Structure‐Reactivity Relationships as Probes for the Inhibition Mechanism of Cholesterol Esterase by Aryl Carbamates. I. Steady‐State Kinetics

For substituted phenyl‐N‐butyl carbamates (1) and 4‐nitrophenyl‐N‐substituted carbamates (2), linear relationships between values of NH proton chemical shift (δ_NH), pKa, and logk_[OH] and Hammett substituent constant (σ) or Taft substituent constant (σ*) are observed. Carbamates 1 and 2 are pseudo‐substrate inhibitors of porcine pancreatic cholesterol esterase. Thus, the mechanism of the reaction necessitates that the inhibitor molecule and the enzyme form the enzyme‐inhibitor tetrahedral species at the K_i step of the reaction and then form the carbamyl enzyme at the k_c step of the reaction. Linear relationships between the logarithms of K_i and k_c for cholesterol esterase by carbamates 1 and σ are observed, and the reaction constants (ρs) are ?3.4 and ?0.13, respectively. Therefore, the above reaction forms the negative‐charge tetrahedral species and follows the formation of the relatively neutral carbamyl enzymes. For the inhibition of cholesterol esterase by carbamates 2 except 4‐nitrophenyl‐N‐phenyl carbamate and 4‐nitrophenyl‐N‐t‐butyl carbamate, linear relationships of ‐logK_i and logk_c with σ* are observed and the ρ* values are ?0.50 and 1.03, respectively. Since the above reaction also forms the negative‐charge tetrahedral intermediate, it is possible that the K_i step of this reaction is further divided into two steps. The first K_i step is the development of the positive‐charge at the carbamate nitrogen from the protonation of the carbamate nitrogen. The second K_i step is the formation of the tetrahedral intermediate with the negative‐charge at the carbonyl oxygen. From Arrhenius plots of a series of inhibition reactions by carbamates 1 and 2, the isokinetic and isoequilibrium temperatures are different from the reaction temperature (25°C). Therefore, the observed ρ and ρ* values only depend upon the electronic effects of the substituents. Taken together, the cholesterol esterase inhibition mechanism by carbamates 1 and 2 is proposed.     

Schiff bases of pyridoxal and polyallylamine. The formation rate determining step

The apparent rate constants of formation (k₁) and hydrolysis (k₂) of the Schiff bases formed between pyridoxal and polyallylamine has been fitted to a kinetic scheme that involve the different protonated species in the reaction medium and the individual rate constants of formation (k₁ⁱ) and hydrolysis (k₂ⁱ). The (k₁ⁱ) values precludes an acid catalyzed intramolecular process. The effects of hydrophobic medium due to the presence of the macromolecule on the reaction is also discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 1–6, 1998.     

Structure of zinc-5,15-di(o-methoxyphenyl)octaalkylporphyrines and their reaction with organic peroxides in the presence of pyridine

By combined spectral and calculation methods the structure of zinc 5,15-di(o-methoxyphenyl)-2,8,12,18 3,7,13,17-octaalkylporphyrinates (I, II) and their properties in the reaction with organic peroxides with addition of different amounts of pyridine were studied. The reaction of zinc porphyrinates with peroxides in the presence of pyridine leads to destruction of the complex chromophore. Kinetic parameters of the investigated reaction (effective k _ef and true k _V rate constants) are obtained. The presence of base in the reaction medium is found to lead to a change in the structure of the zinc porphyrinates and affects the rate of oxidation. By quantum-chemical method PM3 the geometry of the reagents was calculated and the deformation distortions of the reactants molecules and intermediates in the course of the oxidation reaction was demonstrated. The influence of electronic effects of substituents and the degree of deformation of the zinc porphyrinate macrocycle on their redox properties is revealed.     

Ring‐Closing Metathesis Reactions: Interpretation of Conversion–Time Data

Conversion–time data were recorded for various ring‐closing metathesis (RCM) reactions that lead to five‐ or six‐membered cyclic olefins by using different precatalysts of the Hoveyda type. Slowly activated precatalysts were found to produce more RCM product than rapidly activated complexes, but this comes at the price of slower product formation. A kinetic model for the analysis of the conversion–time data was derived, which is based on the conversion of the precatalyst (Pcat) into the active species (Acat), with the rate constant k_act, followed by two parallel reactions: 1) the catalytic reaction, which utilizes Acat to convert reactants into products, with the rate k_cat, and 2) the conversion of Acat into the inactive species (Dcat), with the rate k_dec. The calculations employ two experimental parameters: the concentration of the substrate (c(S)) at a given time and the rate of substrate conversion (?dc(S)/dt). This provides a direct measure of the concentration of Acat and enables the calculation of the pseudo‐first‐order rate constants k_act, k_cat, and k_dec and of k_S (for the RCM conversion of the respective substrate by Acat). Most of the RCM reactions studied with different precatalysts are characterized by fast k_cat rates and by the k_dec value being greater than the k_act value, which leads to quasistationarity for Acat. The active species formed during the activation step was shown to be the same, regardless of the nature of different Pcats. The decomposition of Acat occurs along two parallel pathways, a unimolecular (or pseudo‐first‐order) reaction and a bimolecular reaction involving two ruthenium complexes. Electron‐deficient precatalysts display higher rates of catalyst deactivation than their electron‐rich relatives. Slowly initiating Pcats act as a reservoir, by generating small stationary concentrations of Acat. Based on this, it can be understood why the use of different precatalysts results in different substrate conversions in olefin metathesis reactions.     

Kinetics of the reaction of 4,4′‐biphenol with bromoethane and 1‐bromobutane by phase‐transfer catalysis

The reaction of 4,4′‐biphenol and two species of bromoalkanes (e.g., bromoethane and 1‐bromobutane) to synthesize two symmetric products (4,4′‐diethanoxy biphenyl and 4,4′‐dibutanoxy biphenyl) and one asymmetric product (4‐ethanoxy, 4′‐butanoxy biphenyl) was successfully carried out under two‐phase phase‐transfer catalysis conditions. A rational mechanism and kinetic model were built up by considering the reactions both in aqueous phase and in organic phase. The first active catalyst (QO(Ph)₂OQ) was also synthesized under two‐phase reaction and was identified by instruments. The experimental data were explained satisfactorily by the pseudo‐steady‐state hypothesis. Two sets of rate constants of organic reactions, i.e. primary (k₁ and k₂) and secondary (k₁₁, k₁₂, k₂₁, and k₂₂) rate constants participate in the kinetic model. The two primary rate constants were obtained individually via experimental data for synthesizing the symmetric products. The ratios of the other four secondary rate constants were obtained from the reaction of synthesizing asymmetric products and determined from the initial yield rates of symmetric products. The effects of the ratio of bromoethane and 1‐bromobutane, temperature, organic solvents, amount of catalyst, and amount of sodium hydroxide on the reaction rate and the selectivity of products were investigated in detail. The results were explained satisfactorily by the interaction between the reactants and the environmental species. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 139–153, 2003     

Über die Si-N-bindung: XLI. Kinetische untersuchungen zur hydrolyse von trimethylsilylurethanen des typs Me3Si(p-XC6H4)NCOOEt

Hydrolysis reactions of silylurethanes Me₃Si(p-XC₆H₄)NCOOEt (I) with X = Cl, H or Me in aqueous buffer solutions, with pH values from 1.94 to 10.00 were studied.The catalytic rate constants for the acid and base catalysed reactions and for the “non-catalysed” reaction k(H₃O⁺), k(CH₃COO^?), k(H₂PO₄^?), k(HPO₄^2?), k(NH₃), k(OH^?) and k₀ were evaluated from the pseudo first-order rate constants k_exp determined by UV spectroscopy.The Brönsted coefficients for the base-catalysed reactions were obtained from the catalytic rate constants found and the known constants of dissociation K(HB⁺).The ρ values of the reactions could be derived from the σ constants given by Jaffé.The kientical results obtained are interpreted mechanistically and are believed to also have model character for other nucleophilic substitution reactions with silicon compounds.     

Laws of complex formation in a series of azo-substituted pyrocatechol derivatives and their tin(II) complexes

Physicochemical properties of new reagents, azo-substituted pyrocatechol derivatives and their tin(II) complexes, are studied. The acid-base properties of the hydroxy groups (pK′_i, pK″_i), parameters of complex formation reactions (pH, temperature, time), and instability constants of the complexes formed (pK _i) are determined. Quantitative correlations between the dissociation constants (pK′_a) of the functional analytical group, and the electronic Hammett constant σ for a substituent (pK′_a-pH₅₀ of the complex formation reaction), as well as between pK′_a and instability constants of the complexes (pK _a), are established. The quantitative correlations established allow the prediction of the physicochemical properties of the reagents and tin(II) complexes with new reagents of this class with the same functional analytical group (FAG) but other substituents.     

Effect of cationic and anionic surfactants on the addition–elimination-type interaction between o-toluidine and d-glucose

The kinetics of the o-toluidine–d-glucose reaction has been studied as a function of [o-toluidine], [d-glucose], [acetic acid], and temperature by UV–visible spectrophotometry at 630 nm in the absence and presence of cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS). The reaction follows second-order kinetics, being unity in each of the reactants in both media. The effect of added surfactants has also been investigated. The model of micellar catalysis, such as the Menger–Portony model modified by Bunton, is applied to explain the catalytic role of CTAB and SDS micelles. The association/incorporation constants (K _s and K _n), the rate constant in micellar media (k _m), and the activation parameters of this system have been calculated and discussed. The value of the rate constant is found to be higher in SDS than in CTAB. Hydrophobic and electrostatic interactions are responsible for higher reaction rates in SDS. From all observed facts, a reaction mechanism involving a nucleophilic addition–elimination path has been suggested.     

Kinetics and mechanism of intramolecular general base-catalyzed alkanolysis of phenyl salicylate in the presence of anionic micelles

The alkanolysis of ionized phenyl salicylate, PS^?, has been studied in the presence and absence of micelles of sodium dodecyl sulphate, SDS, at 0.05 M NaOH, 30 or 32°C and within the alkanol, ROH, (ROH = HOCH₂CH₂OH and CH₃OH) contents of 15–74 or 92%, v/v. The alkanolysis of PS^? involves intramolecular general base catalysis. At a constant concentration of SDS, [SDS]_T, the observed pseudo first-order rate constants, k_obs, for the reactions of ROH with PS^? obtained at different concentration of ROH, [ROH]_T, obey the relationship: k_obs = k[ROH]_T/(1 + K_A[ROH]_T) where k is the apparent second-order rate constant and K_A is the association constant for dimerization of ROH molecules. Both k and K_A decrease with increase in [SDS]_T. At a constant [ROH]_T, the rate constants, k_obs, show a decrease of nearly 2-fold with increase in [SDS]_T from 0.0–0.3M. These results are explained in terms of pseudo-phase model of micelle. The rate constants for alkanolysis of PS^? in micellar pseudophase are insignificant compared with the corresponding rate constants in aqueous-alkanol pseudophase. This is attributed largely to considerably low value of [ROH] in the specific micellar environment where micellar bound PS^? molecules exist. The increase in [ROH]_T decrease the value of the binding constant of PS^? with SDS micelle. The effects of anionic micelles on the rates of alkanolysis of PS^? are explained in terms of the porous cluster micellar structure.     

The Binding Affinity of Fe(III) to Aspartic Acid and Glutamic Acid Monohydroxamates

The solution spectra of Fe(III) complexes with aspartic acid (ASX) and glutamic acid (GLX) monohydroxamates were analyzed in the UV-Vis region for different complex species using STAR-94 programs in the pH range ¨ 1.0-4.0, at ionic strength (I) of 0.15 M NaCl and T = 25°C. Several monomeric complex species were obtained including some mixed hydroxo species. The reaction kinetics of the Fe(III)-(ASX or GLX) systems were carried out at I = 0.15 M NaCl and T = 25°C in the time range of the stopped-flow method. The pseudofirst-order rate constants were pH as well as T _L (analytic concentration of ASX or GLX) dependent, i.e. k _obs,i = A_i + B _i T_L (at a given pH _i ) where A_i and B_i are pH-dependent parameters.     

Oxidation of ethers with dimethyldioxirane

Oxidation of a series of tert-butyl ethers Bu^tOR (R = Me, Et, CH₂CH₂Cl, Prⁱ, Buⁱ), diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, diisobutoxymethane, 1,4-dioxane, and tetrahydrofuran with dimethyldioxirane (DMDO) was studied. The reaction kinetics obeys the second-order equation w = k[DMDO][ether]. The rate constants in a range of 5–50 °C and the activation parameters of the reaction were determined. The solvent effect on the oxidation rate was studied. The oxidation products are the corresponding alcohols and carbonyl compounds. The competition between the nonradical (oxygen insertion) and radical mechanisms of the reaction is discussed. The reactions of the parent dioxirane and DMDO with a series of methyl ethers MeOr’ (r’ = Me, Et, CH₂CH₂F, Prⁱ) were studied by the density functional theory (DFT). The (U)B3LYP-6-311G(d,p) method was employed to calculate the geometry and energies of the reactants and transition states. The data obtained indicate a possible increase in the probability of oxidation via the radical route and an increase in the activation barrier for the substrates containing electron-withdrawing substituents. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2309–2318, October, 2005.     

Square-wave voltammetry of 4,4′-diisopropyl-2,2′-bithiazoline and its complex with copper(II)

(4S)-4′-diisopropyl-2,2′-bithiazoline (DPT) is an electroactive organic chiral compound giving two reduction responses in square-wave voltammograms at potentials about −0.2 and −0.4 V by forming a complex with mercury which deposits at the electrode surface. By the addition of copper(II) ion to the solution of DPT a third peak appears between them at about −0.3 V, which corresponds to the reduction of adsorbed Cu-DPT complex. Optimal pH for the investigation of those redox processes was found to be 2.8. By square-wave voltammetric measurements it was interpreted that these redox reactions were quasireversible with immobilized reactants. By plotting i_p/f vs. frequency a quasireversible maximum was obtained, and the apparent standard reaction rate constants were calculated: log (k_s)DPT=(0.91 ± 0.9) and 1 < k_s < 65_S⁻¹, log (k_s)_CuDPT= (0.35 ± 0.9) and 0.3 < k_s < 18 S⁻¹ in 0.55 M NaCl.     

Solvent effects in the reaction of 2-thiophenesulfonyl chloride with aniline

The second order rate constants k₂ and the activation parameters for the reaction of 2-thiophenesulfonyl chloride with aniline together with solution enthalpies of the reactants have been measured in methanol, ethanol, 2-propanol, acetonitrile and acetone. The reaction rates are slower in dipolar aprotic solvents than in protic ones due to a remarkable activation negative entropy. The rate constants k₂ are correlated with empirical solvent polarity parameters. The data seem in accord with a S_AN reaction mechanism.     

Reactions of Group 3 Metal Alkyls in the Gas Phase. Part 10: The addition of olefins to the monomeric diisobutylaluminiumhydride

The relative rate constants for adding ethylene (k₁), propylene (k₂) and 2-methyl-but-1-ene (k₃) to gaseous diisobutylaluminium hydride produced in situ from AlⁱBu₃ have been measured in the temperature range 104–169° in the presence of an excess of equimolar olefin mixtures. The following temperature dependences of the relative rate constants have been obtained: Two compensating factors determine the rate of addition of olefins to Al? H and Al? C bonds: (a) the steric effect, reflected in the differences in the preexponential factors and (b) the polar effects, reflected in differences in the activation energies. In the addition of olefins to R₂Al? H bonds in contrast to R₂Al? C bonds, the steric effect (a) does not always overrule the opposing energy effect. At temperatures below 125° e.g., isobutene adds slightly faster to HAlⁱBu₂, than ethylene. These results are in perfect agreement with expectations based on a reaction mechanism involving a tight asymmetric quadrupolar 4-centre transition state similar to that postulated earlier for the addition of olefins to Al? C bonds.     

Ruthenium(III), osmium(VIII) and ruthenium(III) + osmium(VIII) catalysed oxidations ofi-propanol by N-bromosuccinimide in basic solution

Summary The oxidation ofi-propanol (IPA) by N-bromosuccinimide (NBS) in basic solution was investigated separately in the presence of Ru^III, Os^VIII and Ru^III + Os^VIII ions. The order in [IPA] was found to be 0.7, 0.5 and 0.3 respectively in the above three cases in the concentration range studied. The order in [NBS] was unity in the presence of Ru^III chloride but was found to be zero in the case of Os^VIII and Ru^III+Os^VIII catalysis. The order in [metalion] was found to be nearly unity in all the three catalysed reactions. Increase in [^–OH] increased the rate of reaction while addition of succinimide retarded the rate of reaction. Decrease in dielectric constantsof the medium decreased the rate of oxidation. The pseudo first order rate constants (k), zero order rate constants (k₀) and the formation constants (k_f) of the substrate-catalyst complexes and the thermodynamic parameters have been evaluated. Suitable mechanisms in conformity with the experimental observations have been proposed for the three catalysed reactions.     

Kinetic and mechanistic study of the reduction of 2,6-dichlorophenol indophenol by dithionites

The reaction of 2,6-dichlorophenolindophenol (DCPI) and dithionites is studied kinetically by applying the stopped-flow technique. Reaction rate constants are given for the pH range 1.30–6.80. The reaction was found to follow first-order kinetics with respect to each of the reactants. For pH 3.97, 5.10 and 6.80, the second-order reaction rate constant was determined by applying four different technique. Mean values of k = 172±5, 200±2 and 276±4 l mol^?1s^?1 are given for pH 3.97, 5.10 and 6.80, respectively. A mechanism is proposed for the reaction, which suggests partial reactions of all possible species of DCPI and dithionites at any pH. An equation for the calculation of k at any pH is derived, which gives k as a function of [H⁺], the partial reaction rate constants and the dissociation constants of DCPI and H₂S₂O₄. Values of reaction rate constants of all possible partial reactions are also presented.     

Kinetics and mechanism of the aminolysis of O-ethyl S-phenyl dithiocarbonate in aqueous ethanol

The reactions of secondary alicyclic amines with the title substrate (PDTC) are subjected to a kinetic study in 44 wt.% aqueous ethanol, 25.0°C, ionic strength 0.2 M (KCl). Pseudo-first-order rate coefficients (k_obs) are found under amine excess. Linear plots of [N]/k_obs against 1/[N], where N is the free amine, are obtained for the reactions with piperidine, piperazine, 1-(2-hydroxyethyl)piperazine, and morpholine. The reaction with 1-formylpiperazine exhibits a linear plot of k_obs against [N]². These results are interpreted through a mechanism consisting of two tetrahedral intermediates: a zwitterionic ( T ^±) and an anionic ( T ^?), where the amine catalyzed proton transfer from T ^± to T ^? is partially rate determining for the four former reactions and is fully rate determining for the reaction of 1-formylpiperazine. The rate microcoefficients involved in the reaction scheme are either determined experimentally or estimated. Comparison with the corresponding microcoefficients reported for the same reactions in water reveals that the rate coefficient for formation of T ^± from reactants (k₁) is smaller and that for the reversal of this (k_?1) is larger in aqueous ethanol compared to water, in agreement with the expected structure of the corresponding transition state. Bronsted-type plots are obtained for k₁, k_?1, and K₁ (=k₁/k_?1) with slopes ca. 0.4, ?0.6, and 1.0, respectively. Comparison of the present stepwise reactions with the concerted ones found in the same aminolysis of O-ethyl 2,4,6,-(trinitrophenyl) dithiocarbonate indicates that T ^± is so destabilized by the change of PhS by the 2,4,6-trinitrobenzenethio group that T ^± no longer exists and becomes a transition state. © 1995 John Wiley & Sons, Inc.     

Some General Features in the Autocatalytic Reaction between Sulfite Ion and Different Oxidants

The autocatalytic oxidation of a weak acid is a common building block of the pH oscillators. These reactions can be described by a simple general scheme that includes a protonation equilibrium and the oxidation of the protonated form of the weak acid. Here we show that independently from the chemical nature of the oxidizing agent, these reactions bear some general features, namely (1) the change in pH (ΔpH) observed during the reaction is determined by the acidity constant (K_HA) and by the initial concentration of the unprotonated form of the weak acid (A^?): , (2) the inflection time of the autocatalytic reaction (t_i) depends reciprocally on K_HA and on the initial hydrogen ion concentration, and (3) in the presence of a competitive reversible proton‐binding component (D^?), that is not involved in the oxidation process, ΔpH follows a titration‐like curve as the concentration of D^? is increased, t_i is only slightly affected but the maximum rate of the autocatalytic process is significantly reduced. The slowing of the overall reaction is proportional to the acidity constant of the proton‐binding component.     

Steric Effects in Nucleophilic Aromatic Substitution reactions with aromatic amines 12th communication on nucleophilic aromatic substitution reactions

The kinetics of the S_NAr reactions of aniline and N-methylaniline with a variety of substituted nitrochlorobenzenes in acetonitrile demonstrate that the formation of the intermediate σ-complex is rate determining. The ratio of the rate constants of the aniline and the N-methylaniline reactions (k_A/k_M) increases with increasing size of the 6-substituent; with picryl chloride k_A/k_M reaches a value of over 20 000. The reaction of aniline with 4-X-2,6-dinitrochlorobenzenes is subject to considerably larger para-substituent effects than the corresponding reactions with N-methylaniline. These results are interpreted in terms of two effects: (i) A primary steric effect, which renders the approach of N-methylaniline to the substrate difficult. (ii) A shift towards earlier, more reactant-like transition state structures caused by the primary steric effect. In early transition states the activating power of the electron-withdrawing substituents in the substrate is expected to be relatively small. An early transition state for the slow N-methylaniline reaction and a late transition state for the fast aniline reaction is in apparent contradiction to what would be expected on the basis of the Hammond postulate.     

On the Importance of Decarbonylation as a Side‐Reaction in the Ruthenium‐Catalysed Dehydrogenation of Alcohols: A Combined Experimental and Density Functional Study

We report a density functional study (B97‐D2 level) of the mechanism(s) operating in the alcohol decarbonylation that occurs as an important side‐reaction during dehydrogenation catalysed by [RuH₂(H₂)(PPh₃)₃]. By using MeOH as the substrate, three distinct pathways have been fully characterised involving either neutral tris‐ or bis‐phosphines or anionic bis‐phosphine complexes after deprotonation. α‐Agostic formaldehyde and formyl complexes are key intermediates, and the computed rate‐limiting barriers are similar between the various decarbonylation and dehydrogenation paths. The key steps have also been studied for reactions involving EtOH and iPrOH as substrates, rationalising the known resistance of the latter towards decarbonylation. Kinetic isotope effects (KIEs) were predicted computationally for all pathways and studied experimentally for one specific decarbonylation path designed to start from [RuH(OCH₃)(PPh₃)₃]. From the good agreement between computed and experimental KIEs (observed k_H/k_D=4), the rate‐limiting step for methanol decarbonylation has been ascribed to the formation of the first agostic intermediate from a transient formaldehyde complex.