Nature Of Transition State Research Articles

Aqueous synthesis of 2-aryl-3-nitro-2H[sbnd]chromenes via l-prolinamide mediated tandem oxa-Michael Henry reactions

An efficient and aqueous protocol has been developed for the synthesis of 2-aryl-3-nitro-2H-chromene derivatives. This protocol involves the l-prolinamide mediated tandem oxa-Michael Henry reaction between a variety of β-nitrostyrenes and salicylaldehyde. Among the screened solvents, the catalytic efficiency of prolinamides was found to be high in chloroform, but the best results were obtained in water to provide the 2-phenyl-3-nitro-2H-chromene in excellent yields. Substrate scope was also investigated using various substituted β-Nitrostyrenes. All reactions worked well to provide the corresponding products in very high yields. Theoretical calculations were performed to find out the reaction pathways and nature of transition state at 3–21G* basis set and TS1 corresponding to the product (S)-3a, was found favorable by 1.13 kcal/mol over TS2 corresponding to the product (R)-3a.

Differences in the Nature of the Phosphoryl Transfer Transition State in Protein Phosphatase 1 and Alkaline Phosphatase: Insights from QM Cluster Models.

Quantum mechanical (QM) cluster models are used to probe effects on the catalytic properties of protein phosphatase 1 (PP1) and alkaline phosphatase (AP) due to metal ions and active site residues. The calculations suggest that the phosphoryl transfer transition states in PP1 are synchronous in nature with a significant degree of P-Olg cleavage, while those in AP are tighter with a modest degree of P-Olg cleavage and a range of P-Onuc formation. Similar to observations made in our recent work, a significant degree of cross talk between the forming and breaking P-O bonds complicates the interpretation of the Brønsted relation, especially in regard to AP for which the computed βlg/βEQ,lg value does not correlate with the degree of P-Olg cleavage regardless of the metal ions in the active site. By comparison, the correlation between βlg/βEQ,lg and the P-Olg bond order is more applicable to PP1, which generally exhibits less variation in the transition state than AP. Results for computational models with swapped metal ions between PP1 and AP suggest that the metal ions modulate both the nature of the transition state and the degrees of sensitivity of the transition state to the leaving group. In the reactant state, the degree of the scissile bond polarization is also different in the two enzymes, although this difference appears to be largely determined by the active site residues rather than the metal ions. Therefore, both the identity of the metal ion and the positioning of polar or charged residues in the active site contribute to the distinct catalytic characteristics of these enzymes. Several discrepancies observed between the QM cluster results and the available experimental data highlight the need for further QM/MM method developments for the quantitative analysis of metalloenzymes that contain open-shell transition metal ions.

Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3\u2009+\u20092] cycloaddition

5-(Nitromethyl)-3-phenyl-4,5-dihydroisoxazole was obtained as a product of a high-yielding [3 + 2] cycloaddition reaction of in situ-generated benzonitrile N-oxide and 3-nitroprop-1-ene. For the first time, the regiochemistry of this reaction was unambiguously proven by X-ray structural analysis. The quantum-chemical calculation performed at the M06-2X/6-31G(d) (PCM) theoretical level affords a basis for explaining the course of reaction as well as the nature of transition states. Next, further DFT calculations together with spectral data shed light on structural aspects of the product.Graphical abstract

Analysis of Phosphoryl-Transfer Enzymes with QM/MM Free Energy Simulations.

We discuss the application of quantum mechanics/molecular mechanics (QM/MM) free energy simulations to the analysis of phosphoryl transfers catalyzed by two enzymes: alkaline phosphatase and myosin. We focus on the nature of the transition state and the issue of mechanochemical coupling, respectively, in the two enzymes. The results illustrate unique insights that emerged from the QM/MM simulations, especially concerning the interpretation of experimental data regarding the nature of enzymatic transition states and coupling between global structural transition and catalysis in the active site. We also highlight a number of technical issues worthy of attention when applying QM/MM free energy simulations, and comment on a number of technical and mechanistic issues that require further studies.

Pulling force and surface tension drive membrane fusion.

Despite catalyzed by fusion proteins of quite different molecular architectures, intracellular, viral, and cell-to-cell fusions are found to have the essential common features and the nearly same nature of transition states. The similarity inspires us to find a more general catalysis mechanism for membrane fusion that minimally depends on the specific structures of fusion proteins. In this work, we built a minimal model for membrane fusion, and by using dissipative particle dynamics simulations, we propose a mechanism that the pulling force generated by fusion proteins initiates the fusion process and the membrane tension regulates the subsequent fusion stages. The model shows different features compared to previous computer simulation studies: the pulling force catalyzes membrane fusion through lipid head overcrowding in the contacting region, leading to an increase in the head-head repulsion and/or the unfavorable head-tail contacts from opposing membranes, both of which destabilize the contacting leaflets and thus promote membrane fusion or vesicle rupture. Our simulations produce a variety of shapes and intermediates, closely resembling cases seen experimentally. Our work strongly supports the view that the tight pulling mechanism is a conserved feature of fusion protein-mediated fusion and that the membrane tension plays an essential role in fusion.

A detail kinetic study on vapour phase oxidation of diphenylmethane over mesoporous V-KIT-6 catalyst

Mesoporous V-KIT-6 catalysts with different Si/V ratios of 25,50,75 and 100 were synthesized by hydrothermal method under the controlled acidic conditions and characterized by using low angle XRD, ICP-OES, Diffuse reflectance UV–vis, SEM and TEM analysis. The characterization results are confirmed that most of the vanadium was mainly incorporated in the form of an isolated tetrahedral environment with terminal VO bond units.The synthesized catalysts were tested for the vapour phase selective oxidation of diphenylmethane (DPM) using air as an oxidant. A detail kinetic study was carried out on V-KIT-6 (25) catalyst using Langmuir–Hinshelwood (LH) model. The combined studies of Langmuir–Hinshelwood (LH) model and transition state theory (TST) explain that the reaction follows a second-order rate expression with respect to surface coverage of DPM and molecular oxygen. The reaction data derived from the LH modeling is allowed us to calculate the true activation energy and activation entropy of the reaction. The nature of transition state was determined from transition state theory and possible reaction mechanism was proposed for this reaction.

Effects of Nanoconfinement on Catalysis

We discuss the application of quantum mechanics/molecular mechanics (QM/MM) free energy simulations to the analysis of phosphoryl transfers catalyzed by two enzymes: alkaline phosphatase and myosin. We focus on the nature of the transition state and the issue of mechanochemical coupling, respectively, in the two enzymes. The results illustrate unique insights that emerged from the QM/MM simulations, especially concerning the interpretation of experimental data regarding the nature of enzymatic transition states and coupling between global structural transition and catalysis in the active site. We also highlight a number of technical issues worthy of attention when applying QM/MM free energy simulations, and comment on a number of technical and mechanistic issues that require further studies.

Kinetics of palladium nano-particles catalyzed reduction of Methylene Green by hydrazine: Role of induction period in determining mechanistic pathway

Methylene Green (MG), a thiazine dye, is catalytically reduced by N2H4 in presence of palladium nano-particles (Pdn) in buffer media. The observed rate, ko increases with increase in [Pdn], [N2H4] and pH but decrease with increase in ionic strength (maintained with NaNO3). Unlike other thiazine dyes, the catalyzed reduction of MG shows an induction period which is caused by the restructuring of Pdn surface. The rate of adsorbate-induced surface restructuring which increase with increase in [N2H4] but independent of [MG], suggest that only N2H4 is adsorbed on Pdn surface during the catalyzed reaction. Interestingly, NO3− ions are also adsorbed on the Pdn surface and turn the surface negatively charged. The reductant, N2H4 is adsorbed on this negatively charged Pdn surface before it reacts with MG. The surface restructuring energy of Pdn, though is constant (78.8±1.6kJM−1) over the temperature range of 288–313K but the activation energy for the catalyzed reduction varies with temperatures. The convex Arrhenius plot illustrates that activation energy is different in lower (288–304K, 123.8±12.6kJM−1) and higher temperature range (304–313K, 69.2±2.1kJM−1) and around the inversion temperature, Tinv (304K) a change in the nature of transition state takes place.

Elastic-Plastic Transition Problems

The concept of generalized strain measure has been useful for study of elastic plastic transitions. According to classical theory, the elastic-plastic transitions are linear in nature but this theory does not tell about non-linearity in elastic-plastic transitions. It was B.R Seth who explained the non-linear nature of transition state. The elastic-plastic transition problems are helpful to calculate stresses for initial yielding and for fully plastic state. The concept of elastic-plastic transition has been elaborated by discussing various elastic-plastic problems.

Theoretical study of the reactivity of Rh(I) and Rh(III) Bis(isonitrile) complexes in cycloaddition reactions with nitrones

The mechanism of 1,3-dipolar cycloaddition of nitrone (CH2=N(Me)O) to methylisonitrile coordinated to Rh(I) and Rh(III) in the [RhCl(PH3)(CNMe)2] and [RhCl3(PH3)(CNMe)2] complexes has been studied by quantum-chemical methods. The molecular and electronic structures of the cycloaddition products, the nature of transition states, the mechanism of reactions, their kinetic and thermodynamic parameters, and the solvent effect have been described. The reactions occur via the concerted strongly asynchronous mechanism involving the formation of a five-membered cyclic transition state. The use of rhodium complexes as reagents leads to a noticeable decrease in the activation barriers of the processes under consideration and an increase in the magnitudes of energy effects of the reactions. It has been demonstrated that the Rh(III) complexes are better activators of the cycloaddition of nitrone to isonitrile than the Rh(I) complex. The calculations predict that in the case of the Rh(I) complexes, only one isonitrile ligand can be involved in cycloaddition of nitrone, whereas the use of the Rh(III) complexes enables the participation of both ligands. The solvation effects inhibit the reactions.

Activation Thermodynamics of Poly(Ethylene Glycol)-Mediated Model Membrane Fusion Support Mechanistic Models of Stalk and Pore Formation

Membrane fusion, essential to eukaryotic life, is broadly envisioned as a three-step process proceeding from contacting bilayers through two semistable, nonlamellar lipidic intermediate states to a fusion pore. Here, we introduced a new, to our knowledge, experimental approach to gain insight into the nature of the transition states between initial, intermediate, and final states. Recorded time courses of lipid-mixing, content-mixing, and content-leakage associated with fusion of 23 nm vesicles in the presence of poly(ethylene glycol) at multiple temperatures were fitted globally to a three-step sequential model to yield rate constants and thereby activation thermodynamics for each step of the process, as well as probabilities of occurrence of lipid-mixing, content-mixing, or content-leakage in each state. Experiments with membranes containing hexadecane, known to reduce interstice energy in nonlamellar structures, provided additional insight into the nature of fusion intermediates and transition states. The results support a hypothesis for the mechanism of stalk formation (step-1) that involves acyl chain protrusions into the interbilayer contact region, a hypothesis for a step-2 mechanism involving continuous interconversion of semistable nonlamellar intermediates, and a hypothesis for step-3 (pore formation) mechanism involving correlated movement of whole lipid molecules into hydrophobic spaces created by geometry mismatch between intermediate structures.

Modeling the Transition State of Enzyme-catalyzed Phosphoryl Transfer Reaction Using QM/MM Method

Reversible phosphorylation of proteins is a post-translational modification that regulates diverse biological processes. The molecular mechanism underlying phosphoryl transfer catalyzed by enzymes, in particular the nature of transition state (TS), remains a subject of active debate. Structural evidence supports an associative TS, whereas physical organic studies point to a dissociative character. In this article, we briefly introduce our recent effort using the hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to resolve the controversy. We perform QM/MM simulations for the reversible phosphorylation of phosphoserine phosphatase (PSP), which belongs to one of the largest phosphotransferase families characterized to data. Both phosphorylation and dephosphorylation reactions are investigated based on the two-dimensional energy surfaces along phosphoryl and proton transfer coordinates. The resultant structures of the active site at TS in both reactions have compact geometries but a less electron density of the phosphoryl group. This suggests that the TS of PSP has a geometrically associative yet electronically dissociative character and strongly depends on proton transfer being coupled with phosphoryl transfer. Structure and literature database searches on phosphotransferases suggest that such a hybrid TS is consistent with many structures and physical organic studies and likely holds for most enzymes catalyzing phosphoryl transfer.

Geometrically associative yet electronically dissociative character in the transition state of enzymatic reversible phosphorylation

Reversible phosphorylation of proteins is a post-translational modification that regulates diverse biological processes. The molecular mechanism underlying phosphoryl transfer catalyzed by enzymes remains a subject of active debate. In particular, the nature of transition state (TS), whether it has an associative or dissociative character, has been one of the most controversial issues. Structural evidence supports associative TS, whereas physical organic studies point to a dissociative character. Here we perform hybrid quantum mechanics/molecular mechanics simulations for the reversible phosphorylation of phosphoserine phosphatase (PSP) to study the nature of the TS. Both phosphorylation and dephosphorylation reactions are investigated based on the two-dimensional energy surfaces along phosphoryl and proton transfer coordinates. The structures of the active site at TS in both reactions reveal compact geometries, consistent with crystal structures of PSP with phosphate analogues. However, the electron density of the phosphoryl group in both TS structures slightly decreases compared with that in the reactant states. These findings suggest that the TS of PSP has a geometrically associative yet electronically dissociative character and strongly depends on proton transfer being coupled with phosphoryl transfer. Structure and literature database, which searches on phosphotransferases, suggest that such a hybrid TS is consistent with many structures and physical organic studies and likely holds for most enzymes catalyzing phosphoryl transfer.

Temperature-Dependent Transitions Between Normal and Inverse Isotope Effects Pertaining to the Interaction of H−H and C−H Bonds with Transition Metal Centers

Deuterium kinetic isotope effects (KIEs) serve as versatile tools to infer details about reaction mechanisms and the nature of transition states, while equilibrium isotope effects (EIEs) associated with the site preferences of hydrogen and deuterium enable researchers to study aspects of molecular structure. Researchers typically interpret primary deuterium isotope effects based on two simple guidelines: (i) the KIE for an elementary reaction is normal (k(H)/k(D) > 1) and (ii) the EIE is dictated by deuterium preferring to be located in the site corresponding to the highest frequency oscillator. In this Account, we evaluate the applicability of these rules to the interactions of H-H and C-H bonds with a transition metal center. Significantly, experimental and computational studies question the predictability of primary EIEs in these systems based on the notion that deuterium prefers to occupy the highest frequency oscillator. In particular, the EIEs for (i) formation of sigma-complexes by coordination of H-H and C-H bonds and (ii) oxidative addition of dihydrogen exhibit unusual temperature dependencies, such that the same system may demonstrate both normal (i.e., K(H)/K(D) > 1) and inverse (i.e., K(H)/K(D) < 1) values. The transition between a normal and inverse EIE indicates that these systems do not demonstrate the typical monotonic variation predicted by the van't Hoff relationship. Instead, the calculated EIEs in these systems are 0 at 0 K, increase to a value greater than 1, and then decrease to unity at infinite temperature. This unusual behavior may be rationalized by considering the individual factors that contribute to the EIE. Specifically, the EIE may be expressed in the form EIE = SYM x MMI x EXC x ZPE (where SYM is the symmetry factor, MMI is the mass-moment of inertia term, EXC is the excitation term, and ZPE is the zero-point energy term), and the distinctive temperature profile results from the inverse ZPE (enthalpy) and normal [SYM x MMI x EXC] (entropy) components opposing each other and having different temperature dependencies. At low temperatures, the ZPE component dominates and the EIE is inverse, while at high temperatures, the [SYM x MMI x EXC] component dominates and the EIE is normal. The inverse nature of the ZPE term is a consequence of the rotational and translational degrees of freedom of RH (R = H, CH(3)) becoming low-energy isotopically sensitive vibrations in the product, while the normal nature of the [SYM x MMI x EXC] component results from deuterium substitution having a larger impact on the moment of inertia of the smaller molecule.

Linear free energy relationship and kinetic isotope effects as measures for the transition state variation. A computational study.

Linear free energy relationship (LFER) and kinetic isotope effects (KIEs) are frequently used experimental means to study reaction mechanisms, in particular the nature of transition states (TSs). Density functional theory (B3LYP/6-311+G**) calculations were carried out on a model reaction, acid-catalyzed ionization of phenylethyl alcohol, to analyze how experimentally observable properties, such as nonlinearity in the Hammett and Brønsted relations and variation in KIE, are related to a variation of the transition state structure and the mechanism. Several conclusions and insights were obtained: (1) Linear Hammett plots with a dual parameter treatment may not be evidence for an invariable TS structure for a series of reactions. (2) Variations of KIEs indeed reflect the variations of TS structures. (3) Nonlinear Brønsted plots cannot always be taken as evidence for a stepwise mechanism. (4) A TS structure in the gas phase may change much more easily than a TS structure in solution.

Kinetics and mechanism of Os(VIII)-catalysed oxidation of some substituted trans-cinnamic acids by chloramine-T in alkaline medium — A non-linear Hammett plot

The kinetics and mechanism of Os(VIII) catalysed oxidation of some substituted trans-cinnamic acids by chloramine-T in presence of alkaline medium has been investigated. The order with respect to [CAT] is zero and is [OsO] one. The reaction is fractional order in [substrate). The rate dependence on [OH] is inverse first order. Both the electron-releasing and withdrawing substituents facilitate the reaction rate. The observed rate constants for substituents are plotted against Hammett constant σ, a non-linear, ‘V’ shaped curve is obtained. The electron-withdrawing substituents fall on one side of the curve having a negative ϱ value, and electron-releasing substituents fall on the otherside with positive ϱ value. The break in the Hammett plot is due to change in the nature of transition state. The mechanism proposed and the derived rate law are in confirmity with the observed results.

Introductory remarks to the second session

The four presentations in this session cover studies on different aspects of enzyme structure and function. They effectively illustrate how one has to combine different approaches to arrive at an understanding of enzymatic catalysis and control. Nowadays, the molecular description of an enzyme is hardly credible without detailed crystallographic information. Thus, Dr Blake’s paper on the structure of phosphoglycerate kinase is particularly relevant to our understanding of phosphate-transfer mechanisms. The question of the relation between structure in the solid and solution is still with us and n.m.r. has proved to be the best way to study the differences and similarities. M any enzyme substrate complexes have been ‘mapped’ in solution, by using the perturbation of the n.m.r. spectra by param agnetic centres as a measure of interatomic distances. How such results can lead to both structural and mechanistic information will be discussed by Dr Mildvan. To understand mechanisms we must also get some information about the nature of transition states. Here, stereochemical observations play an important role and Dr Lowe will describe some elegant work on the use of chiral phosphates in approaching this problem. Finally, it is important to describe structures, intermediates and transition states in terms of the kinetic behaviour of the enzyme and Dr Dalziel will give us an example of both steady-state and pre-steady-state rate studies. Measurements of reaction rates ultimately link studies on the isolated enzyme to their behaviour in vivo . As this last step in the sequence is not covered by the formal presentations at this meeting I should like to show briefly how n.m.r. can now be used to obtain fluxes of enzyme catalysed reactions in vivo both in the steady state and at equilibrium.

Kinetics and Mechanism of the Oxidation Reactions of Dialkyldithiocarbamatocopper(I) Tetramer and -silver(I) Hexamer with Tetraalkylthiuram Disulfide

Abstract Kinetics of the oxidations of dialkyldithiocarbamatocopper(I), [{Cu(S2CNR2)}4] (R=Et, n-Pr), and -silver(I), [{Ag(S2CNR2)}6] (R=Et, n-Pr, i-Pr), with the corresponding tetraalkylthiuram disulfide, [(R2NC(S)S) \llap–2], were investigated in dichloromethane employing a stopped-flow technique. The reactions are interpreted to proceed by a mechanism involving a rapid equilibration (i) (the multi-step equilibrium constant=K0) to form adduct, (Remark: Graphics omitted.) [M(S2CNR2){(R2NC(S)S) \llap–2}], which are decomposed in a rate-determining step (the rate constant=k) yielding the final products, [M(S2CNR2)2]. According to this mechanism, the rate law in the presence of excess [(R2NC(S)S) \llap–2] is expressed as v=K0k[[(R2NC(S)S) \llap–2]][[{M(S2CNR2)}x]]/(1+K0[[(R2NC(S)S) \llap–2]]), where K0k(25 °C)=1.17×104 (Et), 5.70×103 (n-Pr) M−1 s−1 (M=mol dm−3) for the copper system, and K0(25 °C)=28.2 (Et), 49.1 (n-Pr), 86.7 (i-Pr) M−1 and k(25 °C)=2.17 (Et), 1.50 (n-Pr), 6.56 (i-Pr) s−1 for the silver system. The activation parameters also were determined and the nature of transition states is discussed.

Asymmetric hydride transfer reactions - the nature of transition state and interpretation of observed discrepancies in asymmetric induction

Asymmetric hydride transfer reactions - the nature of transition state and interpretation of observed discrepancies in asymmetric induction

Mechanism of elimination reactions : The E2 reactions of substituted α-phenylethyl bromides

The rates of the base-catalysed elimination of a series of substituted α-phenylethyl bromides have been determined in t-BuOK-t-BuOH, t-BuOK-t-BuOH-DMSO and EtONa-EtOH systems. The Hammett ϱ values obtained were, although small and not in linear correlation with σ values, positive in all cases. β-Methyl group retarded the rate in t-BuOK-t-BuOH and in t-BuOK-t-BuOH-DMSO, but enhanced it in EtONa-EtOH. β-Hydrogen kinetic isotope effects were 5·0, 3·5 and 3·4, respectively. The nature of transition states is discussed in the light of these observations.