquitin to target proteins and is highly relevant in a number of physiological and pathological processes  that can become acceptors of another ubiquitin moiety in subsequent rounds of ubiquitylation, eventually leading to the generation of different types of polyubiquitin chains  is the major intracellular protein degradation pathway in all eukaryotes. It is responsible for turnover of short‐lived proteins and for the disposal of misfolded proteins. However, ubiquitin does not always signal for protein degradation, but it also controls a number of biological processes such as transcription, enzymatic activation, chromatin remodeling, subcellular relocalization, intracellular trafficking, and DNA repair.2The HECT E3s (28 known enzymes in human) are endowed with intrinsic enzymatic activity. They employ a catalytic Cys residue located in the HECT domain as an acceptor of ubiquitin from E2s. After loading activated ubiquitin on themselves through the formation of a ubiquitin‐thioester catalytic intermediate, they transfer ubiquitin to a Lys residue in the target protein. HECT E3s recruit substrates through specific protein–protein interaction module within the N‐terminal region, but they can require accessory or adaptor proteins for substrate recognition.et al., +2‐dependent binding domain that mediates the interactions of the C2‐WW‐HECT E3s with phospholipids, inositol phosphate and proteins. As a result, these enzymes are targeted to membrane compartments, including plasma membrane, Golgi apparatus, endosomes, and lysosomes ‐like domains (RLDs) for substrate recruitment ‐HECT enzymes that contain neither RLDs nor WW domains and recruit substrates through various number and types of protein interacting modules Fig. .et al., et al., et al., Different HECTs display distinct chain type specificities. They can indeed generate K6, K11, K27, K29, K33, K48, and K63 linkages , damaged organelles , or invading microorganisms (xenophagy) for degradation.Macroautophagy, hereafter termed autophagy, is a highly conserved intracellular catabolic pathway in which cytoplasmic constituents are engulfed by double‐membrane vesicles and subsequently delivered to lysosomes for degradation  proteins, which assemble into four functional complexes that are recruited to autophagy membrane compartments and work in sequential order to deliver the cytosolic cargo to the lysosomes  complex  to recruit targets into autophagosomes for selective autophagy . Clomipramine efficiently blocks ITCH auto‐ubiquitylation, as well as the modification of its protein substrates. Clomipramine displays some general degree of specificity for other HECT E3s, but it does not inhibit RING‐type E3s. Interestingly, this compound interferes with the autophagic flux blocking the degradation of autophagic cargo  is a large E3 (482‐kDa) belonging to the SI(ngle)‐HECT subgroup , HECT E3s act as autophagy inducers. Current evidence indicates that HECT E3s are mainly involved in the early steps of the autophagy response. Their activities converge toward the regulation of autophagy initiation, nucleation of the phagophore, autophagosome formation, and cargo recruitment in selective autophagy. Autophagy initiation is regulated through the inhibition of mTORC1 by NEDD4‐1, though the underlying molecular mechanism has not been elucidated yet. Phagophore formation regulation is achieved as a result of UVRAG ubiquitylation by SMURF1 that, ultimately, enhances PIK3 activity, and via NEDD4‐1‐mediated modification and stabilization of BECLIN 1. Cargo selection and autophagosome building are regulated by SMURF1 that catalyzes the addition of polyubiquitin chains to bacterial‐associated structures to direct them to LC3. NEDD4‐1 also promotes these steps through p62 ubiquitylation. An example of negative regulation of autophagy by HECT E3s is provided by HUWE1. This enzyme is involved in the ubiquitin‐mediated degradation of the effector protein WIPI2 that is relevant to restrain the intensity of basal autophagy. Furthermore, WWP1 prevents autophagy possibly by interfering with the formation of autophagosomes, though the substrates mediating its function have not been identified yet.et al., 2014; Watt et al., et al., Further exploring the contribution of HECT‐type E3s in autophagy regulation will implement our understanding of the autophagic process. Few inhibitors of the HECT enzymes have been reported to display cytotoxic activities against cancer cells or to increase the response of tumor cells to conventional therapies (Rossi The authors declare no conflict of interest.All authors contributed in writing the manuscript, read, edited, and approved the final manuscript.


The dielectric spectroscopy confirms, that the electrical conductivity and polarization processes are associated with the mobility of electrons in the structure of ferrite. It was concluded, that the both, high frequency complex dielectric permittivity as well as complex magnetic permeability are strongly temperature and frequency dependent. The AC electrical conductivity is associated with quantum mechanical tunneling of electrons and related to the transfer of charge carriers between Fe2+ and Fe3+ ions. Moreover, the microwave absorption properties were determined. The best microwave absorption properties have been confirmed in the frequency range 1.9 to 2.1 GHz for a layer which is 0.8–1 cm thick. For this range, reflection loss (RL) is lower than −25 dB and shielding effectiveness (SE) lower than −50 dB.The new Fe Recently, HEOs were tested in different applications, especially in electronics according to their dielectric properties. Sekar et al. has pointed out, that the HEOs can be used for reversible energy storage2. According to the studies of Berardan et al., there is possibility of insertion of Li-ions in the structure of HEOs, allowing to obtain material with high ionic conductivity i.e. approximately 10−3 S cm−1 3. The rare-earth-based HEOs can be used as absorbers of light from the entire visible spectrum. The optical properties are closely related to the presence of multivalent praseodymium, whereas crystal structure and phase purity is controlled by cerium. Moreover, the influence of chemical composition and entropy on magnetic properties was recently described4. Different types of HEOs such as transition-metal-based HEOs, rare-earth-based HEOs and mixed HEOs were synthesized and tested until now. The stabilization of entropy in oxides leads to the formation of single-phase structures within 5 or more cations in equiatomic concentration. Several compositions and elemental combinations allowed to synthesize HEOs with different crystal structures, such as rocksalt, fluorite and perovskite6.High entropy oxides (HEOs) are a new group of materials developed in 20152+1-γFe3+γ)8[Me2+γFe3+2-γ]8O2−32. The magnetite crystalizes in inverse cubic spinel structure, in which Fe3+ ions occupy tetrahedral and octahedral sites, whereas Fe2+ ions only octahedral sites. The introduction of different Me2+ and Me3+ ions in the structure of magnetite is well known and described in the literature. Moreover, the introduced Me2+ ions can occupy tetrahedral and/or octahedral sites unlike the Fe2+ ions8. This introduces the disorder into the structure, which in consequence leads to the altered magnetic and dielectric properties of ferrites12. These properties are relevant to the application of ferrites in microwave industry, magnetic recording, catalysts, sensors, drug delivery and magnetic resonance imaging16. Many of ferrites nanoparticles and hybrid systems with metal nanoparticles were recently developed and tested as biomarkers, magneto-plasmonic materials and catalysts19. The introduction of different chemical elements in the spinel structure changes magnetic, optical and electric properties. According to that, the application of them also changes. For example, R. Sharma et al. tested the influence of the introduction of different ions into magnetite structure on the photocatalytic activity in the degradation of organic pollutants. They confirmed, that the introduction of Cu2+ ions increases significantly rate of degradation reaction in comparison with CoFe2O4 NPs20. Moreover, it was confirmed, that the addition of cobalt and other ions such as Zn2+, Mn2+ and Ni2+ changes the magnetic properties of ferrites such as anisotropy, coercivity, Curie temperature, and saturation magnetization. The modulation of these properties can allow synthesizing materials, which can be used in a wide range of medical applications such as drug delivery, biosensors, magnetic hyperthermia and magnetic resonance imaging21. Interestingly, some of the introduced ions can react with other nanoparticles deposited on the surface of ferrites. For example, the synthesis of gold nanoparticles on the surface of CuFe2O4 nanoparticles can results not only in formation of Au/CuFe2O4 but also with alloying of Au by Cu19. According to that, the introduction of different ions simultaneously can result in formation of nanoparticles with unique multifunctional properties.The ferrites belong to group of inorganic materials with spinel or inverse spinel structure. The cation distribution in a unit cell of spinel can be generally expressed by the formula: (Me2O4) by Cr3+ ions caused the increase of resistivity of material22. The microwave absorption properties of ferrites are associated with synergetic effect of magnetic and dielectric loss. The influence of the chemical composition of (Nix−y1−CoxZny)Fe2O4 spinel ferrites on the electromagnetic interference (EMI) shielding properties was described by Xie et al.23. They reported, that the best microwave absorber at 8.64–11.2 GHz frequency band is the (Ni0.407Co0.207Zn0.386)Fe2O4 and absorbing frequency band is strongly related to the chemical composition of ferrites.The addition of different chemical elements changes the electric, dielectric and microwave absorption properties of ferrites. For example, doping cobalt ferrites 3O4 oxide with Fd-3m single phase can be synthesized by sintering of compressed sample prepared from milled oxides at 1050 °C by 20 h.The possibility of synthesis of high entropy oxide with spinel structure was previously confirmed by Dąbrowa 2+ ions. High entropy oxide was synthesized using a low-temperature two-step method. According to our knowledge, such method was not reported earlier to synthesis of HEOx. Dielectric measurements of Fe2O4 high entropy ferrite allowed us to determine its electrical conduction mechanism and microwave absorption properties. Moreover, in the literature many results indicate that the different nanoparticles and nanocomposites can be used as EMI shielding materials in GHz region28. However, the results are presented usually for very high frequencies (>10 GHz) and at room temperature. For example, it was confirmed, that the Mn0.7Zn0.3Fe2O4 and Ni0.7Zn0.3Fe2O4 nanoparticles have very good absorption properties around 10.4 GHz29. In present study EMI shielding properties were examined in RF frequency range from 100 MHz to 2.1 GHz and in broad temperature range (233–343 K) in order to determine possibility of using the Fe2O4 high entropy ferrite as radio-frequency shielding agent.The aim of this study was to develop and study high entropy ferrite (HEF) in which entropy is being stabilized in tetrahedral and octahedral sites by only Me2O4 high entropy ferrite (HEF) was synthesized in two-step process. Firstly, the amorphous precursor was synthesized by simple co-precipitation method. For this purpose 40 mmol of FeCl3 and 4 mmol of FeSO4·7 H2O, ZnSO4·7 H2O, NiSO4·7 H2O, Mg(NO3)2·6 H2O and Cd(NO3)2·4 H2O of salts were added into 100 ml of deionized (DI) water. In a separate beaker, 100 ml of 2 M NaOH water solution was prepared. Afterwards, under continuous stirring NaOH solution was added to the salt solution. Finally, additional 100 ml of DI water was added to the sample and the precipitate was then aged by 72 h at ambient temperature. The precipitate was filtered using hardened quantitative filter paper and washed by DI water, ethanol and acetone. The powder was dried at 333 K. The amorphous precursor was then annealed at 793 K by 2 h.The Fe2O4 HEF were verified using X-ray diffraction method (XRD). The powder XRD patterns were recorded at ambient temperature using X-ray diffractometer Rigaku MiniFlex 600 with a copper tube Cu Kα (λ = 0.15406 nm), a tube voltage of 40 kV, and a current of 15 mA, using a D/teX Ultra silicon strip detector. The crystal structure of synthesized HEF was analysed and displayed using the Rigaku PDXL software suite. Energy-dispersive X-ray (EDX) spectra, EDX maps, electron microscope images and selected area electron diffraction (SAED) patterns were obtained using a transmission electron microscope S/TEM TITAN 80–300. The images were collected in scanning transmission electron microscopy (STEM) and transmission electron microscopy (TEM) modes. The sample was prepared by redispersion of HEF in ethanol and placed on the lacey carbon films on copper TEM grid (200 mesh). The electronic structure of the sample was examined by X-ray photoelectron spectroscopy method (XPS) with used to Prevac/VGScienta R3000 photoelectron spectrometer. Monochromatic AlKα x-ray radiation (hν = 1486.6 eV) was used to obtain the photoelectron spectra of O1s, C1s, Fe2p, Cd3d, Zn2p, Ni2p3/2 and Mg1s of the core levels with 100 Pass Energy and 0.100 step of parameters. All photoelectron spectra were calibrated against the peaks of Au 4f7/2 at 83.98 eV, Ag 3d5/2 at 368.27 eV and Cu 2p3/2 at 932.67 eV of binding energy. The positions of measured photoemission lines were calibrated to C1s binding energy at 285 eV. The shape of the photoelectron lines was analyzed using the Multipak program  from Physical Electronics. Dielectric and magnetic permeability measurements were performed using the Concept 81 dielectric spectrometer, equipped with an Alpha and Keysight 4991E analysers and the Novo-cool temperature control system. Complex dielectric permittivity was measured for compressed samples with a diameter of 10 mm and thickness of 1.29 mm  in broad frequency range from 5•10−2 to 1*106 Hz using Alpha analyzer and in high frequency range (1*108–2.1*109 Hz) using Keysight analyzer. Low frequency measurements (5*10−2–1*106 Hz) were performed in broad temperature range 173–363 K (ΔT = 10 K) in order to determine dielectric properties and electric conduction mechanism. High frequency measurements (1*108–2.1*109 Hz) were performed in temperature range from 233 to 343 K (ΔT = 5 K) in order to determine high frequency dielectric properties and EMI shielding properties. High frequency complex permeability was measured in the same frequency and temperature range for toroidal samples with outer diameter of 20.1 mm, inner diameter of 6.63 mm and ring height of 1.76 mm prepared by compression with p = 30 bar.The amorphous state of synthesized precursor as well as crystal structure of the Fe0.1 Fe2Ni0.5O4Zn0.4 ferrite structure  with the lattice parameters a = b = c = 0.845 nm and α = β = γ = 90°. The average crystallite size was calculated on the basis of Halder-Wagner method, in which broadening of diffraction peaks is related to the ultrafine size of crystallites and also to the microstrain in their structure30. The crystallite size (D) and strain (ε) are related to the full-width at half maximum (FWHM) according to the equations31:λ is the wavelength of X-ray and θ is the diffraction angle. On the assumption that the Lorentzian and Gaussian components of β* are due to the size and strain, Eq. 2 vs FWHM/(tanθsinθ) plot  and imaginary (ε″) part of permittivity are presented in Fig. ε′ diagram, there is a relaxation process visible in the whole measured temperature range. Taking into account the type of material, this relaxation process can be identified as grain boundaries polarization. In the dielectric loss diagram the same process is hardly visible as it is covered by the conductivity. At elevated temperatures, additional electrode polarization phenomenon is visible at low frequencies in the ε′ diagram. It is related to the accumulation of charge carriers on the sample-electrode interface. Both processes in low frequency region i.e. electrode and grain boundaries polarizations can be identified as Maxwell-Wagner type polarization38. In the low frequency region diffusion or hopping of charges accumulated on grain interfaces requires much more energy than hopping/tunneling in high frequency region39. The polarization in ferrites is related to the conduction process discussed later in this study. The electron exchange between Fe2+ and Fe3+ ions causes local displacement of charge and in consequence the polarization of structure. Moreover, at higher frequencies these movements of charge carriers can lead to formation of small or large polarons42. The role of grains and grain boundaries in these processes can also be described by analysis of complex electric modulus (M*) defined as43:M′ and M″ are the real and imaginary part of complex electric modulus, respectively.In order to determine dielectric properties of FeM′ is equal to 0, which is associated with short-range mobility of charge carriers and electrode polarization. The dispersion of M′ value in high frequencies is associated with long-range charge mobility. The conductivity relaxation can be monitored by imaginary part of electric modulus M″(f)  Fig. . The peatanδ in low frequency region is very high, which can be associated with leaky capacitive nature of high entropy ferrite. Also in lower frequencies, the high value of dielectric loss can be related to impurities, crystal defects and moisture.Additionally, in Fig. σ*) was determined on the basis of measured complex permittivity (Eq. σAC) was further analyzed Fe2O4 HEF in a wide range of frequencies. In high frequency region conductivity mechanism is based on hopping or tunneling of charge carriers, while in low frequencies with slow motion of charge carriers. At low frequencies σAC is almost constant. This frequency dependence of electrical conductivity can be satisfactorily described by Koop’s phenomenological theory45, where conducting grains are surrounded by dielectric grain boundaries46. AC electrical conductivity originated from charge hopping can be described by universal power law and expressed as:A is the characteristic parameter, f is the frequency, s is the exponent dependent on temperature and frequency with values in the range from 0 for ideal ionic-type crystals to 1 for ideal Debye dielectric dipolar-type crystals and σDC is the DC electrical conductivity.Figure σAC follows the universal power law only in low frequencies and the maximum limit value of frequency in which universal power law can be used increases with increasing temperature. This behavior in high frequency range can be described by nearly constant-loss (NCL) regime and was observed and described previously in literature47. The NCL arises entirely from vibrating ions confined in cages by potential barriers. The σDC is associated with diffusion of charge carriers. In higher frequencies Jonscher’s regime occurs and the conductivity is associated with local hopping, while in very high frequencies, unharmonic vibrations might occur48. This observation can be successfully used to describe the electrical conductivity in Fe2O4 HEF. The region without fit presented in Fig. 49. In lower frequencies there is a region of Jonscher’s regime, in which electrical conductivity can be characterized by s(T) function. The analysis presented in Fig. 2O4 HEF has been previously used to describe electrical conductivity for different ferrites and magnetite nanoparticles51. It was found that for a high entropy ferrite, exponent s is almost independent of temperature, therefore the model of quantum-mechanical tunneling (QMT) of charged carriers between localized states near the fermi level can be applied to describe frequency dependent AC conductivity in analyzed temperature range. The tunneling of charge carriers was observed for the first time by Pollak and Geballe52. It was stated previously, that for chalcogenide glasses at low temperatures, QMT model, instead of correlated barrier hopping model has to be applied in order to properly describe σAC(f) relation53. The same relationship can occur in high entropy ferrites at low temperatures. In this case this behavior can be associated with difficulties of electron hopping. This electron hopping is associated with existence of Fe3+ and Fe2+ ions in ferrite structure55. Hosseinpour et al. has stated, that in ferrites the main process of electrical conductivity has two equilibrium reactions56. The first one is associated with electron transfer between Fe ions in octahedral site:In Fig. The second one is related to the electron hopping between ions of other metals in octahedral site:2O4 HEF different ions can occupy octahedral and tetrahedral site. According to the8 the Fe2+, Mg2+, Ni2+ and Cd2+ ions most likely occupies octahedral sites, whereas Zn2+ and Fe3+ the tetrahedral sites. Moreover, as was presented in Fig. 44. In low frequencies and at high temperatures the plateau region associated with conductivity by grain boundaries and related to the σDC occurs. Increasing conductivity with temperature is related to the increasing electron mobility. The value of DC electrical conductivity can be obtained from the universal power law. Moreover, the activation energy (EDC) of process associated with σDC can be calculated according to the Arrhenius law:kB is the Boltzmann constant, T is the temperature and σ0 is the pre- exponential factor. The results of analysis are presented in Fig. EDC obtained for Ni0.6Cu0.4Fe2O4 ferrite (0.43 eV)57. Moreover, this value is also similar to the activation energy calculated from relaxation times Feimes Eq.  extracteeak Fig. , 0.43 eV2O4 high entropy ferrite in these applications their complex permittivity and complex permeability in high radio frequency range were measured and presented in Fig. 58. The nearly constant values of ε′ in wide frequency range can be associated with the fact that the interfacial and dipolar polarizations play important role at lower frequencies (according to the Koop’s theory), whereas in higher frequencies, especially in GHz region, changes Fe2O4 HEF) can be associated with polarization of defects. Moreover, the changes in real part of permittivity with increasing temperature are minor . The changes in the value of dielectric losses (imaginary part of permittivity) are more noticeable. However in higher frequencies the value of ε″ is weakly dependent on temperature, which can be associated with polarization of defects presented in structure of high entropy ferrite. The same relationship is visible for the loss tangent tanδε Fe2O4 HEF as absorber of RF and microwave radiation.The ferrites and nanoferrites can find application in high frequency range, for example as RF and microwave filters, microwave absorbers and antenna magneto-dielectric substrates. This is associated with their dielectric and magnetic properties. In order to determine the possibility of using of Fenδε Fig. . The preRL) and shielding effectiveness (SE) were calculated in wide frequency and temperature range60Γ is the reflection coefficient, T is the transmission coefficient, ε′ and ε″ are the real and imaginary parts of complex electric permittivity, μ′ and μ″ are the real and imaginary parts of complex magnetic permeability, f is the frequency of electromagnetic radiation, c is the speed of light and d is the absorber thickness.To determine electromagnetic interference shielding properties two key factors: reflection loss (d) (from 1 mm to 5 cm) and temperatures (from 233 to 343 K). The analysis results are presented in Fig. RL > 80% and RL > 90%. The area with RL > 90% is the effective bandwidth, in which RL < −10 dB and correspond to the effective absorber thickness i.e. thickness of layer of Fe2O4 HEF, which can be used to absorb RF and microwave radiation. As can be seen in Fig. SE is negative, therefore interaction of electromagnetic wave with material results in the absorption and dissipation of that energy as heat. The RL < −10 dB for all tested absorber thicknesses can be observed mostly in GHz region. For the absorber thickness in the range from 2 to 2.5 cm the same RL can be achieved even at 0.9 GHz. It is well known fact, that the absorption of RF radiation is more difficult than of microwave radiation, but equally important. Therefore RL < −7dB was also marked in the same 2D contour plot. As can be seen in Fig. RL < −7dB contour line reaches 600 MHz frequency, however minimal thickness of absorber is in this case 3.3 cm. At the same frequency region SE is lower than −10 dB, therefore RL is associated with absorption of RF radiation. The analysis of Fig. RL < −25 dB and SE < −50 dB. The temperature dependence on the electromagnetic interference shielding properties has not been well described in the literature, however temperature is a very important parameter affecting the dielectric and magnetic properties of materials. The temperature dependent EMI shielding properties were described for Ti3AlC2 ceramics, graphene nanosheet reinforced alumina ceramics and CVI-SiCf/BN/SiC composites63. Figure 2O4 HEF. As can be seen the influence of temperature on the frequency range in which tested material can be characterized by good absorption properties is minor. For example RL < −10 dB can be observed from 1.5 to 1.6 GHz in the range from 233 K to 343 K. The most significant differences can be seen in the peak value of RL (RLmin). The peak value of RL is observed close to 1.9 GHz for studied temperature range. By comparison of RL for f = 1.9 GHz and d = 1 cm following values have been obtained: RL = −25.6 dB at 278 K, RL = −18 dB at 233 K, RL = –31.2 dB at 298 K and RL = −19.4 dB at 343 K. As one can see the impact of temperature on peak value of RL is significant. The similar results can be observed for shielding effectiveness. For the same absorber parameters  and at the same temperatures  SE is equal to −40.7 dB, −56.3 dB, −67.5 dB, −43.1 dB, respectively. The presented results indicate that the Fe2O4 HEF can be used as microwave absorber in L and S-band and even at lower frequencies of UHF band.The analysis was performed for different absorber thicknesses Fe2O4 high entropy ferrite were described in detail. Electrical polarization in Fe2O4 high entropy ferrite was related to the electron transfer between Fe2+ and Fe3+ ions and the dispersion of real part of permittivity and real part of electric modulus were associated with two different mechanisms: short- and long-range mobility of charge carriers. It was noted, that for high entropy ferrite with random distribution of different ions in tetrahedral site electron hopping cannot occur and quantum-mechanical tunneling of charged carriers between localized states appears, which is manifested by low electrical conductivity. The observed short-range mobility in high frequencies was related to the tunneling of electrons between Fe2+ and Fe3+ ions whereas the long-range mobility was associated with diffusion of charge carriers through grain boundaries. The AC electrical conductivity was described by three different regimes: DC electrical conductivity in low frequencies, Jonscher’s regime in high frequency region and nearly-constant loss arising entirely from vibrating ions confined in potential barrier cages in highest frequencies. The activation energy of DC electrical conductivity for Fe2O4 high entropy ferrite was equal to 0.43 eV and it was similar to activation energy determined from M″ peak (0.44 eV). The high frequency complex permittivity and permeability were strongly temperature dependent. The peak value of RL i.e. RLmin depends strongly on temperature. For example, absorber with d = 1 cm at f = 1.9 GHz has RL = −25.6 dB at T = 278 K, while RL = −18 dB at T = 233 K, RL = −31.2 dB at T = 298 K and RL = −19.4 dB at T = 343 K. The highest microwave absorption properties can be obtained for layer with thickness from 1 to 0.8 cm at 1.9 to 2.1 GHz, respectively. For this range RL < −25 dB and SE < −50 dB. The low value of real part of permeability and high value of magnetic losses at high frequency region can be associated with grain boundaries, small particle size and chemical inhomogeneity.In this study synthesis, structure and properties of Fe


The roles of p62‐Keap1‐Nrf2 pathway in the radioresistance of esophageal squamous cell carcinoma (ESCC) have not yet been revealed. This study aimed to clarify the expression and correlation of p‐p62 and nuclear Nrf2 and their association with radioresistance in ESCC.This study included 164 cases of inoperable locally advanced ESCC. All patients received concurrent chemoradiotherapy (CCRT). Immunohistochemical staining was used to detect the expression of p‐p62 and nuclear Nrf2. The results were analyzed independently by two pathologists.There was no significant relationship between p‐p62 or nuclear Nrf2 and patients' clinical characteristics. Compared to patients with low expression of p‐p62, patients with high expression of p‐p62 showed lower objective response rate (ORR). Similarly, patients with high expression of nuclear Nrf2 exhibited lower ORR compared to those with low expression of nuclear Nrf2. The expression of p‐p62 was positively correlated with that of nuclear Nrf2. Moreover, the correlation coefficient between them was higher among patients showing no response to CCRT. Univariate analysis revealed that higher expression of p‐p62 or nuclear Nrf2 was significantly associated with poorer PFS and OS. Multivariate analysis indicated that the expression of nuclear Nrf2 and treatment response were independent prognostic factors for PFS. Sex, treatment response, expression of p‐p62 and nuclear Nrf2 were independent prognostic factors for OS.Higher expression of p‐p62 and nuclear Nrf2 are associated with lower ORR as well as poorer prognosis, which indicates that p62‐Keap1‐Nrf2 pathway might play an essential role in the radioresistance of ESCC.The expression of p‐p62 and nuclear Nrf2 in ESCC show a significant relationship with patients' responses to CCRT and influence the prognosis of ESCC.p62‐Keap1‐Nrf2 pathway might be a new target for radiosensitization in ESCC. Esophageal cancer is one of the malignancies with the highest incidence and mortality rates worldwide. In China, esophageal squamous cell carcinoma (ESCC) is the most common pathological type. Because the symptoms of early ESCC lack specificities, most patients are in locally advanced or metastatic stage when they are initially diagnosed. Concurrent chemoradiotherapy (CCRT) is the standard therapy for inoperable locally advanced ESCC. Although CCRT shows a considerable response rate,Kelch‐like ECH‐associated protein 1 (Keap1)‐ nuclear factor erythroid 2 related factor 2 (Nrf2)‐antioxidant response element (ARE) pathway is one of the important signal pathways regulating cellular ROS. Under normal condition, Keap1 combines with Nrf2 in the cytoplasm, which leads to the degradation of Nrf2. However, the conformation of Keap1‐Nrf2 complex changes under oxidative or ionized stress. The released Nrf2 enters into the nucleus and transcribes multiple antioxidative and detoxifying genes to protect the cells from oxidative damage.Several studies have demonstrated that the p62‐Keap1‐Nrf2 pathway is not only involved in the progression of oncogenesis2) on Days 1 and 29, and infusion of 5‐Fu (750–1000 mg/m2) on Days 1–4 and 29–32. This regimen was repeated every five weeks. This study was approved by the Institutional Review Board of Shandong Cancer Hospital  and conformed to the Declaration of Helsinki. The outcome of the study will not affect the future management of the patients and their personal data has been secured.We included 164 cases of inoperable locally advanced ESCC  diagnosed from June 2009 to June 2014. The tumor tissue samples were collected by esophageal endoscopy. All the patients received concurrent chemoradiotherapy (CCRT). The gross tumor volume (GTV) was defined as the primary lesion determined by esophageal endoscopy and CT scan. The gross tumor volume of lymph nodes (GTVnd) was defined as the metastatic lymph nodes determined by CT scan. The clinical target volume (CTV) for 60 Gy irradiation included GTV plus a 3 cm craniocaudal margin and GTVnd plus a 1 cm margin. The planning target volume (PTV) was defined as CTV plus 0.5 cm margins for uncertainty. The radiation dose of PTV ranged from 60.4 Gy to 70.0 Gy and the median dose was 65.0 Gy. The number of fractions ranged from 30 to 38 and the median number was 35. Elective nodal irradiation (40 Gy) of mediastinal and perigastric lymph nodes for all cases, cervical lymph nodes for an upper thoracic primary tumor, and celiac lymph nodes for a lower thoracic primary tumor was also performed. The radiation technique was 3D conformal therapy. Chemotherapy compromised two courses of infusion of cisplatin  was defined as the time between the start of active treatment and date of disease progression. Overall survival (OS) was defined as the time between the start of active treatment and date of death.The ESCC tumor tissues from paraffin embedded blocks were cut into 4 μm sections, deparaffinized and rehydrated by xylene and graded alcohol. Heat‐induced antigen retrieval was achieved under high pressure for 20 minutes at 100°C using Bond Epitope Retrieval Solution 1 (Leica Microsystems). The sections were soaked in 3% hydrogen peroxide solution for 10 minutes and incubated with 5% goat serum at room temperature for 30 minutes. The sections were incubated with primary antibodies against Nrf2  and phosphorylated p62  at 4°C overnight. Biotin‐labeled second antibody was applied for 30 minutes, and the slides were then incubated with polymeric horseradish peroxidase immunoglobulin G reagent for 30 minutes. DAB regent kit  was used to detect antigen‐antibody binding. Finally, hematoxylin was applied for five minutes to counterstain the nuclei.Each slide was independently evaluated by two pathologists and the conflicting results were resolved by using a multi‐headed microscope. The expression of p‐p62 and nuclear Nrf2 were quantified by the quick score (Q score), which was determined by multiplying the percentage of positive cells (0–100%) by intensity .2 test. Spearman test was used to determine the correlation between expression of p‐p62 and nuclear Nrf2. PFS and OS curves were constructed by the Kaplan‐Meier method, and differences in survival were compared by using the log‐rank test for univariate analysis. The factors with P‐value lower than 0.1 were included in the Cox proportion regression models. All two‐sided P‐values <0.05 were considered statistically significant. Statistical analysis was performed using SPSS version 22.0.The association of p‐p62 and nuclear Nrf2 with clinical characteristics and treatment response was analyzed by χThis study included 164 cases of ESCC whose clinical characteristics are presented in Table The relationship between p‐p62 or nuclear Nrf2 expression and clinical characteristics of ESCC are summarized in Table P = 0.005). Similarly, patients with high nuclear Nrf2 expression were associated with a poorer response compared to patients with low expression   achieved a complete response (CR) or partial response (PR), while 52 patients (31.7%) experienced stable disease (SD) or progressive disease (PD) /nuclear Nrf2(−), p‐p62(−)/nuclear Nrf2(+), p‐p62(+)/nuclear Nrf2(−) and p‐p62(+)/nuclear Nrf2(+) group. The PFS and OS curves of the four groups are presented in Fig The results of univariate survival analysis revealed that PS score, N stage and treatment response were significantly associated with PFS besides expression of p‐p62 and nuclear Nrf2 Table . The facIn this study, we clarified the expression of p‐p62 and nuclear Nrf2 in ESCC and their association with patients' treatment response and long‐term prognosis after CCRT. Nrf2 is an important transcription factor and could only bind with ARE in the nucleus, so we focused on the expression of nuclear Nrf2 in our study but not the total expression of Nrf2 as in previous studies. The results of IHC revealed that the expression levels of p‐p62 and nuclear Nrf2 among patients were fluctuant, which implied the interindividual heterogeneity of tumors. Interestingly, although the expression of p‐p62 and nuclear Nrf2 were not stable in ESCC tumor tissues, there was a significantly positive correlation between the expression of p‐p62 and nuclear Nrf2, which was in accordance with the results of previous studies. In a homeostatic state, Keap1 combines with Nrf2 in the cytoplasm, which leads to the degradation of Nrf2 and keeps the expression of Nrf2 at low level.et al.et al.NFE2L2 gene, especially in ESCC. The mutation rate of NFE2L2 gene is 5% to 20% in ESCC. The mutant loci often locate in the regions affecting the binding of Nrf2 to Keap1, which means the mutation of NFE2L2 gene usually decreases the binding affinity between Nrf2 and Keap1 and leads to the constant activation of Nrf2.More importantly, the positive correlation between expression of p‐p62 and nuclear Nrf2 was more obvious in ESCC patients showing no response to CCRT. This indicates that the relationship between p‐p62 and nuclear Nrf2 could affect the response of ESCC patients to CCRT. Further investigation showed that patients with high expression of p‐p62 or nuclear Nrf2 had a lower response rate to radiotherapy. We speculate that this is related to the role of ROS in the radioresistance and the function of target genes of Nrf2. ROS induced by radiotherapy could lead to the damage of DNAp62 gene inhibit the proliferation of hepatocellular carcinoma in vivo and in vitro.p62 gene inhibits pulmonary adenocarcinoma induced by Ras.The univariate analysis revealed that high expression of p‐p62 or nuclear Nrf2 was associated with shorter OS and PFS, especially when both the expression of p‐p62 and nuclear Nrf2 were high. Multivariate analysis also showed that expression of p‐p62 and nuclear Nrf2 were independently associated with long‐term survival. The prognostic value of Nrf2 in ESCC was in accordance with the results of previous study.There are several limitations in our study. A previous study has proved that pretreatment body mass index (BMI) was an independent prognostic factor for long‐term survival in esophageal cancer patients and BMI loss showed impact on OS.In conclusion, the expression levels of p‐p62 and nuclear Nrf2 are fluctuant among ESCC patients. The expression of p‐p62 is positively correlated with nuclear Nrf2, especially in patients with no response to CCRT. The high expression of p‐p62 and nuclear Nrf2 are associated with radioresistance and poor prognosis in ESCC. The p62‐Keap1‐Nrf2 pathway might be a new target for the radiosensitization of ESCC.The authors declare that there is no conflict of interest.


A conversion of 90 % with a selectivity of 98 % is achieved at 513 K and 5 MPa H2. Mg(LA)2 could be identified as a crucial intermediate in this reaction, as it undergoes faster conversion than the combination of LA and Mg(OH2) and regeneration of Mg(OH)2 through the conversion of Mg(LA)2 as a substrate. DFT calculations reveal that the energetic span of the reaction decreases from 46.6 kcal mol−1 catalyzed with no cation to 43.6 kcal mol−1 with [Mg(OH)]+, confirming the facilitating effect of Mg(OH)2.Mg(OH) Milk and alcohol: Mg(OH)2 exhibits superior performance in the liquid‐phase conversion of lactic acid (LA) into 1,2‐propanediol over Cu. A conversion of 90 % with a selectivity of 98 % is achieved at 513 K and 5 MPa H2. Mg(LA)2 is found to be a crucial intermediate in this reaction. DFT calculations reveal that the energetic span of the reaction decreases in the presence of [Mg(OH)]+. LA is also produced as an unavoidable side product in the hydrogenolysis of biomass to glycols.2 reduction and the wide application of 1,2‐PDO as a monomer and as a constituent in antifreezes (Scheme Lactic acid (LA) has attracted increasing attention, owing to its use as monomer for biodegradable polylactic acid (PLA).2 using a Re‐black catalyst.2. Furthermore, Takeda et al. improved the catalytic performance of Ru/C by doping with MoOx species, which led to a yield of 95 % at 393 K and 8 MPa H2.2 at 473 K in the gas phase.2 support and hydrogenation over Cu. Notably, in the liquid phase reaction no conversion of LA was observed. However, in our previous study on the hydrogenolysis of sorbitol in water we observed that conversion of LA into 1,2‐PDO leads to increasing glycol selectivity.2‐supported Cu catalysts. The influence of the added base on the course of the reaction and the reaction mechanism was studied in detail. DFT calculations were performed and suggest a strong influence of the cation on the reaction mechanism.Hydrogenation of LA was initially reported by Broadbent and Whittle, who obtained a yield of 84 % at 423 K and 26 MPa H2 catalyst was prepared by using the ammonia evaporation precipitation method. The metal loading was determined by inductively coupled plasma optical emission spectroscopy (ICP‐OES) to be 24.2 wt %. N2 physisorption revealed that Cu/SiO2 had a surface area of 279 m2 g−1 and a pore volume of 0.71 cm3 g−1. The addition of Cu did not modify the surface area (287 m2 g−1) or pore volume (0.88 cm3 g−1) of SiO2 significantly. The adsorption and desorption isotherms are shown in Figure S1 (see the Supporting Information). The particle distribution was investigated by using TEM 2. Furthermore, the influence of the H2 pressure on the reaction rate was investigated . At 513 K, the conversion increased from 16 % at 1 MPa to 86 % at 4 MPa, although further increase in the H2 pressure did not lead to higher conversion. The pressure dependence below 4 MPa is attributed to mass transfer limitations, owing to the three‐phase reaction. To exclude this effect, all reactions were carried out at 5 MPa H2. To test the long‐term catalyst stability, five consecutive recycling experiments were carried out using 25 wt % Cu/SiO2 2 is displayed in Figure − in the reaction mixture was kept the same. A reaction without base gave almost no conversion, indicating that Cu/SiO2 alone is inactive, which is in accordance with the results reported by Cortright et al.2 and La(OH)3 gave almost no conversion (<3 %). KOH, Zr(OH)2 and Ca(OH)2 reached slightly higher conversion of up to 10 %. However, with Mg(OH)2 a significant increase in activity was achieved. 63 % of LA was converted within 4 h and extending the reaction time to 24 h led to 90 % conversion 2  shows that the reaction is accelerated. This suggests that the dissolution of Mg(OH)2 is rate‐limiting. To test whether solid Mg(OH)2 participates in the reaction, a test was performed with magnesium lactate (Mg(LA)2), which is fully water‐soluble. The time course of the reaction is displayed in Figure 2, the conversion of Mg(LA)2 proceeds much faster. A conversion of up to 92 % was obtained in the first 2 h, whereas for LA+Mg(OH)2 only 42 % conversion was observed. Given the poor solubility of Mg(OH)2, the greatly accelerated conversion can be attributed to the high solubility of Mg(LA)2. The evolution of the Mg2+ concentration during the reaction was analyzed by ICP‐OES. The concentration of Mg2+ decreased from 73.9 mmol L−1 at 0.5 h to 6.6 mmol L−1 at 2 h 2 was generated during the reaction. These observations suggest that soluble Mg species play an important role in the conversion of LA facilitated by Mg(OH)2.The influence of the type of base on the conversion of LA over Cu/SiO2+ on the conversion of lactate to 1,2‐PDO, DFT calculations at the B3LYP/6‐311++G**/SMD(water) level of theory were carried out.dG values). As both Cu and Mg(OH)2 are necessary for the conversion, a synergistic reaction mechanism composed of a base/cation‐catalyzed part and a Cu‐catalyzed part is proposed. The OH− catalyzed reaction sequence [i.e. with no cation (NC)] is considered as a benchmark. Preliminary calculations showed that dissolved Mg(OH)2 is hydrated and in equilibrium with the cationic species [Mg(OH)(H2O)5]+ and [Mg(H2O)5]2+ and OH−.− is neutralized, leading to the formation of LA− and after coordination with Mg to [Mg(OH)(LA)(H2O)2)] and [Mg(LA)(H2O)3]+, respectively (IM1). Neutralization is strongly exothermic +) and −27.1 (Mg2+) kcal mol−1]. The lower dG of the magnesium lactate complexes suggests that magnesium cations have a high affinity for the lactate anion. Next, a proton transfer from the α‐hydroxy group to the carboxylic group leads to IM2 and activation of the α‐carbon. In all cases proton transfer are endothermic, requiring 23.6 (NC), 15.3 ([Mg(OH)(LA)(H2O)2]) and 14.9 kcal mol−1 ([Mg(LA)(H2O)3]+), respectively. For path NC, the proton is bridged between the hydroxy and carboxylic acid groups, whereas for the Mg‐ion paths, the proton is fully shifted to the carboxylic acid. Compared to NC, binding with cation is highly beneficial and lowers the energy for proton transfer by 8 kcal mol−1. Subsequently, a hydride shifts from the activated α‐carbon to the carbonyl via transition state TS1 and results in the formation of gem‐diolate IM3. For this step, the Mg‐ion paths exhibit higher barriers of 29.9 ([Mg(OH)]+) and 28.3 (Mg2+) kcal mol−1 as compared to 23.0 for NC. The hydride is approximately located over the middle of C−C bond.To obtain deeper insights into the role of Mg−, going through TS2 and yielding pyruvaldehyde (PA), can proceed directly. In contrast, for the Mg‐ion paths, a proton transfer from one hydroxy group of the gem‐diol to the Mg‐bound hydroxy (IM4) occurs before elimination of OH− (via TS2). As such the base is regenerated at the end of the reaction, which is in accordance with our observations. Finally, PA is hydrogenated over Cu to give 1,2‐PDO.For path NC, elimination of OHδE) model, which corresponds to the apparent activation energy of the entire catalytic cycle, is applied.δE is determined based on the TOF‐determining transition state (TDTS) and TOF‐determining intermediate (TDI). As it has the lowest dG among all investigated species, IM1 is assigned to the TDI. As the dG of TS1 is higher than that of TS2, TS1 is assigned to TDTS. Moreover, the TDI appears before the TDTS, and δE is determined by dGTS1−dGIM1. As such, the δE for the NC, [Mg(OH)]+‐, and Mg2+‐facilitated catalytic routes are 46.6, 43.6, and 44.8 kcal mol−1, respectively. Although δE values of [Mg(OH)]+ and Mg2+ are different, both are significantly lower than that of NC.To evaluate the catalytic efficiency of each route, the energetic span  is comparable with δE(NC), and 2.1 kcal mol−1 higher than δE(Mg2+). Therefore, the obtained DFT result is in well accordance with the experimental observations that Mg(OH)2 facilitates significantly the conversion of LA in water.The Gibbs energy profiles of the conversion of LA into 1,2‐PDO involving the rate‐determining states in the presence of NC, Ca2 was the most active. Mg(LA)2 was experimentally identified as the key intermediate. DFT calculations demonstrated that the δE value of the reaction in the presence of Mg cations is decreased by 3 kcal mol−1 compared to that without cations, confirming the facilitating effect. This combined study provides a promising direction to take advantage of the side product LA in biomass conversion into glycols and deeper insights into this new route.In summary, we have shown that the liquid‐phase conversion of LA into 1,2‐PDO can be efficiently achieved with promising yield by using a Cu catalyst in the presence of base. Among various bases, Mg(OH)The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


It is widely considered the El Nino-South Oscillation (ENSO) has several different types which can be simply classified as eastern Pacific (EP) type and central Pacific (CP) type. However, indices proposed so far can only characterize one single type of ENSO. In this paper, we develop a unified index which can characterize two types of ENSO simultaneously. The new index named as unified complex ENSO index (UCEI) is defined in the complex plane whose real part is NINO3 + NINO4 and imagine part is NINO3-NINO4. The modulus (r) and quadrants (θ) represent the ENSO strength and the ENSO types, respectively. Apart from the EP and CP types, the UCEI could further distinguish the MIX type of ENSO. Besides, the UCEI can capture the type-transforming processes within one ENSO event. Applying UCEI on historical events from 1950 to 2017 demonstrates the new index could be a very useful tool for the research of different types of ENSO. The EP ENSO is the traditional type of ENSO which locates most of the anomalies over the eastern Pacific while the CP type known as the new type of ENSO which appears more frequently in recent decades has much more anomalies in the central Pacific6. For some events, the anomalies over the central and eastern Pacific are relatively both high which cannot be simply divided into EP or CP type and this type is generally called the MIX ENSO7.El Nino-South Oscillation (ENSO) is the most influential pattern of the global climate with sea surface temperature anomalies (SSTA) over the tropical central and eastern Pacific Ocean. It is widely considered that the ENSO has several different types. Based on the SSTA distribution, it can be classified as the eastern Pacific (EP) type (or Cold Tongue type) and the central Pacific (CP) type Trenberth and Stepaniak recognized the gradient between the central and eastern Pacific is necessary to completely describe ENSO and raised the Trans-Nino index (TNI) which is defined as the NINO12 subtracts N41. Then Ashok et al. proposed the El Nino Modoki index (EMI) which uses the anomalies over the central Pacific subtract the eastern and western pacific3. Li et al. further adjusted the proportions of three regions of the EMI and proposed the improved El Nino Modoki index (IEMI) which could monitor the weak CP ENSO events better9. Ren and Jin developed NCT)/NWP as a pair of indices to characterize EP and CP types of ENSO. The NCT and NWP are defined as NCT = N3-αN4, NWP = N4-αN3; α = 0.4 when N3*N4 > 0; α = 0 when N3*N4 < 0. The NCT and NWP demonstrate N3 and N4 could be suitable to distinguish EP and CP ENSO based on an appropriate combination10.The early indices, such as NINO4 (N4)  and NINO3 (N3)  are widely used to capture the anomalies in the central Pacific and eastern Pacific, respectively. However, N3 and N4 cannot well distinguish EP and CP ENSO as the anomalies in N3 (or N4) region will extend to the neighboring N4 (or N3) region. However, the existing indices can only characterize one type of ENSO. It is not convenient enough to determine the ENSO type as at least two indices are required. Not only that, in some cases, values of EP and CP indices are both high which makes the determination difficulty. So, whether one could develop a unified index that could characterize two types of ENSO simultaneously? In this paper, we introduce a novel index which could well achieve this purpose.To better descript how we construct the new index, we demonstrate the averaged SSTA distributions of 1997–1998, 2004–2005 and 1991–1992 El Nino events as the examples that represent the EP, CP and MIX types, respectively Fig. . If we uOn the basis of the above analysis, we introduce a complex plane whose real part is the N3 + N4 while imagine part is the N3 − N4. Figure It should be noted that the threshold of MIX type (15°) is not randomly selected. We assume the threshold of MIX type in the first quadrant is α. Larger the α, more significant the difference between N3 and N4 within the MIX region ((−α~α), (−180 − α ~ −180 + α)). According to this monotonic relationship, we change α from 1 to 90 and for each angle apply a two-tailed Students’s t-test on the N3 and N4 within the threshold. Statistical analyze demonstrates that when α < =15, difference between N3 and N4 is not significant while α > 15, difference is significant (at 95% confidence level). Therefore, 15 is a suitable threshold of MIX type of ENSO. We also examine the influence of asymmetry in El Nino-La Nina on the threshold of MIX ENSO, respectively. The threshold for MIX El Nino (La Nina) of all El Nino (La Nina) is 14° (17°), respectively.After above analysis, we introduce a novel ENSO index called Unified Complex ENSO index (UCEI) which is defined as follows:The r represents the ENSO strength while θ determines the ENSO type. Figure Figure As Fig. SSTA distributions in the Indian Ocean are also shown in the Figure. As the Fig. As the ENSO is a coupled ocean and atmosphere phenomenon, atmospheric features of different types of ENSO are also identified based on UCEI. Figure Phase locking properties of different types of ENSO are also identified by the UCEI. Figure 6. We noticed CP ENSO only appeared 3 times during 1950–1977 but 9 times during 1977–2016 which demonstrates the tendency that CP type of ENSO appeared more frequently6.During ENSO events, the SSTA distribution is constantly changing with the evolution. And even in some cases, the ENSO type may be changed. A unique ability of the UCEI is that the new index could capture the type-transforming processes within ENSO event. As Fig. In this study, we develop a unified complex ENSO index (UCEI) which can characterize and distinguish EP and CP types of ENSO simultaneously. Based on the different features of EP and CP ENSO in regions N3 and N4, we construct the complex plane of N3 + N4 and N3 − N4. The El Nino type could be determined by the sign of N3 + N4 and N3 − N4. According to the significant test of difference between N3 and N4, the MIX ENSO could be further distinguished. Using the polar form, the ENSO type could be determined only by the argument (θ). And the ENSO strength could be represented by the modulus (r). Hence, we could characterize EP, CP and MIX ENSO simultaneously with the new index. As the previous indices can only characterize a specific type of ENSO, such an index will be a very convenience tool for the researches on the different types of ENSO.11 have something in common with UCEI. They are both constructed by NINO3 and NINO4 without additional defined areas and complicated operations. The Correlation coefficients between r (r flips to –r when negative phase) and NCT, NWP, NCT + NWP are 0.89, 0.60, 0.99, respectively. As we can see, NCT or NWP only represents the decomposed strength of ENSO (EP or CP) which is not actual strength of ENSO. To determine the ENSO type, we also need a comparison of two indices. Therefore, the UCEI adopts a new way that using ENSO strength (not the component EP or CP strength) and ENSO type to describe ENSO events. The advantage of this way is that we can get the ENSO strength and types directly. Therefore, UCEI is more intuitive and convenient in practical application. However, the UCEI also has some deficiencies. For example, the generally used statistical analysis based on traditional indices such as auto-correlation, lead-lag correlation, and dominant frequency of each type of ENSO in the dynamical forecast models might be hard performed by UCEI.Previous indices generally adopt the way that using strength of EP and CP type of ENSO to describe ENSO events. Among them, NCT and NWP12. We choose the time period from jan1950 to jan2017. The monthly mean zonal wind and sea level pressure data13 were from the NCEP reanalysis-derived data provided by the NOAA/OAR/ESRL PSD  on their website at http://www.esrl.noaa.gov/psd/.The SSTA data used in this study is the monthly mean anomalies of Hadley Centre Sea Ice and Sea Surface Temperature data set


Based on this observation, a methodology for the re‐evaluation of certain Hammett constants with larger uncertainties has been proposed and demonstrated. Moreover, the scope of HEP was extended to various neutral pnictogen and chalcogen donors during which “transphobia effects” were revealed for mixed NHC complexes containing phosphites, arsine and stibine for the first time.The suitability and accuracy of the Huynh electronic parameter (HEP) was further tested to reveal remote substituent effects in pyridines, which are located five or six bonds away from the reporter probe. These values show an excellent correlation to Hammett  Remote substituent effects can be revealed by Huynh electronic parameters and an excellent correlation to Hammett constants was observed. In addition, the electronic properties of selected pnictogen and chalcogen ligands were determined on a unified scale. The properties of metal complexes are determined by the nature of the metal center and the stereoelectronic signatures imposed by the ligands. Often the steric bulk of a particular ligand can be easily estimated by its Lewis structure drawing, while its electronic properties are more difficult to judge. This is especially so, when the ligand has multiple substituents of different inductive and mesomeric effects, which could enhance or oppose each other. In order to compare the donating abilities of ligands experimentally, a few electronic parameters have been developed Figure .EL (LEP) has been introduced by Lever based on redox potentials of for example, RuII/III metal complexes.EL values of a large number of Werner‐type ligands have been tabulated, which reflect their relative capacity to stabilize a metal in a certain oxidation state. Ligands with smaller EL values can therefore stabilize the RuIII state in the RuII/III couple better than those with larger EL values. Although EL values are not a direct measure for the donating ability of a ligand, they are nevertheless related to its donating power.EL values. The requirement for less common electrochemical setups and the exclusion of non‐innocent ligands is a further limitation.The ligand electrochemical parameter 1 carbonyl IR stretching frequencies of [Ni(CO)3L] complexes, in which L denotes the ligand of interest.4] or carbon monoxide. The largest drawback, however, is that the majority of Werner‐type ligands cannot be systematically probed using carbonyl‐based methods. For example, amines and pyridines do not react with [Ni(CO)4].In organometallic chemistry, the most commonly used parameter is the so‐called Tolman electronic parameter (TEP) developed in 1970, which compares the Atrans‐ligand L on the 13Ccarbene NMR shift of the iPr2‐bimy reporter ligand  in square‐planar complexes of the type trans‐[PdBr2(iPr2‐bimy)L]. It was found that a weaker donor would lead to a relative upfield shift, whereas a stronger donor would lead to a downfield shift of the HEP signal. Different types of NHCs,meta‐ and para‐substituted pyridines and correlated the HEP results to the respective σp and σm Hammett constants.We have introduced a new electronic parameter, which addresses these shortcomings and allows direct comparison of Werner‐type and organometallic ligands on a unified scale without the use of highly toxic materials.2(iPr2‐bimy)]2 (I)trans‐[PdBr2(iPr2‐bimy)(Py‐R)] complexes were prepared with 13 meta‐ (2–14) and 13 para‐substituted pyridines (15–27) and compared to the previously reported parent complex trans‐[PdBr2(iPr2‐bimy)(Py)] (1).One advantage of the HEP is the ease of complex probe preparation. Thus, simple mixing of the dimeric complex  (19) to common alkali metal hydroxides to obtain HEP probes of pyridyl‐4‐carboxylates with different alkali metal ions ] 9 to comm+ and largest for Na+ and K+. This observation implies that the negative charge is best stabilized by the lithium cation, which is in line with its largest charge/size ratio leading to the best hard/hard interactions with the carboxylate group. The HEP value peaks with sodium and gradually decrease with increasing size of the cation. The difference between potassium and rubidium is larger as the latter is known to form compounds with higher coordination numbers. Scheme σp* constants for the different alkali metal carboxylates using Equations 2 and 3.Upon deprotonation, an increased donating ability is expected for the resulting pyridinecarboxylate ligand, which is indeed confirmed by the larger HEP values. As anticipated, different cations induce a different response, and the downfield shifts are smallest for Limeta‐substituted pyridine could be predicted by that of its para‐analogue and vice versa. In order to test such a possibility, HEPs of meta‐ and para‐substituted pyridines bearing identical substituents were plotted against each other where available. With inclusion of all ten substituents, a very good linear regression coefficient of R2=0.9701 was obtained. Exclusion of the NH2 group as an outlier led to a further improvement to R2=0.9846  effect on the HEP, potentially allowing for predictions from each other. This could be particularly powerful for groups with primarily inductive effects, while those with dominant mesomeric contributions have to be treated with more caution. The latter is understandable as mesomeric effects have a drastically different impact in meta‐ compared to para‐position.Based on this encouraging result, it appears that substituents in 3), 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD) and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) are widely used organic bases, but they can also stabilize active metal species by coordination. It is therefore surprising that their donating abilities have not been explicitly compared yet. Hence, the respective HEP probes were routinely prepared by exposure of [PdBr2(iPr2‐bimy)]2 (I)trans‐[PdBr2(iPr2‐bimy)(TBD)] (32) and trans‐[PdBr2(iPr2‐bimy)(DBU)] (33) formed rapidly, while prolonged stirring with an excess of triethylamine was required to fully convert complex I into trans‐[PdBr2(iPr2‐bimy)(NEt3)] (34). TBD is a bicyclic guanidine containing an imine and a secondary amine function that are available for coordination. However, the ligand shows selective coordination of the imine nitrogen to metal centers such as Pd, Cu, Ag, Fe and Li,32 (vide infra). Coordination via the imine function is also expected for the DBU ligand. The three base adducts 32–34 have good solubilities in most organic solvents, and no cis‐isomers were detected. In the 13C NMR spectra, the three carbene carbon atoms resonate in the order of 34 <32 <33 3, P(OPh)3 and P3, which are diverse in terms of stereoelectronic properties. Instant color changes from orange to pale yellow were observed for most reaction mixtures indicative of a generally strong donating ability of these ligands and the fast formation of mixed NHC/phosphite complexes, which are surprisingly rare.trans–cis isomerizations were observed. The thermodynamically preferred cis‐arrangement in these complexes is due to the so‐called “transphobia effect” of phosphorus donors.trans to a carbon donor.3 and P(OiPr)3 complexes containing the smallest phosphites. Hence, only the cis‐[PdBr2(iPr2‐bimy){P(OMe)3}] (cis‐35) and cis‐[PdBr2(iPr2‐bimy){P(OiPr)3}] (cis‐36) complexes were isolated in the standard procedures. The process is slower for P(OPh)3 complex, and signals for both trans/cis‐[PdBr2(iPr2‐bimy){P(OPh)3}] (trans‐/cis‐37) complexes were captured in the NMR spectra. The complex trans‐[PdBr2(iPr2‐bimy){P3}] (trans‐38) resists isomerization due to the enhanced steric bulk, and a HEP value of 171.48 ppm was detected for the P3 ligand without problems {P(OiPr)3}] (trans‐36) or trans‐[PdBr2(iPr2‐bimy){P(OPh)3}] (trans‐37) complexes was observed in the respective 1H NMR spectra. 31P and 13C NMR data were measured immediately thereafter. This approach was successful for complex trans‐37, and a HEP of 171.65 ppm was obtained for the P(OPh)3 ligand. However, signals due to both trans‐ and cis‐isomers were detected in the 13C NMR spectrum of 36. To resolve the carbene signal of trans‐36 in a shorter time, the NMR reaction was repeated with 13C2‐labeled complex I,iPr)3 at 175.25 ppm with a single scan. Unfortunately, the signals of trans‐35 complex could not be captured even within such a short time due to its very rapid trans–cis isomerization. Overall, the donating ability of the phosphites decreases in the order P(OiPr)3≫P(OPh)3>P3 3 and P(OPh)3, which is reflected in the trends of the available cis complexes (SbPh3)] (cis‐40) could be detected by all means. Complex trans‐[PdBr2(iPr2‐bimy)(AsPh3)] (39), on the other hand, isomerizes slower and could be fully characterized by direct NMR reaction, giving a HEP value of 169.17 ppm. This arsine is therefore a weaker donor compared to phosphines and phosphites. Comparison of the cis‐39 and cis‐40 could indicate that the stibine is a weaker donor than the arsine  coupling constants of >280 Hz 3 complex trans‐36 fully converted to cis‐36 within two hours. For the P(OPh)3 complex 37, only 17 % was converted to the cis‐isomer after eight days. However, the 1H NMR spectrum of the product mixture obtained from the initial lab‐scale reaction (30 min stirring in CH2Cl2) shows a trans–cis conversion of 50 %. Besides better mixing, the different solvent would be the key factor in influencing the isomerization rate. The increased polarity of CH2Cl2 compared to CDCl3 should favor the formation of the cis‐isomer with a larger dipole moment. Hence, by repeating the reaction in the even more polar organic solvent MeOH, cis‐[PdBr2(iPr2‐bimy){P(OPh)3}] (cis‐37) was exclusively obtained after 10 hours of stirring at ambient temperature. The P3 complex trans‐38 did not change at all after ten days. Heating the NMR sample in an oil bath (65 °C) for several days led to decomposition to palladium black, but no cis‐isomer was detected. The isomerization of the AsPh3 complex 39 seems to reach equilibrium after six days giving rise to a trans/cis mixture with a ratio of 1:3.5. Due to transphobia, only single crystals of the cis‐adducts could be obtained (vide infra).The P(OI. Pyridine N‐oxide (PNO) as a formally neutral oxygen donor was included instead. The increased dipole moment due to charge separation leads to a stronger nucleophilic property of the oxygen atom, which may allow the cleavage reaction to proceed. The two thioethers smoothly cleaved complex I, affording complexes trans‐[PdBr2(iPr2‐bimy)(DMS)] (41) and trans‐[PdBr2(iPr2‐bimy)(THT)] (42). However, an excess of PNO was required to afford the desired complex trans‐[PdBr2(iPr2‐bimy)(PNO)] (43). The two thioethers are expected to have very similar electron donating properties. However, 13C NMR spectroscopy could still resolve the small difference as indicated by the HEP values of complexes 41 and 42 at 163.46 and 163.63 ppm, respectively. The cyclic THT ligand was found to be slightly stronger donating than the DMS ligand. The PNO complex 43 shows the most upfield HEP of 155.74 ppm indicating a weak donor property of the PNO ligand, which explains the difficulty met in the preparation of this complex.Neutral chalcogen donors form weaker bonds with metal centers compared to their pnictogen counterparts. Their weak donor capability makes them suitable candidates for the design of hemilabile hybrid ligands for catalysis. For example, complexes of thioether‐functionalized NHC ligands have shown promising catalytic activities and an interesting structural dynamics.sp2‐ and sp3‐hybridized N‐donor atoms and aromaticity of the heterocycle. Generally, sp2‐hybridized N‐donors are stronger due to the less hindered lone pair, and aliphatic imines such as DBU and the guanidine TBD are stronger than aromatic pyridines. We also note that the donating ability of pyridines can be fine‐tuned over a range of 5 ppm. Thioethers are found in between aliphatic imines and pyridines, and pyridine‐N‐oxide is the weakest donor on the HEP scale thus far.Overall, the ligands investigated in this work cover a HEP range of 20 ppm Figure . The pho4, 9, 15⋅CH2Cl2, 19⋅2 CH2Cl2, 26⋅0.5 CHCl3, 27⋅0.5 CHCl3⋅0.5 CH2Cl2, 32, cis‐35⋅CH2Cl2, cis‐36⋅CHCl3, cis‐37⋅2 CHCl3, cis‐39, cis‐40, 42 and 43⋅CHCl3 were obtained by slow evaporation of their solutions (see Supporting Information), and X‐ray diffraction reveals square‐planar geometries expected for PdII complexes. In all cases, the iPr2‐bimy ligand is perpendicular to the [PdCBr2L] coordination plane.Single crystals of complexes 4, 9, 15, 19, 26 and 27 closely resemble those of previously published analoguesThe structures of the pyridine adducts 32 is the first mixed NHC/guanidine complex. The N‐heterocycle is also oriented perpendicular to the coordination plane and coordinates via the imine instead of the two amine moieties, confirming once again the superior donating ability of sp2‐N‐donors over sp3‐hybridized counterparts. As common for N‐ligands, a trans arrangement is observed making them ideal candidates for HEP analyses.Compound cis‐isomers of the phosphite adducts 35–37 crystallized as a consequence of rapid trans–cis isomerization due to transphobia. Previously reported mixed NHC/phosphite complexes all have a trans arrangement, since they contain the very bulky NHCs IPr and SIPr.cis complexes is significantly shorter indicating stronger bonds. They are also identical within error margin. The cis‐configuration also leads to shorter and stronger Pd−P bonds with an average length of 2.207 Å.In contrast, only cis‐39 and cis‐40, which are the first structurally characterized cis‐isomers. The Pd−C bonds of 1.970(2) and 1.971(3) are identical and equal to that observed for the cis‐[PdBr2(iPr2‐bimy)(PPh3)]σ. On the other hand, bonds to palladium steadily elongate going from phosphorus {2.2624(8) Å}trans complexes.Similar observations were made for the arsine and stibine complexes 42 and 43 are also the first of their kind. The thioether and N‐oxide donors adopt preferably a trans orientation with respect to the NHC. The Pd–C distance for the thioether complex of 1.969(3) Å is substantially longer than that in the pyridine‐N‐oxide complex Pd1‐C1 1.935(2) Å, which is reflective of their different donor strengths. The latter is equal to that observed for complex formed with acetonitrile,Complexes trans‐[PdBr2(iPr2‐bimy)(Py‐R)] using the Huynh electronic parameter (HEP) have revealed remote substituent effects in meta‐ and para‐substituted pyridines five and six bonds away from the NMR probe. Moreover, the influence of these substituents on the 13Ccarbene NMR signal of the iPr2‐bimy reporter ligand shows an excellent correlation to their respective sigma Hammett constants (σm and σp), providing further support for the suitability of HEP as an efficient and accurate electronic parameter. The resulting regression equations could also be used for the re‐evaluation of certain Hammett constants that carry larger uncertainties. This has been demonstrated for the CO2H and CO2M  substituents. In addition HEPs of meta‐ and para‐substituted pyridines bearing the same substituent also showed an excellent linear correlation. In principle, this allows for HEP predictions of para‐substituted pyridines from that of the respective meta‐isomer and vice versa. Finally, attempts were made to extend the library of HEP values to various ligands that hitherto have not been covered yet. In particular, these include phosphites, arsines, stibines, thioethers and N‐oxides. The mixed NHC/ligand complexes of the pnictogens show an interesting and electronically‐driven trans–cis isomerization. The so‐called “transphobia” effect previously described for phosphorous ligands have thus been extended to include arsenic and antimony compounds. In addition to reporting new types of complexes, this work also expands the toolbox for chemists and provides valuable electronic data for the proper comparison of different ligand classes on a unified scale.The study of 26 complex probes of the type Supporting Information for this article is given via a link at the end of the document. The Supporting Information contains a detailed description of the synthetic work, the characterization of all analytes as well as selected crystallographic data.The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Cobalt‐loaded MFI zeolite showed distinct activity for direct methylation of benzene with methane into toluene. High activity was found at around 0.6 of Co/Al molar ratio. Incorporation of carbon from methane into the methyl group of toluene was confirmed with isotope tracer experiments and mass spectroscopy. Ammonia infrared‐mass spectroscopy temperature‐programmed desorption, transmission electron microscopy, X‐ray absorption near edge spectroscopy and extended X‐ray absorption fine structure indicated that Lewis acidic divalent (+II of oxidation state) Co species mono‐atomically dispersed on the ion exchange site of MFI zeolite was the active species. Conversion of methane into value‐added organic compounds, i. e. alkenes and mono‐cyclic aromatics, has been strongly required.In very early studies, formation of methylated product from a mixture of aromatic compound and methane was reported.−1 and −4.11 J K−1 mol−1  is limited by the low equilibrium constant,On the other hand, it was pointed out that equilibrium of Reaction (1) was a problem as follows. The standard enthalpy and entropy are 41.94 kJ molx with methane,As stated above, Cu/*BEA2 as a side reaction is probably unavoidable in the presence of oxygen. From these viewpoints, the non‐oxidative methylation of benzene with methane (Reaction (1)) should be studied in more detail. Because the rate of Reaction (1) is substantially low, the investigation to find an efficient catalyst should be important compared to the case of Reaction (2).Here we mention the difference between Reaction (1) and (2). Comprehensive studies by Adebajo et al. clarified that many kinds of zeolite‐supported transition metal species  showed catalytic activity for Reaction (2).+ and InO+ species, respectively, held by the ion exchange site of MFI have been identified as the active species.As stated above, the preceding literatures reported essential activity of Cu/*BEA,Based on these backgrounds, we investigate the catalytic performances of various zeolite‐supported transition metal species for the methylation of benzene with methane into toluene in non‐oxidative conditions. The first purpose is the screening of catalysts with wide variation. Most of the preceding papersx with methane,+ species on Ag/MFI for the same reaction (methylation of benzene) at 673 K,The continuous flow reaction of benzene and methane was examined at 773 K on various zeolite‐supported transition metal species, and the formation of toluene was observed on some catalysts. Figure To confirm the superiority of Co/MFI for this reaction, the reaction tests were examined also under high pressures of hydrogen and benzene with higher reaction rates. It was demonstrated that Co/MFI always showed high activity compared to the other catalysts .Preceding literature reported that toluene was formed in the co‐presence of benzene and methane even on H‐MFI without transition metal through the hydrogenolysis of benzene,−1 corresponding to SiO2/Al2O3=22, i. e., the highest Al concentration in MFI commercially available.Figure −1. Because Co/Al molar ratio obtained by the ion exchange in the present conditions was <0.48, further loading of Co was performed only by the impregnation method, whereas the impregnation (•) and ion exchange (◊) method gave a common relationship between the activity and Co/Al molar ratio <0.48. The activity was negligible at Co/Al=0 under these conditions, and introducing Co created the activity. The toluene yield showed the maximum at Co/Al=0.6, and further loading reduced the activity at Co/Al>0.9.Figure 13C (hereafter 13CH4) and ordinal benzene  were used as the reactants, and the products were analyzed with a gas chromatography‐mass spectrometer (GC‐MS) and 13C nuclear magnetic resonance (NMR). Results of the GC‐MS analysis are shown in Figure m/e ratios of major peaks of toluene produced by the reaction of 13CH4+12C6H6 were 92 and 93, consistent with the molecular weight 93 of 13C12C61H8, whereas the reaction of 12CH4 +12C6H6 gave the m/e ratios of toluene 91 and 92, showing the molecular weight 92 of 12C71H8.Experiments using isotope tracer were carried out on IMP‐Co‐0.6 to confirm that the toluene formation was ascribed to the Reaction (1) but not due to the benzene hydrogenolysis.13C NMR spectra. The naturally abundant 13C was found in a mixture of benzene, the solvent (hexane) and the inner standard material  [(i) and (ii)]. In addition to these peaks, a signal at 21.4 ppm assigned to the methyl group of toluene13CH4+12C6H6 (iii) but not in the product of 12CH4+12C6H6 (ii) =0.78 mol kg−1, which is equivalent to the Co content in Co/MFI prepared by the impregnation at Co/Al=0.6 on the MFI with SiO2/Al2O3=22. The thus prepared samples are listed in Table S1 with their abbreviations.Samples of Na‐MFI zeolite with SiO13C  was used for the confirmation of reaction path. In standard conditions, powder sample (0.300 g) was placed in a Pyrex tube (i.d.: 10 mm) and pretreated in a flow of nitrogen (1.23 mmol min−1) in the atmospheric pressure at 823 K for 1 h. Then, a mixture of methane and benzene  was fed to the catalyst bed at 773 K. The outlet materials were trapped by hexane at 273 K with 1,4‐diisopropylbenzene as an inner standard material and analyzed with flame ionization detector‐gas chromatograph  or were analyzed by using a mass‐spectrometer  directly connected to the outlet of a reactor. The MS measurements were carried out by means of inner standard method using helium as the standard. The molecular weight of the product of reaction using 13C‐enriched methane was analyzed with a GC‐MS . The 13C NMR were recorded on JEOL JNM ECP500 at 11.7 T. Chemical shifts are expressed in ppm downfield from Si(CH3)4.Catalytic tests were performed in a fixed‐bed flow reactor. Methane (99.9 % from Iwatani) and benzene  were used, and in some cases, methane enriched with −1 at 101 kPa and 823 K for 1 h, it was mixed with boron nitride (BN), stirred by an agate mortal for 30 min and compressed into a wafer form with 10 mm diameter. A Co‐foil and bulk Co oxides (CoO and Co2O3) were also measured as the references. The Co K‐edge absorption spectra were collected in the quick mode using a Si (111) monochromator. The beam size at the sample position was 5 mm ×1 mm .The acidic property was analyzed by a method of ammonia IRMS‐TPD in conditions described elsewhere.The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.