Concerted Transition Research Articles

High Constitutive Activity Accounts for the Combination of Enhanced Direct Activation and Reduced Potentiation in Mutated GABAA Receptors.

GABAA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs, including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation. We show here that divergent effects on potentiation and direct activation can be mediated by increased constitutive open probability in the mutant receptor without any specific effect on the interactions between the allosteric drug and the receptor. By simulating GABAA receptor activity using the concerted transition model, we demonstrate that the predicted degree of potentiation is reduced as the level of constitutive activity increases. The model further predicts that a potentiating effect of an allosteric modulator is a computable value that depends on the level of constitutive activity, the amplitude of the response to the agonist, and the amplitude of the direct activating response to the modulator. Specific predictions were confirmed by electrophysiological data from the binary α1β3 and concatemeric ternary β2α1γ2L+β2α1 GABAA receptors. The corollaries of reduced potentiation due to increased constitutive activity are isobolograms that conform to simple additivity and a loss of separation between the concentration-response relationships for direct activation and potentiation.

Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations.

The use of frustrated Lewis pairs is an extremely important approach to metal-free hydrogenations. In contrast to the rapid growth of catalytic reactions, asymmetric hydrogenations are far less developed due to a severe shortage of readily available chiral frustrated Lewis pair catalysts with high catalytic activities and selectivities. Unlike the stable Lewis base component of frustrated Lewis pairs, the moisture-sensitive boron Lewis acid component is difficult to prepare. The development of convenient methods for the quick construction of chiral boron Lewis acids is therefore of great interest. In this Account, we summarize our recent studies on frustrated Lewis pair-catalyzed, asymmetric metal-free hydrogenations and hydrosilylations. To address the shortage of highly active and selective catalysts, we developed a novel strategy for the in situ preparation of chiral boron Lewis acids by the hydroboration of chiral dienes or diynes with Piers' borane without further purification, which allows chiral dienes or diynes to act like ligands. This strategy ensures the construction of a useful toolbox of catalysts for asymmetric metal-free hydrogenations and hydrosilylations is rapid and operationally simple. Another strategy is using combinations of readily available Lewis acids and bases containing hydridic and acidic hydrogen atoms, respectively, as a novel type of frustrated Lewis pairs. Such systems provide a great opportunity for using simple chiral Lewis bases as the origins of asymmetric induction. With chiral diene-derived boron Lewis acids as catalysts, a broad range of unsaturated compounds, such as imines, silyl enol ethers, 2,3-disubstituted quinoxalines, and polysubstituted quinolines, are all viable substrates for asymmetric metal-free hydrogenations and give the corresponding products in good yields with high enantioselectivities and/or stereoselectivities. These chiral catalysts are very effective for bulky substrates, and the substrate scope for these metal-free asymmetric hydrogenations has been dramatically expanded. Chiral alkenylboranes were designed to enhance the rigidity of the framework and modify the Lewis acidity through the resulting double bonds. Frustrated Lewis pairs of chiral alkenylboranes and phosphines are a class of highly effective catalysts for asymmetric Piers-type hydrosilylations of 1,2-dicarbonyl compounds, and they give the desired products in high yields and enantioselectivities. Moreover, asymmetric transfer hydrogenations of imines and quinoxalines with ammonia borane as the hydrogen source have been achieved with frustrated Lewis pair of Piers' borane and (R)-tert-butylsulfinamide as the catalyst. Mechanistic studies have suggested that the hydrogen transfer occurs via an 8-membered ring transition state, and regeneration of the reactive frustrated Lewis pair with ammonia borane occurs through a concerted 6-membered ring transition state.

Mechanistic Study on Aryl-Exchange Reaction of Diaryl-λ3-iodane with Aryl Iodide.

Because of its hyper-leaving ability, as well as its strong oxidizing ability, diaryl(triflato)-λ3-iodane transfers one of the aryl groups to iodoarenes simply upon gentle heating (>85 °C) in nonpolar solvents. We have performed an in-depth mechanistic study of this unusual aryl transfer reaction. A combination of experimental (product analysis, kinetic study, and substituent effects) and density functional theoretical approaches revealed that the reaction proceeds through a concerted bimolecular transition state, in which ipso-carbon binds loosely to both iodine centers. We also evaluated electronic effects on the thermodynamic stability of diaryl-λ3-iodanes.

Insights into the evolution, biogeography and natural history of the acorn ants, genus Temnothorax Mayr (hymenoptera: Formicidae)

BackgroundTemnothorax (Formicidae: Myrmicinae) is a diverse genus of ants found in a broad spectrum of ecosystems across the northern hemisphere. These diminutive ants have long served as models for social insect behavior, leading to discoveries about social learning and inspiring hypotheses about the process of speciation and the evolution of social parasitism. This genus is highly morphologically and behaviorally diverse, and this has caused a great deal of taxonomic confusion in recent years. Past efforts to estimate the phylogeny of this genus have been limited in taxonomic scope, leaving the broader evolutionary patterns in Temnothorax unclear. To establish the monophyly of Temnothorax, resolve the evolutionary relationships, reconstruct the historical biogeography and investigate trends in the evolution of key traits, I generated, assembled, and analyzed two molecular datasets: a traditional multi-locus Sanger sequencing dataset, and an ultra-conserved element (UCE) dataset. Using maximum likelihood, Bayesian, and summary-coalescent based approaches, I analyzed 22 data subsets consisting of 103 ingroup taxa and a maximum of 1.8 million base pairs in 2485 loci.ResultsThe results of this study suggest an origin of Temnothorax at the Eocene-Oligocene transition, concerted transitions to arboreal nesting habits in several clades during the Oligocene, coinciding with ancient global cooling, and several convergent origins of social parasitism in the Miocene and Pliocene. As with other Holarctic taxa, Temnothorax has a history of migration across Beringia during the Miocene.ConclusionsTemnothorax is corroborated as a natural group, and the notion that many of the historical subgeneric and species group concepts are artificial is reinforced. The strict form of Emery’s Rule, in which a socially parasitic species is sister to its host species, is not well supported in Temnothorax.

GABA Type A Receptor Activation in the Allosteric Coagonist Model Framework: Relationship between EC50 and Basal Activity.

The concerted transition model for multimeric proteins is a simple formulation for analyzing the behavior of transmitter-gated ion channels. We used the model to examine the relationship between the EC50 for activation of the GABA type A (GABAA) receptor by the transmitter GABA and basal activity employing concatemeric ternary GABAA receptors expressed in Xenopus oocytes. Basal activity, reflecting the receptor function in the absence of the transmitter, can be changed either by mutation to increase constitutive activity or by the addition of a second agonist (acting at a different site) to increase background activity. The model predicts that either mechanism for producing a change in basal activity will result in identical effects on the EC50 We examined receptor activation by GABA while changing the level of basal activity with the allosterically acting anesthetics propofol, pentobarbital, or alfaxalone. We found that the relationship between EC50 and basal activity was well described by the concerted transition model. Changes in the basal activity by gain-of-function mutations also resulted in predictable changes in the EC50 Finally, we altered the number of GABA-binding sites by a mutation and again found that the relationship could be well described by the model. Overall, the results support the idea that interactions between the transmitter GABA and the allosteric agonists propofol, pentobarbital, or alfaxalone can be understood as reflecting additive and independent free energy changes, without assuming any specific interactions.

Insuperable problems of the genetic code initially emerging in an RNA world

Differential equations for error-prone information transfer (template replication, transcription or translation) are developed in order to consider, within the theory of autocatalysis, the advent of coded protein synthesis. Variations of these equations furnish a basis for comparing the plausibility of contrasting scenarios for the emergence of specific tRNA aminoacylation, ultimately by enzymes, and the relationship of this process with the origin of the universal system of molecular biological information processing embodied in the Central Dogma. The hypothetical RNA World does not furnish an adequate basis for explaining how this system came into being, but principles of self-organisation that transcend Darwinian natural selection furnish an unexpectedly robust basis for a rapid, concerted transition to genetic coding from a peptide·RNA world.

The Actions of Drug Combinations on the GABAA Receptor Manifest as Curvilinear Isoboles of Additivity.

Drug interactions are often analyzed in terms of isobolograms. In the isobologram, the line connecting the axial points corresponding to the concentrations of two different drugs that produce an effect of the same magnitude is termed an isobole of additivity. Although the isobole of additivity can be a straight line in some special cases, previous work has proposed that it is curvilinear when the two drugs differ in their maximal effects or Hill slopes. Modulators of transmitter-gated ion channels have a wide range of maximal effects as well as Hill slopes, suggesting that the isoboles for drug actions on ion channel function are not linear. In this study, we have conducted an analysis of direct activation and potentiation of the human α1β2γ2L GABAA receptor to demonstrate that: 1) curvilinear isoboles of additivity are predicted by a concerted transition model where the binding of each GABAergic drug additively and independently reduces the free energy of the open receptor compared with the closed receptor; and 2) experimental data for receptor activation using the agonist pair of GABA and propofol or potentiation of responses to a low concentration of GABA by the drug pair of alfaxalone and propofol agree very well with predictions. The approach assuming independent energetic contributions from GABAergic drugs enables, at least for the drug combinations tested, a straightforward method to accurately predict functional responses to any combination of concentrations.

Dynamic effects in the didehydro‐Diels‐Alder (DDDA) reaction of enyne‐ketoenes: 50% stepwise bond formation in spite of concerted transition state

AbstractThe C2─C6/Diels‐Alder cyclization of enyne‐ketoene 1 was studied by experiments, theoretical calculations, and dynamic trajectory computations. The failure to trap possible intermediate(s), indicates a concerted reaction mechanism. A detailed search for stationary points revealed a concerted mechanism and surprisingly a diradical intermediate with no direct connection to the enyne‐ketoene 1. To probe the accessibility of this intermediate quasiclassical trajectories were initiated from the concerted transition state structure. Notably, 36% of the trajectories reach the product zone directly and 5% arrive at the product via the intermediate diradical. Additionally, 31% of the trajectories go to the intermediate zone and stay there within the simulation time limit.

Mechanistic insights into copper-catalyzed trifluoromethylation of aryl boronic acids: a theoretical study

Density functional theory (DFT) calculations were employed to study the mechanism for copper-catalyzed trifluoromethylation of aryl boronic acids by Togni’s reagent. Computational results suggest that the catalytic cycle proceeds with the transmetallation between phenylboronic acid and copper(I) species, which generates a phenylcopper(I) intermediate. Subsequent coordination of Togni’s reagent and the electrophilic substitution of CF3 group to phenyl group finally afford the trifluoromethylation product through a concerted five-membered ring transition state. The transmetallation process with an activation free energy of 21.7 kcal/mol is determined to be the rate-determining step of this reaction. Moreover, the reactivity of alkylboronic acid was also calculated and proven to be unfavorable due to the higher activation free energy of transmetallation process.

Microscopic analysis of AgCl polymorphism

A detailed theoretical study of the structural properties of the phases involved in the pressure-induced polymorphic sequence of AgCl is reported. As many other binary ionic compounds, AgCl crystallizes in the B1 (NaCl-type) structure at ambient pressure and shows a high-pressure B2 (CsCl-type) structure under pressure. However, unlike alkali halides, there is not a direct transformation from one to the other. The greater polarizability of the silver chloride structure enables the stabilization of two other phases in between B1 and B2: the monoclinic (KOH-type) and the orthorhombic (TlI-type, B33) structures. This polymorphic sequence is specially interesting, since a concerted transition pathway within the monoclinic KOH-type symmetry has also been proposed as a transition pathway in the B1 → B2 transformation. This would point at a connection between symmetries that are thermodynamically and kinetically stabilized, with phases that appear under pressure being good candidates for mechanistic analyses. Our calculations yield cell parameters and structural behavior under pressure in overall good agreement with available experimental data for all these phases and extend the information previously observed for the four polymorphs (e.g., compressibilities). Computed transition pressures confirm the B1→KOH-type→B33 sequence. In order to analyze the occurrence of the KOH-type phase between the B1 and B33 phases, we have resorted to the Atoms In Molecules approach to obtain the evolution of charges with pressure. We find that the descent to the KOH-type symmetry provides a continuous change in ionic charges between B1 and B33 phases, which implies a smaller stress. Thus, coupling group–subgroup relationships to chemical bond analysis can provide microscopic insight into why a given symmetry is favored.

An Uncanny Dehydrogenation Mechanism: Polar Bond Control over Stepwise or Concerted Transition States.

The mechanism of the dehydrogenation of N-heterocycles with the recently established bifunctional catalyst (iPrPNP)Fe(CO)(H) was investigated through experiments and density functional theory calculations (iPrPNP = iPr2PCH2CH2NCH2CH2PiPr2). In this system, the saturated N-heterocyclic substrates are completely dehydrogenated to the aromatic products. Calculations indicate that dehydrogenation barriers of the C-C bonds are very high in energy (ΔG‡ = 37.4-42.2 kcal/mol), and thus dehydrogenation only occurs at the C-N bond (ΔG‡ = 9.6-22.2 kcal/mol). Interestingly, substrates like piperidine with relatively unpolarized C-N bonds are dehydrogenated through a concerted proton/hydride transfer bifunctional transition state involving the nitrogen on the PNP ligand. However, substrates with polarized C-N bonds entail stepwise (proton then hydride) bifunctional dehydrogenation.

The mechanism of the gas-phase elimination kinetics of the β,γ-unsaturated aldehyde 2,2–dimethyl-3-butenal: a theoretical study

ABSTRACTThe study on the mechanism of the gas-phase elimination or thermal decomposition kinetics of 2, 2-dimethyl-3-butenal has been carried out by using theoretical calculation at MP2, combined ab initio CBSQB3 and DFT (B3LYP, B3PW91, MPW1PW91, PBEPBE, PBE1PBE, CAMB3LYP, M06, B97d) levels of theory. A good reasonable agreement between experimental and calculated parameters was obtained by using CAMB3LYP/6-311G(d,pd) calculations. The contrasted calculated parameters against experimental values suggested decarbonylation reaction to proceed through a concerted five-membered cyclic transition state type of mechanism, involving the hydrogen transfer from the carbonyl carbon to the gamma carbon, consistent with observed kinetic isotope effect. The breaking of alpha carbon–carbonyl carbon bond to produce carbon monoxide is 50% advanced in the transition state. The reaction mechanism may be described as a concerted moderately non-synchronous process. Examination of the Atoms in Molecules (AIM) analysis of electron density supports the suggested mechanism.

Genome-wide Analysis of RNA Polymerase II Termination at Protein-Coding Genes

At the end of protein-coding genes, RNA polymerase (Pol) II undergoes a concerted transition that involves 3'-processing of the pre-mRNA and transcription termination. Here, we present a genome-wide analysis of the 3'-transition in budding yeast. We find that the 3'-transition globally requires the Pol II elongation factor Spt5 and factors involved in the recognition of the polyadenylation (pA) site and in endonucleolytic RNA cleavage. Pol II release from DNA occurs in a narrow termination window downstream of the pA site and requires the "torpedo" exonuclease Rat1 (XRN2 in human). The Rat1-interacting factor Rai1 contributes to RNA degradation downstream of the pA site. Defects in the 3'-transition can result in increased transcription at downstream genes.

Kinetic Determination of the Gas-Phase Decarbonylation of Butyraldehyde in the Presence of HCl Catalyst

The gas-phase kinetics and mechanism of the homogeneous elimination of CO from butyraldehyde in the presence of HCl has been experimentally studied. The reaction is homogeneous and follows the second-order kinetics with the following rate expression: log k1 (s−1 L mol−1) = (13.27 ± 0.36) – (173.2 ± 4.4) kJ mol−1(2.303RT)−1. Experimental data suggested a concerted four-membered cyclic transition state type of mechanism. The first and rate-determining step occurs through a four-membered cyclic transition state to produce propane and formyl chloride. The formyl chloride intermediate rapidly decomposes to CO and HCl gases.

Homogeneous, unimolecular gas-phase pyrolysis kinetics of 4- and 2-hydroxyacetophenone

The pyrolyses kinetics of 4- and 2-hydroxyacetophenones in the gas phase were determined in a static system, where the reaction vessel was deactivated with allyl bromide, and in the presence of the free radical inhibitor propene when necessary. The working temperature range was 464–485°C, and the pressure range was 44–133Torr. The reactions were found to be homogeneous and unimolecular and to obey a first-order rate law. The products for 4-hydroxyacetophenone are phenol and ketene, while for 2-hydroxyacetophenone are phenol and ketene, with smaller amounts of phenyl acetate and benzofuran. The Arrhenius expression of the pyrolyses was found for 4-hydroxyacetophenone: logk1 (s−1)=(13.83±0.08)−(258.1±1.1)kJmol−1(2.303RT)−1(r=0.9999); for 2-hydroxyacetophenone: logk1 (s−1)=(13.81±0.43)−(251.9±6.2)kJmol−1(2.303RT)−1(r=0.9991). Deacetylation may be considered as the primary reasonable mechanism, and the process appears to proceed through a semi-polar concerted four-membered cyclic transition state.

Kinetic and mechanism of the gas-phase pyrolysis of exo-2-norbornyl formate

The rate coefficient of the gas-phase pyrolysis or elimination of exo-2-norbornyl formate was determined in a deactivated, static reaction vessel over the temperature range 300–350°C and pressure range 41–105Torr. The substrate exo-2-norbornyl formate yielded surprisingly exo-2-norborneol and CO gas. This reaction, in the presence or absence of the free radical inhibitor toluene, proved to be homogeneous, unimolecular and follows a first-order rate law. The rate of equation is given by the following Arrhenius equation: log k1 (s−1)=(13.85±0.23)−(194.6±2.7)kJmol−1(2.303RT)−1, r=0.9998.Experimental data suggested a semi-polar concerted three-membered cyclic transition state type of mechanism.

Nucleophilic Deoxyfluorination of Phenols via Aryl Fluorosulfonate Intermediates.

This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SO2F2) and tetramethylammonium fluoride (NMe4F) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMe4F proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SO2F2 and NMe4F. Ab initio calculations suggest that carbon-fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate.

An unprecedented trinuclear FeII triazole-based complex exhibiting a concerted and complete sharp spin transition above room temperature.

We report a triazole-based trinuclear complex as the first example that displays a complete one-step first-order [HS-HS-HS] ↔ [LS-LS-LS] spin transition at 318 K. The strong ferro-elastic interactions, between the three metal centers, have been identified as the source of the concerted spin transition in this trinuclear complex.

Mechanistic investigation of cis and trans oxidative addition to acetylacetonato-1,5-cyclooctadieneiridium(I)

Density functional theory (DFT) calculations of the oxidative addition of CH3I, as well as Hg(CN)2, to [Ir(acac)(cod)] are described (acac=acetylacetone). Both cis and trans oxidative addition mechanisms are considered and compared to experimental data. The DFT calculated thermodynamically most stable oxidative addition products are trans-[Ir(acac)(cod)(CH3)(I)] and cis-[Ir(acac)(cod)(HgCN)(CN)]. The steric demand of the cod ligand leads to a distorted octahedral trans-[Ir(acac)(cod)(CH3)(I)] complex, with the CCH3-Ir-I angle deviating by more than 20° from 180°, as expected for real octahedral geometry. However, the steric demand of the cod ligand does not lead to any cis transition state for the [Ir(acac)(cod)]+CH3I reaction, rather the trans transition state is energetically favoured, as is generally found for oxidative addition of CH3I to square planar complexes. On the other hand, oxidative addition of Hg(CN)2 to [Ir(acac)(cod)], occurs via a concerted three-centre cis transition state structure. The concerted three-centre cis transition state structure is confirmed by the existence of a ring critical point, as obtained by the Bader’s quantum theory of atoms in molecules analysis of the cis transition state structure. Both trans addition of CH3I to [Ir(acac)(cod)] as well as cis addition of Hg(CN)2 to [Ir(acac)(cod)], are in agreement with experimental observation.

Catalytic Synthesis of Saturated Oxygen Heterocycles by Hydrofunctionalization of Unactivated Olefins: Unprotected and Protected Strategies.

A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lactones. The Co complex was optimized for previously rare medium ring formation by hydrofunctionalization of unactivated olefins. The powerful Co catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxylation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co complex.