Linear Free Energy Relationship Analysis Research Articles

Insights into the contrasting effects of sulfidation on dechlorination of chlorinated aliphatic hydrocarbons by zero-valent iron

Contrasting effects of sulfidation on contaminants reduction by zero-valent iron (ZVI) has been reported in literature but the underlying mechanisms remain unclear. Here, under well-controlled conditions, we compared the performance of ZVI and sulfidated ZVI (S-ZVI) toward a series of chlorinated compounds. Results revealed that, although S-ZVI was more reactive than ZVI toward hexachloroethane, pentachloroethane, tetrachloroethylene, and trichloroethene, sulfidation hindered the dechlorination of the other ten tested chlorinated aliphatics by a factor of 1.5–125. Moreover, S-ZVI may lead to an accumulation of toxic partially-dechlorinated products. Analogous to its effects on ZVI reactivity, sulfidation also exerted positive, negligible, or negative effects on the electron efficiency of ZVI. Solvent kinetic isotope effect analysis suggested that direct electron transfer rather than reaction with atomic hydrogen was the dominant reduction mechanism in S-ZVI system. Hence, the sulfidation enhancing effects could be expected only when direct electron transfer is the preferred reduction route for target contaminants. Furthermore, linear free energy relationships analysis indicated one-electron reduction potential could be used to predict the transformation of chlorinated ethanes by S-ZVI, whereas for chlorinated ethenes, their adsorption properties on S-ZVI determined the dechlorination process. All these findings may offer guidance for the decision-making regarding the application of S-ZVI.

Enantioconvergent 6π Electrocyclization Enabled by Photoredox Racemization.

This study presents a novel photoredox-enabled enantioconvergent catalytic strategy used to construct chiral 2H-1,3-benzoxazines via an unprecedented oxa-6π electrocyclization utilizing racemic α-substituted glycinates as substrates. The approach leverages a cobalt-based chiral Lewis acid catalyst, which promotes the transformation under thermal or photoredox conditions. While the thermal reaction selectively converts only the (S)-configured glycinates into enantioenriched 2H-1,3-benzoxazines (up to 96:4 e.r.), the addition of 0.5 mol % of a commercially available iridium photocatalyst under visible light irradiation transforms the reaction into an enantioconvergent process. Detailed mechanistic and time course studies of optically pure α-deuterated substrates revealed the presence of an enantiospecific kinetic isotope effect, which helped to clarify the role of both the photo- and chiral Lewis acid catalyst in the reaction sequence. In this dual catalytic system, the photocatalyst promotes a dynamic interconversion between the substrate enantiomers─a process not accessible via ground-state chemistry─while the chiral Lewis acid selectively transforms only the (S)-configured substrates. Further mechanistic evidence for the proposed mechanism is provided by linear free energy relationship analysis, which suggests that the stereodetermining step involves a 6π electrocyclization under both thermal and photoredox conditions.

Yesterday, Today, and Tomorrow. Evolution of a Sleeping Beauty: The Freundlich Isotherm.

The name of Herbert Freundlich is commonly associated with a power relationship for adsorbed amount of a substance (Cads) against the concentration in solution (Csln), such that Cads = KCslnn; this isotherm (together with the Langmuir isotherm) is considered to be the model of choice for correlating the experimental adsorption data of micropollutants or contaminants of emerging concern (pesticides, pharmaceuticals, and personal care products), but it also concerns the adsorption of gases on solids. However, Freundlich's 1907 paper was a "sleeping beauty", which only started to attract significant citations from the early 2000s onward; moreover, these citations were too often wrong. In this paper, the main steps in the historical developments of Freundlich isotherm are identified, along with a discussion of several theoretical points: (1) derivation of the Freundlich isotherm from an exponential distribution of energies, leading to a more general equation, based on the Gauss hypergeometric function, of which the power Freundlich equation is an approximation; (2) application of this hypergeometric isotherm to the case of competitive adsorption, when the binding energies are perfectly correlated; and (3) new equations for estimating the Freundlich coefficient KF from physicochemical properties such as the sticking surface or probability. From new data treatment of two examples from the literature, the influence of several parameters is highlighted, and the application of linear free-energy relationships (LFER) to the Freundlich parameters for different series of compounds is evoked, along with its limitations. We also suggest some ideas that may be worth exploring in the future, such as extending the range of applications of the Freundlich isotherm by means of its hypergeometric version, extending the competitive adsorption isotherm in the case of partial correlation, and exploring the interest of the sticking surfaces or probabilities instead of KF for LFER analysis.

The interplay between hydrogen and halogen bonding: substituent effects and their role in the hydrogen bond enhanced halogen bond.

The hydrogen bond enhanced halogen bond (HBeXB) has recently been used to effectively improve anion binding, organocatalysis, and protein structure/function. In this study, we present the first systematic investigation of substituent effects in the HBeXB. NMR analysis confirmed intramolecular HBing between the amine and the electron-rich belt of the XB donor (N-H⋯I). Gas-phase density functional theory studies showed that the influence of HBing on the halogen atom is more sensitive to substitution on the HB donor ring (R1). The NMR studies revealed that the intramolecular HBing had a significant impact on receptor performance, resulting in a 50-fold improvement. Additionally, linear free energy relationship (LFER) analysis was employed for the first time to study the substituent effect in the HBeXB. The results showed that substituents on the XB donor ring (R2) had a competing effect where electron donating groups strengthened the HB and weakened the XB. Therefore, selecting an appropriate substituent on the adjacent HB donor ring (R1) could be an alternative and effective way to enhance an electron-rich XB donor. X-ray crystallographic analysis demonstrated that intramolecular HBing plays an important role in the receptor adopting the bidentate conformation. Taken together, the findings imply that modifying distal substituents that affect neighboring noncovalent interactions can have a similar impact to conventional para substitution substituent effects.

Pd−X Bond Homolysis Dissociation Free Energy (BDFE) Scales of [(tmeda)Pd(4‐F−C6H4)X] (X=OR, NHAr) in DMSO

AbstractTransition metal intermediates bearing M−X σ‐bonds are ubiquitous in metal‐mediated C−X bond transformations. Thermodynamic knowledge of M−X bond cleavage is crucial to explore relevant reactions; but little was accumulated till present due to lack of suitable determination methods. We here report the first systematic study of the Pd−X bond homolysis dissociation free energies [BDFE(Pd−X)] of representative [(tmeda)Pd(4‐F−C6H4)X] (tmeda=N,N,N′,N′‐tetramethylethylenediamine, X=OR or NHAr) in DMSO on the basis of reliable measurement of their bond heterolysis energies (ΔGhet(Pd−X)). Despite ΔGhet(Pd−O)s of palladium‐phenoxides are generally found about 8 kcal/mol smaller than ΔGhet(Pd−N)s of palladium‐amidos, their BDFE(Pd−X)s are observed comparable. The structure‐property relationship was investigated to disclose an enhancement effect of electron‐withdrawing groups on BDFE(Pd−X)s. Linear free energy relationship analysis revealed that Pd−X bonds are more sensitive than X−H bonds to structural variation. The energetic propensity of reductive elimination from arylpalladium complexes was evaluated by combinatorial use of BDFE(Pd−X)s and BDFE(C−X)s, indicating an overall thermodynamic bias to C−N bond formation.

A Distinctive Pattern for Substituent Effects on Transition Metal Centers: Enhanced Electron-Donating Capacity of Cationic Palladium Species

A Distinctive Pattern for Substituent Effects on Transition Metal Centers: Enhanced Electron-Donating Capacity of Cationic Palladium Species

Preparation of covalently bonded liposome capillary column and its application in evaluation of drug membrane permeability

Two liposomes, including 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) + 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (PE) + cholesterol (Chol) (DSPC/PE/Chol liposomes) and soybean lecithin (SPC) + PE + Chol (SPC/PE/Chol liposomes), were prepared and fixed on the inner wall of capillary column by using the adhesion of polydopamine (PDA) membrane and the cross-linking property of glutaraldehyde (GA). The immobilized liposome capillary column (ILCC) has good repeatability and stability based on the electrophoretic mobility of analyte. A CE method based on the immobilized liposome capillary column chromatography (ILCCC) was successfully developed to study the retention behavior of drugs on ILCC, and the logarithm of retention factor (log k) of neutral and ionic drugs were determined. The results show that the log k measured by the ILCCC based on two liposomes have a good linear fitting (R2 = 0.86). Moreover, the linear relationship between ILCCC system and other related research systems (octanol-water system and immobilized artificial membrane (IAM)) was analyzed, and the results indicate that SPC/PE/Chol ILCCC, DSPC/PE/Chol ILCCC and IAM systems have good fitting results, R2 values are 0.86 and 0.78, respectively. In addition, the normalization coefficients of ILCCC and IAM systems obtained by the linear free energy relationship (LFER) analysis are close and the d value is small. In short, the ILCCC is a simple and feasible method for studying drug membrane permeability.

Understanding the Binding Transition State After the Conformational Selection Step: The Second Half of the Molecular Recognition Process Between NS1 of the 1918 Influenza Virus and Host p85β.

Biomolecular recognition often involves conformational changes as a prerequisite for binding (i.e., conformational selection) or concurrently with binding (i.e., induced-fit). Recent advances in structural and kinetic approaches have enabled the detailed characterization of protein motions at atomic resolution. However, to fully understand the role of the conformational dynamics in molecular recognition, studies on the binding transition state are needed. Here, we investigate the binding transition state between nonstructural protein 1 (NS1) of the pandemic 1918 influenza A virus and the human p85β subunit of PI3K. 1918 NS1 binds to p85β via conformational selection. We present the free-energy mapping of the transition and bound states of the 1918 NS1:p85β interaction using linear free energy relationship and ϕ-value analyses. We find that the binding transition state of 1918 NS1 and p85β is structurally similar to the bound state with well-defined binding orientation and hydrophobic interactions. Our finding provides a detailed view of how protein motion contributes to the development of intermolecular interactions along the binding reaction coordinate.

Determination of lipid–water partition coefficient of neutral and ionic drugs by liposome electrokinetic chromatography

Profiling of lipid-water partition coefficients (KL/W ) of drugs is an essential issue during the early stage of drug development. In this study, two liposomes, including 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) + cholesterol (Chol) (DSPC/Chol liposomes) and soybean lecithin (SPC) + Chol (SPC/Chol liposomes), were prepared for the liposome electrokinetic chromatography (LEKC) analysis, and the logarithm of lipid-water partition coefficients (log KL/W ) of neutral and ionic drugs were determined based on an iterative method. The log KL/W values determined by the SPC/Chol or DSPC/Chol liposomes LEKC were linearly fitted, which showed a good fitting coefficient (R2 = 0.89). Furthermore, the linear relationship between the data obtained from LEKC system and octanol-water system, immobilized artificial membrane, Caco-2 cell model, and software prediction was analyzed, respectively. Results illustrated that DSPC/Chol liposomes or SPC/Chol liposomes had a good linear relationship with Caco-2 cell model, and R2 was 0.81 and 0.72, respectively. Moreover, the linear free energy relationship analysis suggested that the solute volume, hydrogen bond basicity, and J- were the main descriptors that drove the partition process of solutes in the SPC/Chol or DSPC/Chol LEKC system. In addition, the normalized properties of the SPC/Chol and DSPC/Chol LEKC systems through linear free energy relationship analysis were very close. In short, DSPC/Chol liposomes are more suitable for simulating cell membranes than SPC/Chol liposomes, and the developed LEKC is an effective partitioning model for measuring the log KL/W of drugs.

Linear Free Energy Relationships for Enzymatic Reactions: Fresh Insight from a Venerable Probe.

ConspectusLinear free energy relationships (LFERs) for substituent effects on reactions that proceed through similar transition states provide insight into transition state structures. A classical approach to the analysis of LFERs showed that differences in the slopes of Brønsted correlations for addition of substituted alkyl alcohols to ring-substituted 1-phenylethyl carbocations and to the β-galactopyranosyl carbocation intermediate of reactions catalyzed by β-galactosidase provide evidence that the enzyme catalyst modifies the curvature of the energy surface at the saddle point for the transition state for nucleophile addition. We have worked to generalize the use of LFERs in the determination of enzyme mechanisms. The defining property of enzyme catalysts is their specificity for binding the transition state with a much higher affinity than the substrate. Triosephosphate isomerase (TIM), orotidine 5′-monophosphate decarboxylase (OMPDC), and glycerol 3-phosphate dehydrogenase (GPDH) show effective catalysis of reactions of phosphorylated substrates and strong phosphite dianion activation of reactions of phosphodianion truncated substrates, with rate constants kcat/Km (M–1 s–1) and kcat/KdKHPi (M–2 s–1), respectively. Good linear logarithmic correlations, with a slope of 1.1, between these kinetic parameters determined for reactions catalyzed by five or more variant forms of each catalyst are observed, where the protein substitutions are mainly at side chains which function to stabilize the cage complex between the enzyme and substrate. This shows that the enzyme-catalyzed reactions of a whole substrate and substrate pieces proceed through transition states of similar structures. It provides support for the proposal that the dianion binding energy of whole phosphodianion substrates and of phosphite dianion is used to drive the conversion of these protein catalysts from flexible and entropically rich ground states to stiff and catalytically active Michaelis complexes that show the same activity toward catalysis of the reactions of whole and phosphodianion truncated substrates. There is a good linear correlation, with a slope of 0.73, between values of the dissociation constants log Ki for release of the transition state analog phosphoglycolate (PGA) trianion and log kcat/Km for isomerization of GAP for wild-type and variants of TIM. This correlation shows that the substituted amino acid side chains act to stabilize the complex between TIM and the PGA trianion and that ca. 70% of this stabilization is observed at the transition state for substrate deprotonation. The correlation provides evidence that these side chains function to enhance the basicity of the E165 side chain of TIM, which deprotonates the bound carbon acid substrate. There is a good linear correlation, with a slope of 0.74, between the values of ΔG‡ and ΔG° determined by electron valence bond (EVB) calculations to model deprotonation of dihydroxyacetone phosphate (DHAP) in water and when bound to wild-type and variant forms of TIM to form the enediolate reaction intermediate. This correlation provides evidence that the stabilizing interactions of the transition state for TIM-catalyzed deprotonation of DHAP are optimized by placement of amino acid side chains in positions that provide for the maximum stabilization of the charged reaction intermediate, relative to the neutral substrate.

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*.

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.[1] In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho- deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.

Online Real-Time Monitoring of Exhaled Breath Particles Reveals Unnoticed Transport of Nonvolatile Drugs from Blood to Breath

We used online secondary electrospray ionization mass spectrometry to measure venlafaxine (VEN), a nonvolatile drug, in the exhaled air of mice intraperitoneally treated with VEN. The breath pharmacokinetic (PK) profile of VEN was recorded, which was in good agreement with that of the blood. Combined with online collection of exhaled breath particles (EBPs), it was shown that VEN existed as part of EBPs rather than gas molecules in the breath. Linear free-energy relationship analysis confirmed that almost completely ionized VEN at physiological conditions unlikely partition from the lung lining fluid (LLF) into breath air. This implies that the occurrence of VEN in exhaled air accompanies the formation of EBPs from the LLF. By comparison with the low breath signals of VEN metabolites, passive membrane permeability and lung/blood partition coefficient are suggested as the main influencing factors for the levels of drugs in the breath. This study advances our knowledge on the mechanism by which nonvolatile drugs are transferred from blood into exhaled breath, providing guidance for breath test-based therapeutic drug monitoring.

Removal of acetaminophen through direct electron transfer by reactive Mn2O3: Efficiency, mechanism and pathway

Mn2O3 with certain oxidative reactivity, was fabricated via sol-gel method and applied for the removal of acetaminophen (APAP). The mechanism of APAP oxidation was revealed in depth through electrochemical tests and X-ray photoelectron spectroscopy (XPS). Moreover, the selective abatement of various organic contaminants contained different functional groups by Mn2O3 was investigated through linear free energy relationship (LFER) estimated with peak potentials (Eop) of these organic contaminants. Under acidic condition, APAP could be effectively eliminated by Mn2O3. The open circuit potential (OCP) and zeta potential tests illustrate that the oxidative reactivity of Mn2O3 is associated to the surface acid-base behavior of Mn2O3 and its surface charge situation. The XPS experiments and Mn leaching results imply that Mn(III) could capture electron from APAP and release Mn2+ to aqueous phase. The intermediates could be ascribed to fragmentation of acetamido radicals and phenoxy radicals, both of which were formed through electron transfer from APAP to Mn2O3. The reactive Mn2O3 shows selective oxidation of different contaminants in the electron transfer process. LFER analysis indicates good negative linear correlation between lnk1 and Eop of various pollutants. The efficiency of Mn2O3 in the elimination of APAP and selective oxidation of different contaminants suggest some new insights for transformation of APAP and other electron-rich pollutants in the environments.

The high-energy transition state of the glutamate transporter homologue GltPh.

Membrane transporters mediate cellular uptake of nutrients, signaling molecules, and drugs. Their overall mechanisms are often well understood, but the structural features setting their rates are mostly unknown. Earlier single‐molecule fluorescence imaging of the archaeal model glutamate transporter homologue GltPh from Pyrococcus horikoshii suggested that the slow conformational transition from the outward‐ to the inward‐facing state, when the bound substrate is translocated from the extracellular to the cytoplasmic side of the membrane, is rate limiting to transport. Here, we provide insight into the structure of the high‐energy transition state of GltPh that limits the rate of the substrate translocation process. Using bioinformatics, we identified GltPh gain‐of‐function mutations in the flexible helical hairpin domain HP2 and applied linear free energy relationship analysis to infer that the transition state structurally resembles the inward‐facing conformation. Based on these analyses, we propose an approach to search for allosteric modulators for transporters.

TAML- and Buffer-Catalyzed Oxidation of Picric Acid by H2O2: Products, Kinetics, DFT, and the Mechanism of Dual Catalysis.

Studies of the oxidative degradation of picric acid (2,4,6-trinitrophenol) by H2O2 catalyzed by a fluorine-tailed tetraamido macrocyclic ligand (TAML) activator of peroxides [FeIII{4,5-Cl2C6H2-1,2-(NCOCMe2NCO)2CF2}(OH2)]- (2) in neutral and mildly basic solutions revealed that oxidative degradation of this explosive demands components of phosphate or carbonate buffers and is not oxidized in their absence. The TAML- and buffer-catalyzed oxidation is subject to severe substrate inhibition, which results in at least 1000-fold retardation of the interaction between the iron(III) resting state of 2 and H2O2. The inhibition accounts for a unique pH profile for the TAML catalysis with the highest activity at pH 7. Less aggressive TAMLs such as [FeIII{C6H4-1,2-(NCOCMe2NCO)2CMe2}(OH2)]- are catalytically inactive. The roles of buffer components in modulating catalysis have been clarified through detailed kinetic investigations of the degradation process, which is first order in the concentration of 2 and shows ascending hyperbolic dependencies in the concentrations of all three participants, i.e., H2O2, picrate, and phosphate/carbonate. The reactivity trends are consistent with a mechanism involving the formation of double ([LFeIII-Q]2-) and triple ([LFeIII-{Q-H2PO4}]3-) associates, which are unreactive and reactive toward H2O2, respectively. The binding of phosphate converts [LFeIII-Q]2- to the reactive triple associate. Density functional theory suggests that the stability of the double associate is achieved via both Fe-Ophenol binding and π-π stacking. The triple associate is an outer-sphere complex where phosphate binding occurs noncovalently through hydrogen bonds. A linear free energy relationship analysis of the reactivity of the mono-, di-, and trinitro phenols suggests that the rate-limiting step involves an electron transfer from phenolate to an oxidized ironoxo intermediate, giving phenoxy radicals that undergo further rapid oxidation that lead to eventual mineralization.

Peroxymonosulfate activated with waste battery-based Mn-Fe oxides for pollutant removal: Electron transfer mechanism, selective oxidation and LFER analysis

Mn2O3-Fe2O3 catalyst was fabricated from spent alkaline batteries and used for effective elimination of acetaminophen (APAP) by activating peroxymonosulfate (PMS). APAP removal at various initial pH, its degradation pathway and the stability of catalyst were investigated. The Mn(III) was inferred to be the primary active site and Fe(III) could improve the corrosion resistance through intermetallic interactions. Chemical quenching experiments, electron paramagnetic resonance (EPR) spectroscopy, solvent exchange, open circuit potential (OCP) and chronoamperometry tests imply that APAP is oxidized by electron transfer through highly reactive surface-adsorbed PMS. Fourier transform infrared (FTIR), in situ Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) spectra and ionic strength experiments further revealed the interaction between the catalyst and PMS. The Mn2O3-Fe2O3/PMS system exhibits selective oxidation for different contaminants, and linear free energy relationship (LFER) was employed to investigate the effect of structure and properties of pollutant on the reaction kinetics. Pollutant with peak potential (Eop) > 0.91 V, the steady-state OCP in the Mn2O3-Fe2O3/PMS system, is resistant to oxidation; while pollutant with Eop < 0.91 V is prone to be oxidized and there is a good correlation between apparent first-order rate constant (k1) and Eop. The research not only puts in-depth study into PMS activation through environment-friendly Mn-Fe oxides from spent alkaline batteries, but also provides some new insights for nonradical mechanism, selective oxidation and LFER study.

Real-Time Fluorescence-Based Approaches to Disentangle Mechanisms of a Protein's RNA Chaperone Activity.

RNA-binding proteins with an RNA chaperone activity exert either one or both of the following catalytic activities: (1) RNA annealing, i.e., the protein supports intra- as well as intermolecular RNA-RNA interactions and (2) strand displacement, i.e., the protein mediates the exchange of individual strands of a preexisting RNA duplex. To discriminate and further characterize these activities, it requires defined assay systems. These are based on entirely or partially complementary RNA oligonucleotides that are labeled with fluorescent and/or quencher dyes. The non-catalyzed and the protein-supported associations of the RNA molecules are followed by a real-time fluorescence resonance energy transfer (FRET) system. By site-specific modification of the RNAs or the protein, the substrate- and protein-specific parameters of the RNA chaperone activity can be explored and identified.In this chapter, we present strategies on the design of labeled RNA molecules to be used to characterize the activities of an RNA-binding protein and explain how to monitor progress curves of RNA annealing and strand displacement reactions in single cuvette or well-plate scales. We provide sets of equations and models to determine and analyze different types of reactions, e.g., by calculation of first- and second-order rate constants. Likewise, we demonstrate how to exploit these simple experimental setups to elucidate elementary principles of the reaction mechanisms performed by the protein of interest by applying basic kinetic applications, such as ARRHENIUS and linear free energy relationship analyses. These approaches will be explained by providing example plots and graphs from experiments investigating the RNA chaperone activities of the RNA-binding proteins NF90-NF45 and AUF1 p45.

Analysis of the aqueous solubility of trialkyl phosphates, dialkyl alkylphosphonates, dialkylphosphites and alkyl dialkylphosphinates

Linear free energy relationship (LFER) analysis based on the molar intrinsic volume (Vx), McGowan hydrophile‒lipophile balance (HLB) and cumulative Kabachnik constants (Σσϕ) of considered solutes has been performed for the solubility of trialkyl phosphates, dialkyl alkylphosphonates, dialkyl phosphites and alkyl dialkylphosphonates in pure water (called also as their aqueous solubility). The descriptors mentioned above are known for all considered solutes and are strongly correlated with their aqueous solubility. From the correlation found for trialkyl phosphates, dialkyl alkylphosphonates and dialkyl phosphites it follows that the mean contribution of each methylene group in their structure (Δlog Sw) is a constant for these homologous series and equal to − 0.41. It means that within of homologous series the aqueous solubility of succeeding solutes decreases regularly. The established increment has been further used as a tool for the preliminary selection of solutes whose aqueous solubility at 25 °C is in agreement with this condition. The adequate model (further denoted as AR model) based on the accessible data of temperature effects upon the aqueous solubility of tributyl phosphate, dibutyl butylphosphonate and butyl dibutylphosphinate has been formulated and then tested with positive results for the other solutes whose solubility is known at a selected constant temperature, e.g. at 25 °C. It should noticed, however, that in this case there are some serious restrictions. First, the interpretation and formulation of conclusions for the solutes which aqueous solubility is known at one selected temperature (e.g. 25 °C) or if it has been determined at a few temperatures only, should be made with care. Second, the obtained results with AR model cannot be used for prediction of temperature effects upon the aqueous solubility of such solutes. Simultaneously, the results obtained with AR model have been compared with those following from the modified Abraham model. Such comparison has been possible due to a significant progress in the different application of Abraham model for several organophosphorus derivatives as monobasic dialkyl- and diarylphosphoric acids, dialkyl- and diphenylphosphinic acids, trialkyl- and triaryl phosphates, dimethyl methylphosphonate, dialkylphosphites and some of trialkyl- and triarylphosphine oxides, respectively.

The Conformational Wave in Capsaicin Activation of Transient Receptor Potential Vanilloid 1 Ion Channel

The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Phi-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4-S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.

Atroposelective Catalytic Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides with Achiral Morita-Baylis-Hillman Carbonates.

A highly efficient method to access axially chiral anilides through asymmetric allylic alkylation reaction with achiral Morita-Baylis-Hillman carbonates by using a biscinchona alkaloid catalyst was reported. Through the atroposelective approach, a broad range of axially chiral anilide products with different acyl groups, such as substituted phenyl, naphthyl, alkyl, enyl, styryl, and benzyl, were generated with very good yields, moderate to excellent cis: trans ratios, and good to excellent enantioselectivities. The reaction can be scaled up, and the synthetic utility of axially chiral anilides was proved by transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction.