Late Transition State Research Articles

Insights into the Catalytic Mechanism and Transition State Stabilization of 5′‐Methylthioadenosine Nucleosidase using Neutron Crystallography

5′‐Methylthioadenosine nucleosidase (MTAN) is an obligatory homodimeric protein that catalyzes the hydrolysis of the N‐ribosidic bond of a variety of adenosine‐containing metabolites. The proposed catalytic mechanism of MTAN is initiated by D198 protonating the N7 position of the adenyl moiety, which consequently causes elongation and ultimate breaking of the N‐ribosidic bond, resulting in the formation of an oxocarbenium ion intermediate. Of particular interest is the pKa elevation of D198 that was proposed to have a value of 8.2, which is significantly higher than the theoretical pKa for an aspartic acid side chain. In this study we present the first joint X‐ray/neutron crystal structures of Helicobacter pylori MTAN (HpMTAN) in complex with a substrate (S‐adenosylhomocysteine), early (Formycin A) and late (p‐ClPh‐Thio‐DADMe‐ImmA) dissociative transition state analogues, as well as with the catalytic products (adenine and S‐ribosylhomocysteine). The solved X‐ray/neutron crystal structures provide the positions of exchangeable hydrogen atoms and protonation states of ionizable groups that further our understanding of the catalytic mechanism as well as the stabilization of the transition state for HpMTAN. These results confirm that the catalytic reaction is initiated by D198 functioning as a general acid through the observation of a shared deuterium atom with unconventional hydrogen bond geometry between the carboxylate group of D198 and the N7 position of adenine. Additionally, the transition state analogues neutron structures illustrate the minor differences in the hydrogen bond interactions resulting in the DADMe‐ImmA analogues being extremely potent inhibitors with Kd values in the picomolar range, despite HpMTAN shown to contain an early dissociative transition state structure.Support or Funding InformationThis work was supported by the Center for the Advancement of Science in Space via a cooperative agreement with National Aeronautics and Space Administration Grant N‐123528‐01 (to D.R.R) and by National Institute of Allergy and Infectious Disease/NIH Grant AI105084 (to D.R.R.).

Assessing the effective factors affecting the conformational preferences and the early and late transition states of the unimolecular retro-ene decomposition reactions of ethyl cyanate, ethyl thiocyanate and ethyl selenocyanate

The variations of Δ[(HCGAE(X3–C4weakening) – HCGAE(X3–C4strengthening)] parameters correlate well with the variations of the retro-ene decomposition reactions barrier heights going from compound1to compound3.

The Lattice Kinetic Monte Carlo Simulation of Atomic Diffusion and Structural Transition for Gold

For the kinetic simulation of metal nanoparticles, we developed a self-consistent coordination-averaged energies for Au atoms based on energy properties of gold bulk phases. The energy barrier of the atom pairing change is proposed and holds for the microscopic reversibility principle. By applying the lattice kinetic Monte Carlo simulation on gold films, we found that the atomic diffusion of Au on the Au(111) surface undergoes a late transition state with an energy barrier of about 0.2 eV and a prefactor between 40~50 Å2/ps. This study also investigates the structural transition from spherical to faceted gold nanoparticles upon heating. The temperatures of structural transition are in agreement with the experimental melting temperatures of gold nanoparticles with diameters ranging from 2 nm to 8 nm.

Philicities, Fugalities, and Equilibrium Constants.

The mechanistic model of Organic Chemistry is based on relationships between rate and equilibrium constants. Thus, strong bases are generally considered to be good nucleophiles and poor nucleofuges. Exceptions to this rule have long been known, and the ability of iodide ions to catalyze nucleophilic substitutions, because they are good nucleophiles as well as good nucleofuges, is just a prominent example for exceptions from the general rule. In a reaction series, the Leffler-Hammond parameter α = δΔG(⧧)/δΔG° describes the fraction of the change in the Gibbs energy of reaction, which is reflected in the change of the Gibbs energy of activation. It has long been considered as a measure for the position of the transition state; thus, an α value close to 0 was associated with an early transition state, while an α value close to 1 was considered to be indicative of a late transition state. Bordwell's observation in 1969 that substituent variation in phenylnitromethanes has a larger effect on the rates of deprotonation than on the corresponding equilibrium constants (nitroalkane anomaly) triggered the breakdown of this interpretation. In the past, most systematic investigations of the relationships between rates and equilibria of organic reactions have dealt with proton transfer reactions, because only for few other reaction series complementary kinetic and thermodynamic data have been available. In this Account we report on a more general investigation of the relationships between Lewis basicities, nucleophilicities, and nucleofugalities as well as between Lewis acidities, electrophilicities, and electrofugalities. Definitions of these terms are summarized, and it is suggested to replace the hybrid terms "kinetic basicity" and "kinetic acidity" by "protophilicity" and "protofugality", respectively; in this way, the terms "acidity" and "basicity" are exclusively assigned to thermodynamic properties, while "philicity" and "fugality" refer to kinetics. Benzhydrylium ions (diarylcarbenium ions) with para- and meta-substituents are used as reference compounds for these investigations, because their Lewis acidities and electrophilicities can be varied by many orders of magnitude, while the steric surroundings of the reaction centers are kept constant. The rate constants for their reactions with nucleophiles correlate linearly over a wide range with the Lewis acidities of the benzhydrylium ions: from slow reactions with late transition states to very fast reactions with early, reactant-like transition states (including reactions which proceed without an enthalpic barrier, ΔH(⧧) = 0). Thus, unequivocal evidence is obtained that even within a series of closely related reactions, the Leffler-Hammond α cannot be a measure for the position of the transition state. Differences in intrinsic barriers lead to deviations from the linear rate-equilibrium correlations and give rise to counterintuitive phenomena. Thus, 1,4-diazabicyclo[2.2.2]octane (DABCO) reacts with lower intrinsic barriers than 4-(dimethylamino)pyridine (DMAP) and, therefore, is a stronger nucleophile as well as a better nucleofuge than DMAP. Common synthetically used SN2 reactions are presented, in which weak nucleophiles replace stronger ones. Whereas solvolysis rates of alkoxy- and alkyl-substituted benzhydryl derivatives correlate linearly with the Lewis acidities of the resulting carbenium ions, this is not the case for amino-substituted benzhydrylium ions, where differences in intrinsic barriers play a major role. The common rule that a structural variation, which increases the electrophilicity of a carbocation at the same time reduces its electrofugality, does not hold any longer. The need to systematically analyze the role of intrinsic barriers is emphasized.

Transition State Structure of RNA Depurination by Saporin L3.

Saporin L3 from the leaves of the common soapwort is a catalyst for hydrolytic depurination of adenine from RNA. Saporin L3 is a type 1 ribosome inactivating protein (RIP) composed only of a catalytic domain. Other RIPs have been used in immunotoxin cancer therapy, but off-target effects have limited their development. In the current study, we use transition state theory to understand the chemical mechanism and transition state structure of saporin L3. In favorable cases, transition state structures guide the design of transition state analogues as inhibitors. Kinetic isotope effects (KIEs) were determined for an A14C mutant of saporin L3. To permit KIE measurements, small stem-loop RNAs that contain an AGGG tetraloop structure were enzymatically synthesized with the single adenylate bearing specific isotopic substitutions. KIEs were measured and corrected for forward commitment to obtain intrinsic values. A model of the transition state structure for depurination of stem-loop RNA (5'-GGGAGGGCCC-3') by saporin L3 was determined by matching KIE values predicted via quantum chemical calculations to a family of intrinsic KIEs. This model indicates saporin L3 displays a late transition state with the N-ribosidic bond to the adenine nearly cleaved, and the attacking water nucleophile weakly bonded to the ribosyl anomeric carbon. The transition state retains partial ribocation character, a feature common to most N-ribosyl transferases. However, the transition state geometry for saporin L3 is distinct from ricin A-chain, the only other RIP whose transition state is known.

Comparative analysis of linear and non-linear transition state of hydrogen transfer reaction between benzoyl type radicals with skipped alkadienes

Traditional linear transition states have been extensively investigated, and many models have been used to study them. However, few studies have described the detailed mechanism of nonlinear transition states. This paper describes a system to analyze nonlinear transition states. The hydrogen abstraction reaction is the simplest atom transfer reaction, and this reaction was used to generate the nonlinear transition state. We used a distortion/interaction model and the bond-energy–bond-order method to probe the differences between the nonlinear and the linear transition states. We also investigated whether flexible and rigid structures have an effect on the reaction energies. Based on the quantum chemical study, we obtained relevant energies and factors for the four reactions studied. The results showed that the distortion energy and activation barrier of nonlinear transition state reactions are much higher than those of the corresponding linear transition state reactions. It is concluded that the reaction of a rigid structure and a nonlinear transition state has a late transition state, while the reaction of a flexible structure and a linear transition state has an early transition state. We believe that the nonlinear transition state is different from the traditional linear transition state.

Extension of Structure-Reactivity Correlations for the Hydrogen Abstraction Reaction by Bromine Atom and Comparison to Chlorine Atom and Hydroxyl Radical.

Recently we presented structure-reactivity correlations for the gas-phase ambient-temperature rate constants for hydrogen abstraction from sp(3)-hybridized carbon by chlorine atom and hydroxyl radical (Cl•/HO• + HCR3 → HCl/HOH + •CR3); the reaction enthalpy effect was represented by the independent variable ΔrH and the "polar effect" by the independent variables F and R, the Hammett constants for field/inductive and resonance effects. Both these reactions are predominantly exothermic and have early transition states. Here, we present a parallel treatment for Br• whose reaction is significantly endothermic with a correspondingly late transition state. Despite lower expectations because the available database is less extensive and much more scattered and because long temperature extrapolations are often required, the resulting least-squares fit (log k298,Br = -0.147 ΔrH - 4.32 ΣF - 4.28 ΣR - 12.38 with r(2) = 0.92) was modestly successful and useful for initial predictions. The coefficient of ΔrH was ∼4-fold greater, indicative of the change from an early to a late transition state; meanwhile the sizable coefficients of ΣF and ΣR indicate the persistence of the "polar effect". Although the mean unsigned deviation of 0.79 log k298 units is rather large, it must be considered in the context of a total span of over 15 log units in the data set. The major outliers are briefly discussed.

Designing graphene as a new frustrated Lewis pair catalyst for hydrogen activation by co-doping.

Boron and nitrogen co-doped bilayer graphene (BN-G) and graphene ribbon (BN-GR) as Frustrated Lewis Pair (FLP) catalysts are investigated for hydrogen molecule activation. The nitrogen and boron atoms are separated as they are in different layers of BN-G/GR. Calculations show that this novel FLP catalyst is capable of activating hydrogen molecules. From the Bader charge, Mayer bond order, and the geometrical structures, it can be seen that the hydrogen molecules undergo heterolytic scission and have a late product-like transition state. More interestingly, the active sites are identified as being the carbon atoms around dopants for BN-G. The BN-G/GR catalysts deliver performances comparable to that of the reported FLP catalyst when considering their barrier and reaction energy values. The current work demonstrates the great potential of doped carbon catalysts as FLP catalysts and paves the way to nanostructured carbon catalyst applications in reactions by directly utilizing hydrogen molecules.

Simulating periodic trends in the structure and catalytic activity of coinage metal nanoribbons

We present a systematic density functional theory (DFT) study of the structure and catalytic activity of group 10 (Ni, Pd, Pt) and group 11 (Cu, Ag, Au) coinage metal nanoribbons. These infinite, periodic, quasi-one-dimensional structures are conceptually important as intermediates between small metal clusters and close-packed metal surfaces, and have been shown experimentally to be practical catalysts. We find that nanoribbons have significantly higher predicted H2 dissociation activity than close-packed metal surfaces consistent with their lower coordination numbers. Computed periodic trends are reasonable, with late transition states and low barriers for H2 dissociation over late group 10 nanoribbons, suggesting their promise as practical catalysts. These trends are consistent with the isolated nanoribbons' computed molecular electrostatic potentials. Calculations also predict nearly linear Bronsted–Evans–Polanyi relationships between the nanoribbons' H2 dissociation energies and dissociation barriers. We also test new meta-generalized gradient approximation (GGA) and hybrid DFT approximations for H2 dissociation over these nanoribbons. These new functionals increase the (generally underestimated) dissociation barriers predicted by standard GGAs, motivating their continued application in surface chemistry. © 2015 Wiley Periodicals, Inc.

Computational study of the reaction of dimethyl carbonate with methyl amine on Zn4O4 cluster

Reactions of dimethyl carbonate with primary amines resulting in carbamates are important step of phosgene-free method for producing of isocyanates. Isocyanates are monomers to produce large scale polymers. Many questions about the mechanism of reactions of dimethyl carbonate with primary amines are unknown. In this study a structure of Zn4O4 cluster and mechanism of the reaction between dimethyl carbonate and methyl amine on Zn4O4 cluster have been investigated theoretically. Thermodynamics parameters have been described at wB97XD/6-311++G(df,p), M06/6-311++G(df,p) and PBE1PBE/6-311++G(df,p) levels. The calculations show that the participating in the reaction of ZnO cluster noticeably reduce the energy barrier compared with non-catalytic reaction. All conversions occur through cyclic late transition states. Using the hydrogen-bonded complexes of methylamine with methanol as well as methylamine itself in the reaction was also shown to lower the activation barrier.

Examining the Linearity of Transition State Scaling Relations

The dissociation of strong bonds in molecules shows large variations in the geometric structure of the transition state depending on the reactivity of the surface. It is therefore remarkable that the transition state energy can be accurately described through linear relations such as the Bronsted-Evans–Polanyi relations. Linear scaling relations for adsorbates with fixed structure can be understood in terms of bond order conservation but such arguments should not apply to transition states where the geometric structure varies. We have investigated how to relate the concepts from linear adsorption energy scaling to transition state energies. We expect that strong deviations from linearity only occur for very early or very late transition states. According to the Sabatier principle, the rate-limiting step of the best catalysts is not expected to be in either of these regions. Our results therefore support the use of linear transition state scaling relations for the optimization of catalysts.

Mechanistic Details and Reactivity Descriptors in Oxidation and Acid Catalysis of Methanol

Acid and redox reaction rates of CH3OH-O2 mixtures on polyoxometalate (POM) clusters, together with isotopic, spectroscopic, and theoretical assessments of catalyst properties and reaction pathways, were used to define rigorous descriptors of reactivity and to probe the compositional effects for oxidative dehydrogenation (ODH) and dehydration reactions. 31P-MAS NMR, transmission electron microscopy and titrations of protons with di-tert-butylpyridine during catalysis showed that POM clusters retained their Keggin structure upon dispersion on SiO2 and after use in CH3OH reactions. The effects of CH3OH and O2 pressures and of D-substitution on ODH rates show that C–H activation in molecularly adsorbed CH3OH is the sole kinetically relevant step and leads to reduced centers as intermediates present at low coverages; their concentrations, measured from UV–vis spectra obtained during catalysis, are consistent with the effects of CH3OH/O2 ratios predicted from the elementary steps proposed. First-order ODH rate constants depend strongly on the addenda atoms (Mo vs W) but weakly on the central atom (P vs Si) in POM clusters, because C–H activation steps inject electrons into the lowest unoccupied molecular orbitals (LUMO) of the clusters, which are the d-orbitals at Mo6+ and W6+ centers. H-atom addition energies (HAE) at O-atoms in POM clusters represent the relevant theoretical probe of the LUMO energies and of ODH reactivity. The calculated energies of ODH transition states at each O-atom depend linearly on their HAE values with slopes near unity, as predicted for late transition states in which electron transfer and C–H cleavage are essentially complete. HAE values averaged over all accessible O-atoms in POM clusters provide the appropriate reactivity descriptor for oxides whose known structures allow accurate HAE calculations. CH3OH dehydration proceeds via parallel pathways mediated by late carbenium-ion transition states; effects of composition on dehydration reactivity reflect changes in charge reorganizations and electrostatic forces that stabilize protons at Brønsted acid sites.

Methanol Oxidative Dehydrogenation on Oxide Catalysts: Molecular and Dissociative Routes and Hydrogen Addition Energies as Descriptors of Reactivity

The oxidative dehydrogenation (ODH) of alkanols on oxide catalysts is generally described as involving H-abstraction from alkoxy species formed via O–H dissociation. Kinetic and isotopic data cannot discern between such routes and those involving kinetically-relevant H-abstraction from undissociated alkanols. Here, we combine such experiments with theoretical estimates of activation energies and entropies to show that the latter molecular routes prevail over dissociative routes for methanol reactions on polyoxometalate (POM) clusters at all practical reaction temperatures. The stability of the late transition states that mediate H-abstraction depend predominantly on the stability of the O–H bond formed, making H-addition energies (HAE) accurate and single-valued descriptors of reactivity. Density functional theory-derived activation energies depend linearly on HAE values at each O-atom location on clusters with a range of composition (H3PMo12, H4SiMo12, H3PW12, H4PV1Mo11, and H4PV1W11); both barriers and ...

Classification and dynamics of developmental stages in late-successional temperate forests

Late-successional forests often have complex disturbance histories that can result in stands with widely varying structure, ranging from young pole stands to uneven-aged old growth. Arranging stands in chronosequences, however, is problematic because ‘stand age’ is not a meaningful concept for multi-aged stands and ‘time since last stand-replacing disturbance’ often cannot be determined from tree-ring evidence. In this paper, we describe a systematic approach for classifying developmental stages in late-successional forests using structural metrics known to be correlated with key ecological properties such as total biomass, carbon storage, stand production rates, and wildlife habitat. While conceptually based on the amount of aggregate crown area occupied by different size classes of trees, the computations in this study, for ease of use, are based entirely on absolute and relative basal area of four size classes (saplings, poles, mature, and large trees). Eight forest structural stages are recognized, including four stages of old growth (early-, mid-, late-transition, and steady state). The method was used to classify developmental stages of 70 primary northern hardwood stands (Acer–Betula–Tsuga) in large landscape reserves in upper Michigan, USA. The degree to which the developmental stages mimic underlying temporal trends in stand dynamics was investigated with the aid of 30-year permanent plot records in primary forests and multi-century simulations using the CANOPY forest dynamics model. Results indicated good correspondence between the postulated developmental sequence in the 70 field stands compared with CANOPY simulations of structural changes over time and changes observed on the permanent plots. Results support the Bormann–Likens hypothesis that the number of large trees reaches a maximum toward the end of the lifespan of an even-aged cohort and subsequently declines in the steady state. While most of the field plots were uneven-aged, both simulations and field data suggest that developmental pathways of even-aged and multi-aged stands after disturbance are very similar and are difficult to distinguish based on the form of the size distributions. In the study area landscapes, 78% of the stands were classified as old growth, with 39% in early or mid-transition and 39% in late transition or steady state. The method should be useful, with appropriate site-specific modifications, in evaluating the degree to which stands meet structural goals under ecological forestry methods, in monitoring responses to environmental change, and in examining biotic changes along a gradient of structural development following disturbance.

Computational study of the reaction of dimethyl carbonate with methyl amine

A detailed study on mechanism of the reaction between dimethyl carbonate and methyl amine have been investigated theoretically. Thermodynamics parameters have been described at wB97XD/6-311++G(df,p), M06/6-311++G(df,p) and PBE1PBE/6-311++G(df,p) levels. The calculations show that the presence of hydrogen-bonded methyl amine dimer or hydrogen-bonded complexes of methyl amine with methanol can noticeably reduce the energy barrier. These complexes possess higher electron-donor properties than free alcohol molecules thus increasing the activity of complexes in the reaction with dimethyl carbonate. All conversions occur through cyclic late transition states.

Widespread transient Hoogsteen base pairs in canonical duplex DNA with variable energetics.

Hoogsteen (HG) base pairing involves a 180° rotation of the purine base relative to Watson-Crick (WC) base pairing within DNA duplexes, creating alternative DNA conformations that can play roles in recognition, damage induction and replication. Here, using nuclear magnetic resonance R1ρ relaxation dispersion, we show that transient HG base pairs occur across more diverse sequence and positional contexts than previously anticipated. We observe sequence-specific variations in HG base pair energetic stabilities that are comparable with variations in WC base pair stability, with HG base pairs being more abundant for energetically less favourable WC base pairs. Our results suggest that the variations in HG stabilities and rates of formation are dominated by variations in WC base pair stability, suggesting a late transition state for the WC-to-HG conformational switch. The occurrence of sequence and position-dependent HG base pairs provide a new potential mechanism for achieving sequence-dependent DNA transactions.

Roaming dynamics in ion-molecule reactions: Phase space reaction pathways and geometrical interpretation

A model Hamiltonian for the reaction CH4(+) -> CH3(+) + H, parametrized to exhibit either early or late inner transition states, is employed to investigate the dynamical characteristics of the roaming mechanism. Tight/loose transition states and conventional/roaming reaction pathways are identified in terms of time-invariant objects in phase space. These are dividing surfaces associated with normally hyperbolic invariant manifolds (NHIMs). For systems with two degrees of freedom NHIMS are unstable periodic orbits which, in conjunction with their stable and unstable manifolds, unambiguously define the (locally) non-recrossing dividing surfaces assumed in statistical theories of reaction rates. By constructing periodic orbit continuation/bifurcation diagrams for two values of the potential function parameter corresponding to late and early transition states, respectively, and using the total energy as another parameter, we dynamically assign different regions of phase space to reactants and products as well as to conventional and roaming reaction pathways. The classical dynamics of the system are investigated by uniformly sampling trajectory initial conditions on the dividing surfaces. Trajectories are classified into four different categories: direct reactive and non-reactive trajectories, which lead to the formation of molecular and radical products respectively, and roaming reactive and non-reactive orbiting trajectories, which represent alternative pathways to form molecular and radical products. By analysing gap time distributions at several energies, we demonstrate that the phase space structure of the roaming region, which is strongly influenced by nonlinear resonances between the two degrees of freedom, results in nonexponential (nonstatistical) decay.

δ-Deuterium isotope effects as probes for transition-state structures of isoprenoid substrates.

The biosynthetic pathways to isoprenoid compounds involve transfer of the prenyl moiety in allylic diphosphates to electron-rich (nucleophilic) acceptors. The acceptors can be many types of nucleophiles, while the allylic diphosphates only differ in the number of isoprene units and stereochemistry of the double bonds in the hydrocarbon moieties. Because of the wide range of nucleophilicities of naturally occurring acceptors, the mechanism for prenyltransfer reactions may be dissociative or associative with early to late transition states. We have measured δ-secondary kinetic isotope effects operating through four bonds for substitution reactions with dimethylallyl derivatives bearing deuterated methyl groups at the distal (C3) carbon atom in the double bond under dissociative and associative conditions. Computational studies with density functional theory indicate that the magnitudes of the isotope effects correlate with the extent of bond formation between the allylic moiety and the electron-rich acceptor in the transition state for alkylation and provide insights into the structures of the transition states for associative and dissociative alkylation reactions.

Linear Free-Energy Relationship and Rate Study on a Silylation-Based Kinetic Resolution: Mechanistic Insights

The substituent effect of different p-substituted triphenylsilyl chlorides on silylation-based kinetic resolutions was explored. Electron-donating groups slow down the reaction rate and improve the selectivity, while electron-withdrawing groups increase the reaction rate and decrease the selectivity. Linear free-energy relationships were found correlating both selectivity factors and initial rates to the σ(para) Hammett parameters. A weak correlation of selectivity factors to Charton values was also observed when just alkyl substituents were employed but was nonexistent when substituents with more electronic effects were incorporated. The rate data suggest that a significant redistribution of charge occurs in the transition state, with an overall decrease in positive charge. The linear free-energy relationship derived from selectivity factors is best understood by the Hammond postulate. Early and late transition states describe the amount of substrate participation in the transition state and therefore the difference in energy between the diastereomeric transition states of the two enantiomers. This work highlights our efforts toward understanding the mechanism and origin of selectivity in our silylation-based kinetic resolution.

Quantum-chemical study of isocyanate reactions with linear methanol associates: IX. Methyl isocyanate reaction with methanol-phenol complexes

Quantum-chemical method B3LYP/6-311++G(df,p) was applied to the study of complex formation between phenol and methanol. The complexes of molecules bound by the hydrogen bond possess enhanced donoracceptor and acid-base properties as compared to monomer molecules. The reactions of phenol and methanol complexes with methyl isocyanate proceed through a concerted late asymmetric transition state by the type of nucleophilic addition. The most kinetically and thermodynamically favorable transformation is the process involving the complex “phenol-acceptor, methanol-donor.” Phenol compounds are able to catalyze the addition of alcohols to isocyanates.