Showing papers on "Transition state published in 2012"

Design of biomimetic catalysts by molecular imprinting in synthetic polymers: the role of transition state stabilization.

Abstract: The impressive efficiency and selectivity of biological catalysts has engendered a long-standing effort to understand the details of enzyme action. It is widely accepted that enzymes accelerate reactions through their steric and electronic complementarity to the reactants in the rate-determining transition states. Thus, tight binding to the transition state of a reactant (rather than to the corresponding substrate) lowers the activation energy of the reaction, providing strong catalytic activity. Debates concerning the fundamentals of enzyme catalysis continue, however, and non-natural enzyme mimics offer important additional insight in this area. Molecular structures that mimic enzymes through the design of a predetermined binding site that stabilizes the transition state of a desired reaction are invaluable in this regard. Catalytic antibodies, which can be quite active when raised against stable transition state analogues of the corresponding reaction, represent particularly successful examples. Recent...

Watching DNA polymerase η make a phosphodiester bond.

Abstract: DNA synthesis has been extensively studied, but the chemical reaction itself has not been visualized Here we follow the course of phosphodiester bond formation using time-resolved X-ray crystallography Native human DNA polymerase η, DNA and dATP were co-crystallized at pH 60 without Mg2+ The polymerization reaction was initiated by exposing crystals to 1 mM Mg2+ at pH 70, and stopped by freezing at desired time points for structural analysis The substrates and two Mg2+ ions are aligned within 40 s, but the bond formation is not evident until 80 s From 80 to 300 s structures show a mixture of decreasing substrate and increasing product of the nucleotidyl-transfer reaction Transient electron densities indicate that deprotonation and an accompanying C2′-endo to C3′-endo conversion of the nucleophile 3′-OH are rate limiting A third Mg2+ ion, which arrives with the new bond and stabilizes the intermediate state, may be an unappreciated feature of the two-metal-ion mechanism Atomic-resolution time courses of phosphodiester bond formation catalysed by DNA polymerase η reveal transient intermediate states and an unexpected third metal ion in the reaction mechanism Chemists would like to be able to determine the structures of true transition states in chemical reactions, but the high energy and unstable nature of transition states had made this goal unattainable Using a repair reaction catalysed by DNA polymerase η (Pol η) as their model, Wei Yang and colleagues have extended the use of flash–freeze technology to observe DNA synthesis in real time and at atomic resolution using X-ray crystallography to analyse the trapped covalent intermediates Pol η is particularly well suited to this approach because it has a slow rate of reaction and a relatively rigid catalytic centre The observed reaction intermediates reveal several unanticipated transient states, and implicate an unexpected third magnesium ion in the reaction mechanism

Role of O2 + QOOH in low-temperature ignition of propane. 1. Temperature and pressure dependent rate coefficients.

Abstract: The kinetics of the reaction of molecular oxygen with hydroperoxyalkyl radicals have been studied theoretically. These reactions, often referred to as second O2 addition, or O2 + QOOH reactions, are believed to be responsible for low-temperature chain branching in hydrocarbon oxidation. The O2 + propyl system was chosen as a model system. High-level ab initio calculations of the C3H7O2 and C3H7O4 potential energy surfaces are coupled with RRKM master equation methods to compute the temperature and pressure dependence of the rate coefficients. Variable reaction coordinate transition-state theory is used to characterize the barrierless transition states for the O2 + QOOH addition reactions as well as subsequent C3H6O3 dissociation reactions. A simple kinetic mechanism is developed to illustrate the conditions under which the second O2 addition increases the number of radicals. The sequential reactions O2 + QOOH → OOQOOH → OH + keto-hydroperoxide → OH + OH + oxy-radical and the corresponding formally direct ...

Mechanistic Study of Alcohol Dehydration on γ-Al2O3

Abstract: The acid sites on γ-Al2O3 were characterized using FTIR spectroscopy of adsorbed pyridine and temperature programmed desorption (TPD) of 2-propanamine, ethanol, 1-propanol, 2-propanol, and 2-methyl-2-propanol, together with density functional theory (DFT) calculations. Following room-temperature adsorption and evacuation, the surface coverages of the adsorbed alcohols were between 2 and 3.2 × 1018 molecules/m2. For each of the adsorbed alcohols, reaction to olefin and water products occurred in a narrow peak that indicated reaction is a first-order process with a well-defined activation energy, which in turn depended strongly on the particular alcohol. DFT calculations on an Al8O12 cluster are in excellent agreement with the experimental observations and show that the transition states for dehydration had carbenium-ion character. The carbenium ion stability in terms of proton affinity (of alkenes) matches well with the activation energy of the dehydration reaction. Adsorption of water on the γ-Al2O3, foll...

The roles of entropy and enthalpy in stabilizing ion-pairs at transition states in zeolite acid catalysis.

Abstract: Acidic zeolites are indispensable catalysts in the petrochemical industry because they select reactants and their chemical pathways based on size and shape. Voids of molecular dimensions confine reactive intermediates and transition states that mediate chemical reactions, stabilizing them by van der Waals interactions. This behavior is reminiscent of the solvation effects prevalent within enzyme pockets and has analogous consequences for catalytic specificity. Voids provide the “right fit” for certain transition states, reflected in their lower free energies, thus extending the catalytic diversity of zeolites well beyond simple size discrimination. This catalytic diversity is even more remarkable because acid strength is essentially unaffected by confinement among known crystalline aluminosilicates. In this Account, we discuss factors that determine the “right fit” for a specific chemical reaction, exploring predictive criteria that extend the prevailing discourse based on size and shape. We link the stru...

Dynamics, transition states, and timing of bond formation in Diels–Alder reactions

Abstract: The time-resolved mechanisms for eight Diels–Alder reactions have been studied by quasiclassical trajectories at 298 K, with energies and derivatives computed by UB3LYP/6-31G(d). Three of these reactions were also simulated at high temperature to compare with experimental results. The reaction trajectories require 50–150 fs on average to transverse the region near the saddle point where bonding changes occur. Even with symmetrical reactants, the trajectories invariably involve unequal bond formation in the transition state. Nevertheless, the time gap between formation of the two new bonds is shorter than a C─C vibrational period. At 298 K, most Diels–Alder reactions are concerted and stereospecific, but at high temperatures (approximately 1,000 K) a small fraction of trajectories lead to diradicals. The simulations illustrate and affirm the bottleneck property of the transition state and the close connection between dynamics and the conventional analysis based on saddle point structure.

Concerted reactions and mechanism of glucose pyrolysis and implications for cellulose kinetics.

Abstract: Concerted reactions are proposed to be keys to understanding thermal decomposition of glucose in the absence of ionic chemistry, including molecular catalysis by ROH molecules such as H2O, other glucose molecules, and most of the intermediates and products. Concerted transition states, elementary-reaction pathways, and rate coefficients are computed for pyrolysis of β-d-glucose (β-d-glucopyranose), the monomer of cellulose, and for related molecules, giving an improved and elementary-reaction interpretation of the reaction network proposed by Sanders et al. (J. Anal. Appl. Pyrolysis, 2003, 66, 29–50). Reactions for ring-opening and formation, ring contraction, retro-aldol condensation, keto–enol tautomerization, and dehydration are included. The dehydration reactions are focused on bicyclic ring formations that lead to levoglucosan and 1,6-β-d-anhydrousglucofuranose. The bimolecular ROH-assisted reactions are found to have lower activation energy compared to the unimolecular reactions. The same dehydratio...

Multi-path variational transition state theory for chemical reaction rates of complex polyatomic species: ethanol + OH reactions

Abstract: Complex molecules often have many structures (conformations) of the reactants and the transition states, and these structures may be connected by coupled-mode torsions and pseudorotations; some but not all structures may have hydrogen bonds in the transition state or reagents. A quantitative theory of the reaction rates of complex molecules must take account of these structures, their coupled-mode nature, their qualitatively different character, and the possibility of merging reaction paths at high temperature. We have recently developed a coupled-mode theory called multi-structural variational transition state theory (MS-VTST) and an extension, called multi-path variational transition state theory (MP-VTST), that includes a treatment of the differences in the multi-dimensional tunneling paths and their contributions to the reaction rate. The MP-VTST method was presented for unimolecular reactions in the original paper and has now been extended to bimolecular reactions. The MS-VTST and MP-VTST formulations of variational transition state theory include multi-faceted configuration-space dividing surfaces to define the variational transition state. They occupy an intermediate position between single-conformation variational transition state theory (VTST), which has been used successfully for small molecules, and ensemble-averaged variational transition state theory (EA-VTST), which has been used successfully for enzyme kinetics. The theories are illustrated and compared here by application to three thermal rate constants for reactions of ethanol with hydroxyl radical—reactions with 4, 6, and 14 saddle points.

Localizing internal friction along the reaction coordinate of protein folding by combining ensemble and single-molecule fluorescence spectroscopy

Abstract: Theory, simulations and experimental results have suggested an important role of internal friction in the kinetics of protein folding. Recent experiments on spectrin domains provided the first evidence for a pronounced contribution of internal friction in proteins that fold on the millisecond timescale. However, it has remained unclear how this contribution is distributed along the reaction and what influence it has on the folding dynamics. Here we use a combination of single-molecule Forster resonance energy transfer, nanosecond fluorescence correlation spectroscopy, microfluidic mixing and denaturant- and viscosity-dependent protein-folding kinetics to probe internal friction in the unfolded state and at the early and late transition states of slow- and fast-folding spectrin domains. We find that the internal friction affecting the folding rates of spectrin domains is highly localized to the early transition state, suggesting an important role of rather specific interactions in the rate-limiting conformational changes.

Brønsted Acid Catalyzed Asymmetric Propargylation of Aldehydes

Abstract: Enantiomerically pure homopropargylic alcohols are highly useful intermediates, with broad synthetic utility. The terminal alkyne functionality serves as a synthetic handle for cross-coupling, metathesis, and heterocycle synthesis.[1] The addition of allenic or propargylic reagents to carbonyl compounds is mechanistically similar to the analogous reaction with allylic reagents. Though many useful and innovative methods exist for the synthesis of homoallylic alcohols,[2] the enantio-selective synthesis of homopropargylic alcohols remains arduous. Two main complications are 1) the lower reactivity of the allenylic and propargylic substrates in comparison to allylic substrates, and 2) the difficulties associated with controlling the reaction regioselectivity.[3] Herein, we describe a highly enantioselective catalytic method for the preparation of homopropargylic alcohols. Computational studies of the reaction provide insight into the catalysis and stereochemistry of the reaction. Many current methods for enantioselective propargylation reactions rely upon the use of chiral reagents.[4] Alternative catalytic methods have been developed, but are limited to the use of allenylic or propargylic metal-based reagents or intermediates.[2a,5] Despite notable work, many of these methods are restricted by one or more limitations. Among them are 1) the use of reagents that are relatively difficult to prepare or are unstable to air and/or moisture, 2) the use of undesirable metal reagents or catalysts, and 3) regioselectivity concerns. In the past decade, Lewis and Bronsted acid-catalyzed allylboration reactions have fascinated the synthetic community.[6,7] However, this methodology remains relatively undeveloped for the more challenging allenylboration of aldehydes. Following our recent report on the development of a chiral phosphoric acid-catalyzed allylboration,[7] we examined the extension of our methodology to the enantioselective propargylation of aldehydes. We began our investigation with the reaction of benzaldehyde and allenyl boronic acid pinacol ester. Boronate 2 is a relatively stable, non-toxic and commercially available reagent. The C–C bond formation proceeded smoothly in the presence of various chiral acid catalysts,[8] with complete control over the regioselectivity (Table 1). PA5[9] afforded product 3 with the highest enantio-selectivity, when toluene was used as the reaction solvent. An increase to 87% ee was seen with the use of higher catalyst loading, in the presence of 4A M.S. (entry 13). The enantio-selectivity could be further increased, when the reaction was conducted at lower reaction temperatures of 0°C (entry 14) and −20°C (entry 15), albeit with longer reaction times. Table 1 Catalyst screening and optimization for the propargylation of benzaldehyde.[a] With the optimized conditions in hand,[10] a variety of aldehydes with different electronic and steric properties were tested to study the scope and limitation of the developed methodology (Table 2). The reaction proved tolerant to electron-donating and electron-withdrawing groups (1a–1j), giving excellent yields and enantioselectivities (92–96% ee). The methodology was extended to aliphatic aldehydes (1k–1m), furnishing the corresponding homopropargylic alcohol products 3k–m in 77–82% ee. Table 2 Enantioselective propargylation of aldehydes.[a] We prepared several important synthetic scaffolds, previously unavailable from enantioenriched homopropargylic alcohols (Scheme 1). Chiral dihydrofuran-3-ones, such as 4, are important building blocks[11] for the synthesis of biologically active compounds. Despite their importance, a general enantioselective synthesis for this class of molecule has yet to be reported. We successfully transformed 3a[12] into dihydrofuran-3-one 4, by employing gold-catalyzed reaction methodology developed by Zhang and co-workers,[13] with complete preservation of the enantiomeric excess. Crabbe homologation of 3a provided optically active 3,4-allenol 5, which has the potential to serve as a substrate in natural product synthesis.[14] Chiral dihydrofuran 6, currently dependent on the Heck reaction for its synthesis,[15] was obtained through a molybdenum-mediated cycloisomerization of 3a, based on methodology developed by McDonald and co-workers.[16] Scheme 1 Synthesis of important chiral moieties. It is our belief that the propargylation proceeds through a six-membered cyclic transition state, where catalyst activation operates by hydrogen-bonding of the boronate oxygen. To further understand the mechanism and stereoselectivity of this phosphoric acid-catalyzed propargylation reaction, we performed theoretical calculations. Calculated energies of different pathways for allylboration[17] and propargylation showed that Bronsted acids form a strong hydrogen bond with the pseudo-equatorial oxygen of the allenyl boronate.[18] A computed transition state structure involving protonation is shown in Figure 1. Figure 1 Transition state structure for the Bronsted acid-catalyzed propargylation reaction. To explore the origins of the enantioselectivity, we studied the transition state structures for the propargylation reaction, where the phosphoric acid catalyst activates the pseudo-equatorial oxygen of the allenyl boronate. Biphenol(bipol)-derived phosphoric acid was used as the model, in place of the fully derived binol phosphoric acid, to reduce the computational time. Catalyst PA5, bearing a 2,4,6-triisopropylphenyl group at the 3,3′-positions, provides high experimental enantioselectivity. Thus, the diastereomeric transition states of the re-face and si-face attack involving the bipol model of PA5 were compared. Transition states TSr1 and TSs1 are represented in Figure 2. Re-face attack (TSr1) is predicted to be more favored than si-face attack (TSs1) by 1.3 kcalmol−1. This is in agreement with the 74% ee obtained experimentally. Figure 2 Optimized structures of TSr1 and TSs1. Relative energies (kcal mol−1) are shown in parentheses. Figure 2 shows a lack of obvious steric differences in the transition states. H–H distances are 2.4 A or more. However, the distortion of the catalyst is larger in TSs1 than in TSr1 by about 1.2 kcalmol−1. This distortion relieves steric repulsions that would otherwise occur. The preference for re-facial selectivity is therefore the result of the larger distortion of the catalyst–boronate complex in TSs1. The origins of the differences in distortion energies of the catalyst–boronate complex in the two TSs can be visualized from geometries of the catalyst in the TSs. Figure 3a shows the catalyst–boronate complex structure in TSr1. Here, the dioxaborolane ring has no significant steric interaction with the catalyst, and the dihedral angle between the 2,4,6-triisopropylphenyl substituent and the bipol core is 74°, almost the same as the dihedral angle of 72° in the optimized catalyst. Figure 3b shows the catalyst–boronate complex structure in TSs1, with the dioxaborolane ring on the left. The methyl groups (circled in Figure 3b) of the dioxaborolane ring and the isopropyl groups of the catalyst (circled in Figure 3b) are close to each other. In order to minimize such steric repulsions, the 2,4,6-triisopropylphenyl substituent is rotated around the bond to the bipol phenyl core with a dihedral angle of 78°. This is a 6° rotation away from the dihedral angle in the optimized catalyst (72°). The asymmetric induction can be rationalized by differences in distortion energies originating from the steric interactions between the substrates and the bulky 3,3′-substituents on the catalyst. Figure 3 a) 3D structure of TSr1 without benzaldehyde. b) 3D structure of TSs1 without benzaldehyde. For other catalysts screened experimentally, calculations showed the absence of an energy difference between re- and si-attack diastereomeric transition states, suggesting why these catalysts gave low enantioselectivities. In summary, we have developed the first Bronsted acid-catalyzed propargylation of aldehydes, for the synthesis of chiral homopropargylic alcohols. The reaction is simple and highly efficient, demonstrating broad synthetic utility. Mechanistic studies show the catalyst activating the reaction by forming a strong hydrogen bond with the pseudo-equatorial oxygen of the boronate. The high enantioselectivity obtained with catalyst PA5 originates from steric interactions between the methyl groups of the allenylboronate, the bulky catalyst substituents, and the resulting distortion of the catalyst.

Ammonia decomposition on Fe(110), Co(111) and Ni(111) surfaces: A density functional theory study

Abstract: Ammonia decomposition on transition metal surfaces is of great importance in energy and environmental industries. With the aim to obtain a systematic knowledge about the reaction mechanism of NH3 decomposition on the close-packed surfaces of the 3d-late transition metals, we perform first-principles calculations to determine the preferred adsorption sites and the adsorption energies of NHx (x = 0–3) and H, and identify the transition states of the NH3 stepwise dehydrogenation reactions and the N recombination reactions on the close-packed Fe(1 1 0), Co(1 1 1) and Ni(1 1 1) surfaces. The results show that the calculated adsorption energies and activated energies mainly depend on the d-band center of metal surfaces. Barrier decomposition analysis reveals that the interaction among binding species in transition states will increase the energy barrier while the bonding to the surface of the species in the initial states and the transition states will decrease the energy barrier. Moreover, a linear relationship, known as the Brϕnsted–Evans–Polanyi relation, also exists between the activation energy of the N recombination reaction and the adsorption energy of N on the close-packed surfaces of the 3d-late transition metals.

Selective Transition State Stabilization via Hyperconjugative and Conjugative Assistance: Stereoelectronic Concept for Copper-Free Click Chemistry

Abstract: Dissection of stereoelectronic effects in the transition states (TSs) for noncatalyzed azide–alkyne cycloadditions suggests two approaches to selective transition state stabilization in this reaction. First, the formation of both 1,4- and 1,5-isomers is facilitated via hyperconjugative assistance to alkyne bending and C···N bond formation provided by antiperiplanar σ-acceptors at the propargylic carbons. In addition, the 1,5-TS can be stabilized via attractive C–H···F interactions. Although the two effects cannot stabilize the same transition state for the cycloaddition to α,α-difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP calculations predict up to ∼1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in electrostatic potential along the reaction path revealed that azide ...

Transition metal catalysis by density functional theory and density functional theory/molecular mechanics

Abstract: Density functional theory (DFT) and density functional theory/molecular mechanics (DFT/MM) methods are useful tools in modern homogeneous catalysis. Calculation, with its ability to characterize otherwise hardly accessible intermediates and transition states, is a key complement to experiment for the full characterization of the often intricate reaction mechanisms involved in transition metal catalysis. DFT and DFT/MM techniques have been applied to the characterization of full catalytic cycles, as those in cross-coupling; to the systematic analysis of single reaction steps common to several catalytic cycles, such as CH activation; to the elucidation of processes involving different spin states, such as the rebound mechanism for CH activation; to the identification of transient intermediates with key mechanistic roles, such as those in oxygen-evolving complexes; to the analysis of the catalytic keys to polymerization control, as in olefin polymerization; and to reproduction and rationalization of experimentally reported enantioselectvities, as in the case of olefin dihydroxylation. The currently available techniques provide sufficient accuracy to offer chemical insight into the systems involved in experiment, as proved by the growing body of successful applications in the field. © 2012 John Wiley & Sons, Ltd.

Deactivation mechanism of AuCl3 catalyst in acetylene hydrochlorination reaction: a DFT study

Abstract: The deactivation mechanism of AuCl3 catalyst in the reaction of acetylene hydrochlorination was studied by using AuCl3 dimer model and the density functional theory (DFT) method. Four possible paths for the acetylene hydrochlorination reaction catalyzed by AuCl3 were illustrated with corresponding transition states. The activation free energies and reaction rate constants of the four paths were also analyzed. It is apparent that when HCl and C2H2 coadsorbed on the AuCl3 dimer, the C2H2 was co-catalyzed by HCl and the AuCl3 dimer to produce C2H3Cl and the reaction energy barrier was as low as 23.35 kcal mol−1. If the HCl in the gas phase could not adsorb on the Au site within the set time, the intermediate chlorovinyl was difficult to desorb from the AuCl3 catalyst as its desorption energy was as high as 41.336 kcal mol−1. As the reaction temperature increased, C2H2 became easier to be adsorbed on the AuCl3 catalyst prior to HCl, which resulted in the side reaction and the rapid deactivation of the AuCl3 dimer due to the loss of Cl atoms. Our calculations are necessary for us to clearly understand the experimental results, which indicate a great dependence of activity and stability of AuCl3 catalysts on the HCl : C2H2 ratio as well as the temperature.

Influence of Acid Strength and Confinement Effect on the Ethylene Dimerization Reaction over Solid Acid Catalysts: A Theoretical Calculation Study

Abstract: The influence of both Bronsted acid strength and pore confinement effect on the ethylene dimerization reaction has been systematically studied by density functional theory (DFT) calculations. In the theoretical calculations, both stepwise and concerted reaction mechanisms are considered. It is demonstrated that the reactivity of the ethylene dimerization reaction can be significantly enhanced by increasing acid strength no matter which mechanism is included, while on the basis of activated barriers, the concerted mechanism is preferred on weak acids and two mechanisms are competitive when the acid strength increases to a medium strong acid. Due to the pore confinement effect that can effectively stabilize the ionic transition states of the dimerization reaction, the activity of the dimerization reaction is considerably improved inside the zeolite pore. Compared with the reaction on the isolated acid sites, the transition states of the stepwise reaction are more effectively stabilized than those of the concerted reaction inside the zeolite confined pore, resulting in the former reaction being preferred when the dimerization reaction occurs inside the zeolite confinement spaces. Additionally, on the basis of the systematic investigations on the alkene dimerization reactions over zeolites with varying pore sizes (such as ZSM-22, ZSM-S, and SSZ-13), it is demonstrated that ZSM-22 and ZSM-5 zeolites are effective catalysts for the ethylene dimerization.

Studies of the di-iron(VI) Intermediate in ferrate-dependent oxygen evolution from water.

Abstract: Molecular oxygen is produced from water via the following reaction of potassium ferrate (K2FeO4) in acidic solution: 4[H3FeVIO4]+ + 8H3O+ → 4Fe3+ + 3O2 + 18H2O. This study focuses upon the mechanism by which the O–O bond is formed. Stopped-flow kinetics at variable acidities in H2O and D2O are used to complement the analysis of competitive oxygen-18 kinetic isotope effects (18O KIEs) upon consumption of natural abundance water. The derived 18O KIEs provide insights concerning the identity of the transition state. Water attack (WA) and oxo-coupling (OC) transition states were evaluated for various reactions of monomeric and dimeric ferrates using a calibrated density functional theory protocol. Vibrational frequencies from optimized isotopic structures are used here to predict 18O KIEs for comparison to experimental values determined using an established competitive isotope-fractionation method. The high level of agreement between experimental and theoretic isotope effects points to an intramolecular OC me...

Kinetics of the Hydrogen Abstraction from Carbon-3 of 1-Butanol by Hydroperoxyl Radical: Multi-Structural Variational Transition-State Calculations of a Reaction with 262 Conformations of the Transition State

Abstract: We estimated rate constants for the hydrogen abstraction from carbon-3 of 1-butanol by hydroperoxyl radical, a critically important reaction in the combustion of biofuel. We employed the recently developed multi-structural variational transition-state theory (MS-VTST), which utilizes a multifaceted dividing surface that allows us to include the contributions of multiple structures for reacting species and transition states. First, multiconfigurational Shepard interpolation—based on molecular-mechanics-guided interpolation of electronic-structure Hessian data obtained by the M08 HX/jun-cc-pVTZ electronic model chemistry—was used to obtain the portion of the potential energy surface needed for single-structure variational transition-state theory rate constants including multidimensional tunneling; then, the M08-HX/MG3S electronic model chemistry was used to calculate multi-structural torsional anharmonicity factors to complete the MS-VTST rate constant calculations. The lowest-energy structures of the trans...

Characterization of the Reaction Path and Transition States for RNA Transphosphorylation Models from Theory and Experiment

Abstract: The elucidation of the chemical mechanisms whereby biological molecules control, regulate and catalyze phosphoryl transfer reactions has profound implications for processes such as transcription, energy storage and transfer, cell signalling and gene regulation.[1, 2] The catalytic properties of RNA, in particular, have application in the design of new biotechnology and implications into the evolutionary origins of life itself.[3] Of primary importance to the understanding of mechanism is the characterization of the transition state for these reactions. Kinetic isotope effects (KIEs) offer one of the most powerful and sensitive experimental probes to interrogate the chemical environment of the transition state.[4-6] However, for complex reactions, theoretical methods are required to interpret the experimental measurements in terms of a detailed mechanistic model that traces the pathway from the reactant state through the transition state and into the product state.[7, 8] This paper presents experimental and computational results to characterize the mechanism of model phosphoryl transfer reactions that mimic RNA cleavage transesterification catalyzed by enzymes such as RNase A[1] as well as endonucleolytic ribozymes such as the hammerhead, hairpin, hepatitis delta virus (HDV), VS and glmS ribozymes.[9-11] Herein, secondary kinetic isotope effects are reported for the cleavage transesterification of a dinucleotide system, which, together with previously reported primary isotope effect measurements,[12, 13] represent a comprehensive characterization of isotope effects for a native (unmodified) RNA system. Scheme 1 illustrates the general mechanism for the reverse dianionic in-line methanolysis of ethylene phosphate, a model for base-catalysed RNA phosphate transesterification, with phosphoryl oxygen positions labelled in accord with their RNA counterparts. In this study, the free energy profiles for Scheme 1 were determined with density-functional quantum mechanical/molecular mechanical (QM/MM) simulations in explicit solvent.[14-17] These simulations are state-of-the-art, and take into account the dynamical fluctuations of the solute and solvent degrees of freedom in determination of the free energy profiles. In addition, adiabatic reaction energy profiles were determined with solvation effects treated implicitly with a polarizable continuum model (PCM)[18] specifically calibrated for the native and 3′ and 5′ thio-substituted compounds (Figure 1). The 3′ and 5′ thio-substituted compounds model the corresponding chemically modified RNAs that serve as valuable experimental probes of phosphoryl transfer mechanisms catalyzed by ribozymes.[19] The S5′ substitution, for example, in the HDV ribozyme serves as an enhanced leaving group that suppresses the deleterious effect of mutation of a critical cytosine residue, which has been interpreted to support its role as a general acid catalyst.[20] The energy values for stationary points of the native and thio-substituted reactions are in Table 1. Using our recently developed ab initio path-integral method based on Kleinert’s variational perturbation theory,[7, 21-23] we also calculated kinetic isotope effects, which are shown along with the most relevant experimental values for comparison in Table 2. The agreement that is achieved between the theoretical and experimental results allows a detailed mechanistic interpretation based on the theoretical models.[7, 8] Figure 1 (Color online) Comparison of density-functional QM/MM free-energy and adiabatic PCM profiles for the native reaction (top), and density-functional adiabatic PCM profiles for native and thio-substituted reactions (bottom) as a function of the difference ... Scheme 1 General reaction scheme for the (associative) reverse of dianionic in-line methanolysis of ethylene phosphate: a model for RNA phosphate transesterification under alkaline conditions. In the present work, the native reaction shown in the scheme is studied ... Table 1 Relative free energy (kcal/mol) and reaction coordinate (Δbond) values (A) computed for stationary points along the coordinate of the native and thio-substituted RNA phosphate transesterification reaction models shown in Scheme 1.[[a] ... Table 2 Primary kinetic isotope effects (KIEs) on 2′ nucleophile (18kNu) and 5′ leaving (18kLg) oxygens, and secondary KIEs on O1P (18kO1P) and O2P (18kO2P) oxygens in aqueous solution for the TS1 and TS2 transition states, along with the most ... All of the profiles calculated in this work correspond to associative (or concerted) mechanisms characterized by initial nucleophilic attack, as is typical of phosphate diesters.[6] The departure of the leaving group can be concerted with nucleophilic attack (as in the S5′ substituted reaction) or can occur in a stepwise fashion resulting in the formation of a stable pentavalent phosphorane intermediate. In the stepwise mechanism, two transition states occur: one in which nucleophilic attack occurs (TS1) and another one in which leaving group departure takes place (TS2) as indicated in Scheme 1. These transition states themselves can be characterized as either “early” or “late”, depending on the degree of P-O2′ and P-O5′ bond formation/cleavage.

State-to-state reaction probabilities within the quantum transition state framework

Abstract: Rigorous quantum dynamics calculations of reaction rates and initial state-selected reaction probabilities of polyatomic reactions can be efficiently performed within the quantum transition state concept employing flux correlation functions and wave packet propagation utilizing the multi-configurational time-dependent Hartree approach. Here, analytical formulas and a numerical scheme extending this approach to the calculation of state-to-state reaction probabilities are presented. The formulas derived facilitate the use of three different dividing surfaces: two dividing surfaces located in the product and reactant asymptotic region facilitate full state resolution while a third dividing surface placed in the transition state region can be used to define an additional flux operator. The eigenstates of the corresponding thermal flux operator then correspond to vibrational states of the activated complex. Transforming these states to reactant and product coordinates and propagating them into the respective asymptotic region, the full scattering matrix can be obtained. To illustrate the new approach, test calculations study the D + H2(ν, j) → HD(ν′, j′) + H reaction for J = 0.

Stepwise Diels-Alder : More than Just an Oddity? A Computational Mechanistic Study

Abstract: We have employed hybrid DFT and SCS-MP2 calculations at the SMD-PCM–6-311++G(2d,2p)//6-31+G(d) level to investigate the relationship between three possible channels for forming a Diels–Alder adduct from a highly nucleophilic diene and moderately to highly electrophilic dienophiles. We discuss geometries optimized using the B3LYP and M06-2X functionals with the 6-31+(d) basis set. The transition states and intermediates are characterized on the basis of geometric and electronic properties, and we also address the possibility of predicting detectability of a zwitterionic intermediate based on its relative stability. Our results show that a conventional Diels–Alder transition state conformation yields intermediates in all four investigated cases, but that these are too short-lived to be detected experimentally for the less activated reactants. The stepwise trans pathway, beginning with a conjugate addition-like transition state, becomes increasingly competitive with more activated reactants and is indeed fav...

Theoretical Kinetic Study of Thermal Decomposition of Cyclohexane

Abstract: In the present work, the reaction mechanisms for thermal decomposition of cyclohexane in the gas phase have been investigated using quantum chemical calculations and transition-state theory Three series of reaction schemes containing 38 elementary reactions are proposed The geometry optimization and vibrational frequencies of reactants, transition states, and products are determined at the BH&HLYP/cc-pVDZ level, while energies are calculated at the CCSD(T)/cc-pVDZ level The rate constants for the reactions without transition states, including the initial steps of cyclohexane decomposition (C–C bond scission or C–H bond scission), are obtained by the canonical variational transition-state theory (CVT), while the rate constants for the other reactions with saddle-point transition states are obtained by the conventional transition-state theory (TST) in the temperature range of 300–3000 K The rate constants are in good agreement with data available from the literature The kinetic parameters in the modifi

The Element Effect Revisited: Factors Determining Leaving Group Ability in Activated Nucleophilic Aromatic Substitution Reactions

Abstract: The "element effect" in nucleophilic aromatic substitution reactions (S(N)Ar) is characterized by the leaving group order, F > NO(2) > Cl ≈ Br > I, in activated aryl halides. Multiple causes for this result have been proposed. Experimental evidence shows that the element effect order in the reaction of piperidine with 2,4-dinitrophenyl halides in methanol is governed by the differences in enthalpies of activation. Computational studies of the reaction of piperidine and dimethylamine with the same aryl halides using the polarizable continuum model (PCM) for solvation indicate that polar, polarizability, solvation, and negative hyperconjugative effects are all of some importance in producing the element effect in methanol. In addition, a reversal of polarity of the C-X bond from reactant to transition state in the case of ArCl and ArBr compared to ArF also contributes to their differences in reactivity. The polarity reversal and hyperconjugative influences have received little or no attention in the past. Nor has differential solvation of the different transition states been strongly emphasized. An anionic nucleophile, thiolate, gives very early transition states and negative activation enthalpies with activated aryl halides. The element effect is not established for these reactions. We suggest that the leaving group order in the gas phase will be dependent on the exact combination of nucleophile, leaving group, and substrate framework. The geometry of the S(N)Ar transition state permits useful, qualitative conceptual distinctions to be made between this reaction and other modes of nucleophilic attack.

Elucidation of the reaction mechanisms and diastereoselectivities of phosphine-catalyzed [4 + 2] annulations between allenoates and ketones or aldimines

Abstract: The phosphine-catalyzed [4 + 2] annulations between allenoates and electron-poor trifluoromethyl ketones or N-tosylbenzaldimine dipolarophiles have been investigated in continuum solvation using density functional theory (DFT) calculations. The detailed reaction mechanisms as well as the high cis-diastereoselectivities of the reactions have been firstly clarified. Our calculated results reveal that the whole catalytic process is presumably initiated with the nucleophilic attack of phosphine catalyst at the allenoate to produce the zwitterionic intermediate , which subsequently undergoes γ-addition to the electron-poor C=O (or C=N) dipolarophile to form another intermediate . The following [1,3] hydrogen shift of is demonstrated to proceed via two consecutive proton transfer steps without the assistance of protic solvent: the anionic O6 (or N6) of first acts as a base catalyst to abstract a proton from C1 to produce the intermediate , and then the OH (or NH) group can donate the acidic proton to C3 to complete the [1,3] hydrogen shift and generate the intermediate . Finally, the intramolecular Michael-type addition followed by the elimination of catalyst furnishes the final product. High cis-diastereoselectivities are also predicted for both the two reactions, which is in good agreement with the experimental observations. For the reaction of allenoates with trifluoromethyl ketones, the first proton transfer is found to be the diastereoselectivity-determining step. The cumulative effects of the steric repulsion, electrostatic interaction as well as other weak interactions appear to contribute to the relative energies of transition states leading to the diastereomeric products. On the contrary, in the case of N-tosylbenzaldimines, the Michael-type addition is found to be the diastereoselectivity-determining step. Similarly, steric repulsion, as well as electrostatic interaction is also identified to be the dominant factors in controlling the high cis-diastereoselectivity of this reaction.

Density Functional Theory Study of Selectivity Considerations for C–C Versus C–O Bond Scission in Glycerol Decomposition on Pt(111)

Abstract: Glycerol decomposition via a combination of dehydrogenation, C–C bond scission, and C–O bond scission reactions is examined on Pt(111) with periodic Density Functional Theory (DFT) calculations. Building upon a previous study focused on C–C bond scission in glycerol, the current work presents a first analysis of the competition between C–O and C–C bond cleavage in this reaction network. The thermochemistry of various species produced from C–O bond breaking in glycerol dehydrogenation intermediates is estimated using an extension of a previously introduced empirical correlation scheme, with parameters fit to DFT calculations. Bronsted–Evans–Polanyi (BEP) relationships are then used to estimate the kinetics of C–O bond breaking. When combined with the previous results, the thermochemical and kinetic analyses imply that, while C–O bond scission may be competitive with C–C bond scission during the early stages of glycerol dehydrogenation, the overall rates are likely to be very low. Later in the dehydrogenation process, where rates will be much higher, transition states for C–C bond scission involving decarbonylation are much lower in energy than are the corresponding transition states for C–O bond breaking, implying that the selectivity for C–C scission will be high for glycerol decomposition on smooth platinum surfaces. It is anticipated that the correlation schemes described in this work will provide an efficient strategy for estimating thermochemical and kinetic energetics for a variety of elementary bond breaking processes on Pt(111) and may ultimately facilitate computational catalyst design for these and related catalytic processes.

Insights into the Mechanism of an SN2 Reaction from the Reaction Force and the Reaction Electronic Flux

Abstract: The mechanism of a simple SN2 reaction, viz; OH– + CH3F = CH3OH + F– has been studied within the framework of reaction force and reaction electronic flux. We have computationally investigated three different types of reaction mechanisms with two different types of transition states, leading to two different products. The electronic transfer contribution of the reaction electronic flux was found to play a crucial role in this reaction. Natural bond order analysis and dual descriptor provide additional support for elucidating the mechanism of this reaction.