Theoretical studies on the deacylation step of serine protease catalysis in the gas phase, in solution, and in elastase

The deacylation step of serine protease catalysis is studied using DFT and ab initio QM/MM calculations combined with MD/umbrella sampling calculations. Free energies of the entire reaction are calculated in the gas phase, in a continuum solvent, and in the enzyme elastase. The calculations show that a concerted mechanism in the gas phase is replaced by a stepwise mechanism when solvent effects or an acetate ion are added to the reference system, with the tetrahedral intermediate being a shallow minimum on the free energy surface. In the enzyme, the tetrahedral intermediate is a relatively stable species ( approximately 7 kcal/mol lower in energy than the transition state), mainly due to the electrostatic effects of the oxyanion hole and Asp102. It is formed in the first step of the reaction, as a result of a proton transfer from the nucleophilic water to His57 and of an attack of the remaining hydroxyl on the ester carbonyl. This is the rate-determining step of the reaction, which requires approximately 22 kcal/mol for activation, approximately 5 kcal/mol less than the reference reaction in water. In the second stage of the reaction, only small energy barriers are detected to facilitate the proton transfer from His57 to Ser195 and the breakdown of the tetrahedral intermediate. Those are attributed mainly to a movement of Ser195 and to a rotation of the His57 side chain. During the rotation, the imidazolium ion is stabilized by a strong H-bond with Asp102, and the C(epsilon)(1)-H...O H-bond with Ser214 is replaced by one with Thr213, suggesting that a "ring-flip mechanism" is not necessary as a driving force for the reaction. The movements of His57 and Ser195 are highly correlated with rearrangements of the binding site, suggesting that product release may be implicated in the deacylation process.     

Large-scale, surfactant-free, hydrothermal synthesis of lithium aluminate nanorods: optimization of parameters and investigation of growth mechanism

Lithium aluminate nanorods were successfully synthesized from Al2O3 nanoparticles and lithium hydroxide by a simple, large-scale hydrothermal process without any surfactant or template. The various reaction parameters were optimized to achieve the maximum yield. The as-obtained nanorods had orthorhombic beta-lithium aluminate structure with edges in the range of 40-200 nm and lengths of 1-2 mum confirmed by SEM, TEM, XRD, and NMR. Upon calcination at 1273 K for 12 h it transformed to gamma-lithium aluminate, yet maintained the initial morphology, demonstrating the thermal stability. The ratio of lithium hydroxide to aluminum oxide showed a significant effect on the morphology as Li/Al = 1 gives "microroses", whereas Li/Al = 3 and Li/Al = 15 gave "microbricks" and "nanorods", respectively. Investigation of the mechanism showed that the nanorods were formed via a "rolling-up" mechanism. As we used all-inorganic raw materials and a simple synthetic procedure under mild conditions, the scale-up of this process for large-scale production should be very easy.     

Dienamine catalysis: organocatalytic asymmetric gamma-amination of alpha,beta-unsaturated aldehydes

A new concept in organocatalysis is presented, the direct asymmetric gamma-functionalization of alpha,beta-unsaturated aldehydes. We disclose that secondary amines can invert the usual reactivity of alpha,beta-unsaturated aldehydes, enabling a direct gamma-amination of the carbonyl compound using azodicarboxylates as the electrophilic nitrogen-source. The scope of the reaction is demonstrated for the enantioselective gamma-amination of different alpha,beta-unsaturated aldehydes, giving the products in moderate to good yields and with high enantioselectivities up to 93% ee. Experimental investigations and DFT calculations indicate that the reaction might proceed as a hetero-Diels-Alder cycloaddition reaction. Such a mechanism can explain the "unexpected" stereochemical outcome of the reaction.     

The classic "brown-ring" reaction in a new medium: kinetics, mechanism, and spectroscopy of the reversible binding of nitric oxide to iron(II) in an ionic liquid

To elucidate the applicability and properties of ionic liquids (ILs) to serve as chemical reaction media for the activation of small molecules by transition-metal complexes, detailed kinetic and mechanistic studies were performed on the reversible binding of NO to FeCl(2) dissolved in the IL 1-ethyl-3-methylimidazolium dicyanamide ([emim][dca]) as a solvent. We report, for the first time, the application of laser flash photolysis at ambient and high pressure to study the kinetics of this reaction in an IL. The kinetic data and activation parameters for the "on" and "off" reactions suggest that both processes follow a limiting dissociative (D) ligand substitution mechanism, in contrast to that reported for the same reaction in aqueous solution, where this well-known "brown-ring" reaction follows an interchange dissociative (I(d)) ligand substitution mechanism. The observed difference apparently arises from the participation of the IL anion as a N-donor ligand, as evidenced by the formation of polymeric [Fe(dca)(3)Cl](x)[emim](2x) chains in the solid state and verified by X-ray crystallography. In addition, infrared (IR), Mo?ssbauer, and EPR spectra were recorded for the monomeric reaction product [Fe(dca)(5)NO](3-) formed in the IL, and the parameters closely resemble those of the {FeNO}(7) unit in other well-characterized nitrosyl complexes. It is concluded that its electronic structure is best described by the presence of a high-spin Fe(III) (S = 5/2) center antiferromagnetically coupled to NO(-) (S = 1), yielding the observed spin quartet ground state (S(t) = 3/2).     

Functionalized tetrastannacyclobutanes, Part I

The reaction of di^tbutyldichlorostannane with 5 equivalents of magnesium leads to 1,1,2,2,3,3,4-hepta-^tbutyl-4-(chloromagnesio)-tetrastannacyclobutane 1. A mechanism of this reaction is proposed. 1 is structurally characterized by 1D and 2D ¹¹⁹Sn NMR experiments. New monofunctionalised four membered cyclostannanes could be obtained by derivatisation of 1. X-Ray analysis of 1,1,2,2,3,3,4-hepta-^tbutyl-4-methyl-tetrastannacyclobutane 2 and 1,1,2,2,3,3,4-hepta-^tbutyl-4-chlorpropyl-tetrastannacyclobutane 5 show bent ring systems with folding angles about 157°.     

Thermal Degradation Behavior and Kinetic Analysis of Biodegradable Polymers Using Various Comparative Models, 1

Thermal degradation behavior of a biodegradable polymer (PBS) has been investigated by conventional and MTGA methods. The kinetic parameters of degradation were calculated by a general analytical solution and by the Coats‐Redfern, Ozawa, Horowitz‐Metzger, and MTGA methods. The results reveal that the reaction mechanism at lower temperature is probably the F1 model through the reaction of random chain cleavage via cis‐elimination. However, the reaction mechanism at higher temperature is likely to be D1 model because of the dominant diffusion control effect.

     

Molecular mechanism for eliminylation, a newly discovered post-translational modification

The newly discovered bacterial phosphothreonine lyases perform a post-translational modification of host cell signaling proteins through a novel catalytic mechanism that irreversibly removes the phosphate group from a phosphorylated threonine via β-elimination. This "eliminylation" reaction is shown by ab initio QM/MM studies to proceed via an E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC.     

浅析有机化学反应机理的教与学

有机化学的基本理论和反应机理是有机化学的核心内容。反应机理的教与学是有机化学教学过程中的难点,一直困扰着教师和学生。笔者采用了"教师引导–学生练习–学生综合讲解"三段式的反应机理教学方式。首先是教师引导:教师结合国内外教材和文献,先讲授基本理论,再详细讲解反应机理;接着是学生练习:教师根据教学进度布置习题让学生练习,然后结合前后相关的反应机理,组装成比较复杂的多步反应,要求学生根据机理推导反应产物;最后是学生综合讲解:给每个学生分配一个反应,要求围绕该反应,通过查阅文献和资料,整理好素材,在课堂上讲解展示反馈,教师据此进行补充和修改。经过实践证明,该方式便于学生理解有机化学反应机理,从而达到事半功倍的教学效果。     

Autoxidation of ascorbic acid catalyzed by the copper(II) bound to L-histidine oligopeptides, (His)iGly and acetyl-(His)i Gly (i=9, 19, 29). Relationship between catalytic activity and coordination mode

Spectroscopic and kinetic studies on the autoxidation of ascorbic acid catalyzed by copper complexes of histidine oligopeptides, (His)iGly (i=4, 9, 19, 29), and their acetyl derivatives, Ac-(His)iGly (i=9, 19) have been carried out at pH 4.4 and 25 degrees C under dioxygen. The reaction was monitored at 260 nm using a stopped-flow spectrophotometric technique. The reaction fitted the "Michaelis- Menten" mechanism, and ascorbate was oxidized by the "Ping-Pong" mechanism. The Cu(lI) complexed with the oligopeptide (i > or = 9) enhanced the reaction approximately two-fold relative to the aqueous Cu(II). The catalytic activity depends on the molecular weight which is related to the number of histidyl residues and on the coordination mode of the copper-binding site. Results of circular dichroism (CD) experiments revealed the existence of two types of Cu(II). The catalytically active Cu(II), which is accommodated in the imidazole clusters composed of at least six histidyl residues, exhibits d-d transition bands at 520 and 630 nm, and is easily dissociable, enhances the autoxidation; Ac-(His)19Gly is likely to accommodate approximately three active Cu(II) ions. The Cu(II), which is complexed tightly with the terminal H2N-X-Y-His- moiety, where X and Y denote amino acids, inhibits the autoxidation, and exhibits absorption bands at 480 and 550 nm.     

The pyrolysis of dimethyl sulfide,kinetics and mechanism

The kinetics of the gas phase pyrolysis of dimethyl sulfide (DMS) was studied in a static system at 681–723 K by monitoring total pressure-time behavior. Analysis showed the pressure increase to follow DMS loss. The reaction follows two concurrent paths: with a slow, minor, secondary reaction: In a seasoned reactor the reaction follows a 3/2 order rate law with rate coefficient given by with θ = 2.303 RT in kcal/mol. A free radical mechanism is proposed to account for the data and a theoretical rate coefficient is derived from independent data: which agrees well with the experimental one over the range studied. The reaction is initiated by Me₂S → Me + MeS? and propagated by metathetical radical attack on Me₂S. C₂H₄ is formed by an isomerization reaction which may in part be due to a hot radical: Thermochemical data are listed, many from estimations, for both molecular and radical species of interest in the present system.     

Mechanism and activity of ruthenium olefin metathesis catalysts: the role of ligands and substrates from a theoretical perspective

The reaction mechanism of olefin metathesis by ruthenium carbene catalysts is studied by gradient-corrected density functional calculations (BP86). Alternative reaction mechanisms for the reaction of the "first-generation" Grubbs-type catalyst (PCy(3))(2)Cl(2)Ru=CH(2) (1) for the reaction with ethylene are studied. The most likely dissociative mechanism with trans olefin coordination is investigated for the metathesis reaction between the "first-" and the "second-generation" Grubbs-type catalysts 1 and (H(2)IMes)(PCy(3))Cl(2)Ru=CH(2) (2) with different substrates, ethylene, ethyl vinyl ether, and norbornene, and a profound influence of the substrate is found. In contrast to the degenerate reaction with ethylene, the reactions with ethyl vinyl ether and norbornene are strongly exergonic by 8-15 kcal/mol, and this excess energy is released after passing through the metallacyclobutane structure. While the metallacyclobutane is in a deep potential minimum for degenerate metathesis reactions, the energy barrier for the [2+2] cycloreversion vanishes for the most exergonic reactions. On the free energy surface under typical experimental conditions, the rate-limiting steps for the overall reactions are then either metallacyclobutane formation for 1 or phosphane ligand dissociation for 2.     

PPY／PVP催化剂合成11，2，4—三—0酰化红霉素的研究

本文利用4－（1'－四氢吡咯）吡啶（PPY）及聚乙烯吡啶（PVP）复合催化剂催化合成了11,2',4'－三－0酰化红霉素衍生物,与传统方法相比,该法具有简单、快速、收率高等优点。一些影响素及反应机理被讨论,目标物收率为90％以上。     

Semiempirical quantum-chemical investigation of fragmentation of O-fluorosulfonyl-N,N-difluorohydroxylamine anion-radical

The semiempirical quantum-chemical method PM3 has been used to calculate the heats of reaction for the decomposition of the anion-radical of O-fluorosulfonyl-N,N-difluorohydroxylamine in the gas phase and in solution. It has been shown that the reaction of the anion-radical leading to the formation of the radical^.NF₂ is thermodynamically favorable, either in the gas phase or in solution. For this exothermic reaction, a section of the potential energy surface along the reaction coordinate has been calculated, and it has been found that the reaction proceeds with virtually no barrier:E _a=1 kcal/mole. The O-fluorosulfonyl-N,N-difluorohydroxylamine is characterized by a high electron affinity (3 eV); i.e., its interaction with nucleophiles with a low ionization potential may proceed through anS _RN 1 mechanism.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 4, pp. 855–860, April, 1992.     

Kinetics and Mechanism of the Reaction between Barbituric Acid and Glycidol,Part III: Methylene Group Reaction with Glycidol at High Concentration

The reaction of barbituric acid and glycidol leads to formation of oligoetherols upon addition of glycidol both to the methylene group and imide groups of barbituric acid. The mechanism of reaction was established by kinetic studies on the reaction between 1,3‐dimethylbarbituric acid and glycidol used at high concentration. The obtained rate law and mechanism have been derived from kinetic studies and the results obtained before, where 1,3‐dimethylbarbituric acid and glycidol were used in comparable concentrations. The completed kinetic characteristics of the system is described. It has been found that glycidol reacted with methylene groups of 3‐dimethylbarbituric according to the equation: . The rate‐determining step was transformation of enolate into carbanion. Activation energy of the reaction was 61.3 kJ mol⁻¹ · K⁻¹. Proton transfer from methylene group of 1,3‐dimethylbarbituric into glycidol oxirane oxygen was observed by the ¹H‐NMR spectroscopy.     

Stereochemistry of the intermediates in the synthesis of 1,4,7,10-tetraazacyclododecane from triethylenetetramine, glyoxal and diethyl oxalate

The equilibrium and rearrangement phenomena encountered in two steps for the synthesis of 1,4,7,10-tetraazacyclododecane from triethylenetetramine, glyoxal and diethyl oxalate were studied and elucidated after the development of two micellar electrokinetic chromatographic (MEKC) methods. The latter were able to separate: (i) the four bis-aminals (2-5) obtained from the condensation of triethylenetetramine with glyoxal; (ii) the four diones (6-9) derived from the reaction of the bis-aminals with diethyl oxalate, whose solid state structures were determined by single crystal X-ray diffraction. The three not yet reported diones (6, 7 and 9) were synthesised by taking advantage of both the reaction conditions and the use of a particular catalyst (MeONa). A plausible reaction mechanism, as well as a discussion of the solid state structures, is presented.     

Thermal reaction of hydrogen–butene-2-cis mixtures at 500°C: Hydrogenation,hydrogenolysis, and thermal reaction of the olefin

The thermal reaction of hydrogen–butene-2-cis mixtures has been studied in a static system at low extent of reaction around 500°C. Hydrogen does not affect the thermal reaction itself of the olefin, but gives rise to new stoichiometries of hydrogenolysis and hydrogenation, which are specified: The reaction is described in terms of a molecular and free-radical mechanism. It is shown that the key process for the hydrogenolysis–hydrogenation reaction is (1) and that the rate constant of this process can be determined from either propylene, or methane, or butene-1 formations: with θ = 4.57 × 10^?3 T kcal/mol. Other rate constants are estimated and agree with literature data.     

Catchment region partitioning of energy hypersurfaces,I

The space of internal coordinates of a molecular system is partitioned into catchment regions of various critical points of the energy hypersurface. The partitioning is based on an ordering of steepest descent paths into equivalence classes. The properties of these catchment regions and their boundaries are analyzed and the concepts of chemical structure, reaction path and reaction mechanism are discussed within the framework of the Born-Oppenheimer and energy hypersurface approximations. Relations between catchment regions and the chemically important reactive domains of energy hypersurfaces, as well as models for branching of reaction mechanisms, caused by instability domainsD , 1, are investigated.     

Bimodal proton transfer in acid-base reactions in water

We investigate one of the fundamental reactions in solutions, the neutralization of an acid by a base. We use a photoacid, 8-hydroxy-1,3,6-trisulfonate-pyrene (HPTS; pyranine), which upon photoexcitation reacts with acetate under transfer of a deuteron (solvent: deuterated water). We analyze in detail the resulting bimodal reaction dynamics between the photoacid and the base, the first report on which was recently published. We have ascribed the bimodal proton-transfer dynamics to contributions from preformed hydrogen bonding complexes and from initially uncomplexed acid and base. We report on the observation of an additional (6 ps)(-1) contribution to the reaction rate constant. As before, we analyze the slower part of the reaction within the framework of the diffusion model and the fastest part by a static, sub-150 fs reaction rate. Adding the second static term considerably improves the overall modeling of the experimental results. It also allows to connect experimentally the diffusion controlled bimolecular reaction models as defined by Eigen-Weller and by Collins-Kimball. Our findings are in agreement with a three-stage mechanism for liquid phase intermolecular proton transfer: mutual diffusion of acid and base to form a "loose" encounter complex, followed by reorganization of the solvent shells and by "tightening" of the acid-base encounter complex. These rearrangements last a few picoseconds and enable a prompt proton transfer along the reaction coordinate, which occurs faster than our time resolution of 150 fs. Alternative models for the explanation of the slower "on-contact" reaction time of the loose encounter complex in terms of proton transmission through a von Grotthuss mechanism are also discussed.     

Kinetics,Substrate Selectivity,and Activation Parameters for the Reaction of Methylbenzenes with Hydroxymethyl Cations in Sulfuric Acid Solutions

The kinetics of the hydroxymethylation of benzene and methylbenzenes in a formaldehyde–sulfuric acid (52.5 wt.%) system in the temperature range 14-90 °C has been studied. With [ArH] [CH₂O] the reaction is first order in substrate and less than first order in formaldehyde. The substrate selectivity, entropy and enthalpy of activation in the series of arenes studied correlate with the basicity of ArH. A reaction mechanism is proposed which includes the rapid equilibrium formation of a charge transfer complex between ArH and CH₂OH⁺ and a slow stage in which it is converted to a -complex.