Structure‐Reactivity Relationships as Probes to Acetylcholinesterase Inhibition Mechanisms by Aryl Carbamates. I. Steady‐State Kinetics

From enzyme kinetics, 4‐nitrophenyl‐N‐substituted carbamates 1 are characterized as pseudo‐substrate inhibitors of acetylcholinesterase. However, the activity of the carbamyl enzyme does not recover in the presence of a competitive inhibitor, edrophonium. Therefore, carbamates 1 should be called as the “pseudo‐pseudo‐substrate” inhibitors of the enzyme. Moreover, the ‐logK_i, logk_c, and logk_i values are linearly correlated with Taft‐Ingold equation, log (k/k_o) = ρ*σ* + δ E_s. A three‐step AChE inhibition mechanism by carbamates 1 is proposed. The first step is the pre‐equilibrium protonations of carbamates 1 with ρ* value of ?1.4 from pK_a‐σ*‐correlation. The second step is the enzyme‐carbamates 1 tetrahedral intermediate formation from nucleophilic attack of the active site Ser200 on the protonated carbamates 1 . The ρ* value for the ‐logK_i‐σ*‐E_s‐correlation indicates that the true ρ* value for the second step is 0.5 [= ?0.9 ‐ (‐1.4)]. The δ value of 0.56 for the ‐logK_i‐σ*‐E_s‐correlation indicates that carbamates 1 with bulky substituents retarded the formation of enzyme‐inhibitor tetrahedral intermediates. The third step (k_c step) is the carbamylation step and is the carbamyl enzyme conjugate formation from the enzyme‐carbamates 1 tetrahedral intermediate. The ρ* value of 0.21 for the logk_c‐correlation indicates that the transition state for the carbamylation step is more negative charge than the enzyme‐carbamates 1 tetrahedral intermediate. Moreover, the k_c step is insensitive to substituent effects since there is a cancellation of electronic demands for bond‐making and bond‐breaking components, like S_N2 reactions. The δ value of 0.00 for the logk_c‐correlation indicates that the k_c step is independent of substituent steric effect. Therefore, the product of this step carbamyl enzyme conjugate is as crowded as the enzyme‐carbamates 1 tetrahedral intermediate and is likely bound to the leaving group, p‐nitrophenol.     

Synthesis and Structures of Homoleptic Methyl‐ and Phenylthiomethylaluminium Complexes [Al(CH2SR)3](R = Me,Ph)

Sulfur‐substituted methylmercury compounds [Hg(CH₂SR)₂]( 1a, R = Me; 1b, R = Ph ) react with aluminium amalgam in refluxing toluene with transmetallation to give homoleptic tris(thiomethyl)aluminium complexes [Al(CH₂SR)₃]( 2a, R = Me; 2b, R = Ph ) (degree of conversion: >80%, isolated yields: 2a 63%, 2b 41%). Their identities were confirmed by NMR spectros‐copy (¹H, ¹³C) and X‐ray crystal structure analyses. In crystals of compound 2a the aluminium atoms possess a trigonal‐bipyramidal arrangement with the coordination polyhedron defined by three carbon and two sulfur atoms. Two of the three CH₂SMe ligands are bridging ligands (μ‐η²; 1kC:2kS), the third one is terminal bound (η¹; kC). The structure is polymeric. Crystals are threaded by helical chains built up of six‐membered Al₂C₂S₂ rings. Crystals of 2b are built up of centrosymmetrical dimers with six‐membered Al₂C₂S₂ rings having bridging CH₂SPh ligands (μ‐η²; 1kC:2kS). On each Al atom two terminal (η¹; kC)CH₂SPh ligands are bound. They exhibit quite different Al‐C‐S angles (116.7(4) and 106.5(3)?). Similar values (114.32115.7? and 109.52109.9?) were found in ab initio calculations of model compounds [{Al(CH₂SR)₃}₂]( 3a, R=H; 3b, R=Me; 3c, R=CH=CH₂ ). A conformational energy diagram for rotation of one of the terminal CH₂SH ligand in the parent compound 3a around the Al‐C bond is discussed in terms of repulsive interactions of lone electron pairs of sulfur atoms.     

Reactions of Substituted Phenylnitromethane Carbanions with Aromatic Nitro Compounds in Methanol: Carbanion Reactivity,Kinetic, and Equilibrium Studies

The feasibility of carrying out nucleophilic addition from electron‐deficient heteroaromatics has been addressed through a detailed investigation of the interaction of a two 7‐substituted‐nitrobenzofurazan (R = OMe 2a ; R = Cl 2b ) with a series of substituted‐nitroaryl anions (X = 4‐NO₂ 1a ; X = 3‐NO₂ 1b ; X = 4‐CN 1c ; X = 4‐Br 1d ), all reactions first lead to the quantitative formation of the σ‐adducts 3a–d and 4a–d arising from covalent addition of the nucleophile to the C‐5 carbon. The rate and equilibrium constants for the formation of σ‐adducts 3a–d and 4a–d (k₅, K ₅ ) together with the rate constants for their decomposition (k_?5) have been determined in methanol at 25°C, allowing a determination of intrinsic rate constants, k₀ = 0.03, the lower k₀ value reflects the very strong salvation by methanol of the negative charge on the nitro group. The discovery of a linear correlation between the E and pK_a^MeOH parameters allows a calibration of the electrophilicity power of 2a and 2b , E = ?11.67 and ?10.29, respectively. Applying the general approach to nucleophilicity/electrophilicity recently developed by Mayr et al. through the relationship log k = s(E + N), a successful ranking of our nitroaryl anions 1a–d on the general nucleophilicity scale (N) has been carried out. The N values of 1a–d are found to cover a range from 15.78 to 16.69. The results are compared with previously reported data in water and DMSO.     

Consecutive Chemical Activation Steps in the OH‐Initiated Atmospheric Degradation of Isoprene: An Analysis with Coupled Master Equations

The influence of a two‐step chemical activation on 1,5‐H and 1,6‐H shift reactions of hydroxyl‐peroxy radicals formed in the atmospheric photooxidation of isoprene was investigated by means of a master equation analysis. To account for multiple chemical activation processes, three master equations were coupled. The general approach of this coupling is described, and consequences for steady‐state regimes are examined. The specific calculations show that chemical activation has no substantial influence on the rate coefficients of the above‐mentioned reactions under tropospheric conditions. However, it is demonstrated that high‐pressure limits of the thermal rate coefficients instead of the falloff‐corrected values have to be used for kinetic modeling. This is a consequence of the continuous population of the high‐energy part of the isoprene‐OH‐O₂ adduct distribution by the forming reactions under steady‐state conditions. The rate coefficients of the isomerization reactions at T = 298 K were calculated to be k_3a^∞ = 1.5 × 10^?3 s^?1 (1,5‐H‐shift of the 1,2‐isomer) and k_4a^∞ = 6.5 s^?1 (1,6‐H‐shift of the (Z)‐1,4‐isomer). The calculated value of k_4a^∞ is three orders of magnitude larger than a recently reported experimentally observed rate coefficient for the hydrogen shift reactions of the hydroxyl‐peroxy intermediates. It is shown that this discrepancy is in part due to the fact that the experiment does not distinguish between different structural isomers. A comparison of the experimentally determined isotope effect with the calculated value shows a reasonable agreement.     

A difference of six orders of magnitude: A reply to “the magnitude of the fragmentation rate coefficient”

There has been an ongoing debate regarding the mechanism that causes rate retardation phenomena observed in some reversible addition‐fragmentation transfer (RAFT) polymerization systems. Some attribute the retardation to slow fragmentation of adduct radicals, others attribute it to fast fragmentation coupled with cross‐termination between propagating and adduct radicals. There exists a difference of six orders of magnitude (10^?2 versus 10⁴/s) in the reported values of the fragmentation rate constant (k_f0) for virtually similar RAFT systems of PSt? S? C · (Ph)? S? PSt. In this communication, we explain the estimates of k_f ～ 10⁴/s and the choices of the rate constant in modeling based on experimental polymerization rate and radical concentration data. The use of k_f ～ 10^?2/s in the model results in a calculated adduct radical concentration level of 10^?4 to 10^?3 mol/L, which appears to directly contradict the reported electron spin resonance (ESR) data in the range of <10^?6 mol/L. We hope that this open discussion can stimulate more effort to resolve this outstanding difference. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2833–2839, 2003     

The Impact of Surfactants on FeIII–TAML‐Catalyzed Oxidations by Peroxides: Accelerations,Decelerations, and Loss of Activity

Iron(III) complexes of tetraamidato macrocyclic ligands (TAMLs), [Fe{4‐XC₆H₃‐1,2‐(NCOCMe₂NCO)₂CR₂}(OH₂)]^?, 1 ( 1 a : X=H, R=Me; 1 b : X=COOH, R=Me); 1 c : X=CONH(CH₂)₂COOH, R=Me; 1 d : CONH(CH₂)₂NMe₂, R=Me; 1 e : X=CONH(CH₂)₂NMe₃⁺, R=Me; 1 f : X=H, R=F), have been tested as catalysts for the oxidative decolorization of Orange II and Sudan III dyes by hydrogen peroxide and tert‐butyl hydroperoxide in the presence of micelles that are neutral (Triton X‐100), positively charged (cetyltrimethylammonium bromide, CTAB), and negatively charged (sodium dodecyl sulfate, SDS). The previously reported mechanism of catalysis involves the formation of an oxidized intermediate from 1 and ROOH (k_I) followed by dye bleaching (k_II). The micellar effects on k_I and k_II have been separately studied and analyzed by using the Berezin pseudophase model of micellar catalysis. The largest micellar acceleration in terms of k_I occurs for the 1 a ? tBuOOH? CTAB system. At pH 9.0–10.5 the rate constant k_I increased by approximately five times with increasing CTAB concentration and then gradually decreased. There was no acceleration at higher pH, presumably owing to the deprotonation of the axial water ligand of 1 a in this pH range. The k_I value was only slightly affected by SDS (in the oxidation of Orange II), but was strongly decelerated by Triton X‐100. No oxidation of the water‐insoluble, hydrophobic dye Sudan III was observed in the presence of the SDS micelles. The k_II value was accelerated by cationic CTAB micelles when the hydrophobic primary oxidant tert‐butyl hydroperoxide was used. It is hypothesized that tBuOOH may affect the CTAB micelles and increase the binding of the oxidized catalysts. The tBuOOH? CTAB combination accelerated both of the catalysis steps k_I and k_II.     

Kinetic and Mechanisms of the Homogeneous,Unimolecular Elimination of Phenyl Chloroformate and p‐Tolyl Chloroformate in the Gas Phase

The gas‐phase elimination of phenyl chloroformate gives chlorobenzene, 2‐chlorophenol, CO₂, and CO, whereasp‐tolyl chloroformate produces p‐chlorotoluene and 2‐chloro‐4‐methylphenol CO₂ and CO. The kinetic determination of phenyl chloroformate (440–480^oC, 60–110 Torr) and p‐tolyl chloroformate (430–480°C, 60–137 Torr) carried out in a deactivated static vessel, with the free radical inhibitor toluene always present, is homogeneous, unimolecular and follows a first‐order rate law. The rate coefficient is expressed by the following Arrhenius equations: Phenyl chloroformate: Formation of chlorobenzene, log k_I = (14.85 ± 0.38) – (260.4 ± 5.4) kJ mol^?1 (2.303RT)^?1; r = 0.9993 Formation of 2‐chlorophenol, log k_II = (12.76 ± 0.40) – (237.4 ± 5.6) kJ mol^?1(2.303RT)^?1; r = 0.9993 p‐Tolyl chloroformate: Formation of p‐chlorotoluene: log k_I = (14.35 ± 0.28) – (252.0 ± 1.5) kJ mol^–1 (2.303RT)^?1; r = 0.9993 Formation of 2‐chloro‐4‐methylphenol, log k_II = (12.81 ± 0.16) – (222.2 ± 0.9) kJ mol^?1(2.303RT)^–1; r = 0.9995 The estimation of the k_I values, which is the decarboxylation process in both substrates, suggests a mechanism involving an intramolecular nucleophilic displacement of the chlorine atom through a semipolar, concerted four‐membered cyclic transition state structure; whereas the k_II values, the decarbonylation in both substrates, imply an unusual migration of the chlorine atom to the aromatic ring through a semipolar, concerted five‐membered cyclic transition state type of mechanism. The bond polarization of the C–Cl, in the sense C^{δ+ …} Cl^δ?, appears to be the rate‐determining step of these elimination reactions.     

Lewis Acids as Activators in CBS‐Catalysed Diels–Alder Reactions: Distortion Induced Lewis Acidity Enhancement of SnCl4

The effect of several Lewis acids on the CBS catalyst (named after Corey, Bakshi and Shibata) was investigated in this study. While ²H NMR spectroscopic measurements served as gauge for the activation capability of the Lewis acids, in situ FT‐IR spectroscopy was employed to assess the catalytic activity of the Lewis acid oxazaborolidine complexes. A correlation was found between the Δδ(²H) values and rate constants k_DA, which indicates a direct translation of Lewis acidity into reactivity of the Lewis acid–CBS complexes. Unexpectedly, a significant deviation was found for SnCl₄ as Lewis acid. The SnCl₄–CBS adduct was much more reactive than the Δδ(²H) values predicted and gave similar reaction rates to those observed for the prominent AlBr₃–CBS adduct. To rationalize these results, quantum mechanical calculations were performed. The frontier molecular orbital approach was applied and a good correlation between the LUMO energies of the Lewis acid–CBS–naphthoquinone adducts and k_DA could be found. For the SnCl₄–CBS–naphthoquinone adduct an unusual distortion was observed leading to an enhanced Lewis acidity. Energy decomposition analysis with natural orbitals for chemical valence (EDA‐NOCV) calculations revealed the relevant interactions and activation mode of SnCl₄ as Lewis acid in Diels–Alder reactions.     

Kinetics and mechanism of oxidation of the drug mephenesin by bis(hydrogenperiodato)argentate(III) complex anion

Mephenesin is being used as a central‐acting skeletal muscle relaxant. Oxidation of mephenesin by bis(hydrogenperiodato)argentate(III) complex anion, [Ag(HIO₆)₂]^5?, has been studied in aqueous alkaline medium. The major oxidation product of mephenesin has been identified as 3‐(2‐methylphenoxy)‐2‐ketone‐1‐propanol by mass spectrometry. An overall second‐order kinetics has been observed with first order in [Ag(III)] and [mephenesin]. The effects of [OH^?] and periodate concentration on the observed second‐order rate constants k′ have been analyzed, and accordingly an empirical expression has been deduced: k′ = (k_a + k_b[OH^?])K₁/{f([OH^?])[IO^?₄]_tot + K₁}, where [IO^?₄]_tot denotes the total concentration of periodate, k_a = (1.35 ± 0.14) × 10^?2M^?1s^?1 and k_b = 1.06 ± 0.01 M^?2s^?1 at 25.0°C, and ionic strength 0.30 M. Activation parameters associated with k_a and k_b have been calculated. A mechanism has been proposed to involve two pre‐equilibria, leading to formation of a periodato‐Ag(III)‐mephenesin complex. In the subsequent rate‐determining steps, this complex undergoes inner‐sphere electron transfer from the coordinated drug to the metal center by two paths: one path is independent of OH^? whereas the other is facilitated by a hydroxide ion. In the appendix, detailed discussion on the structure of the Ag(III) complex, reactive species, as well as pre‐equilibrium regarding the oxidant is provided. © 2007 Wiley Periodicals, Inc. Int J Chem Kinet 39: 440–446, 2007     

Kilohertz Pulsed‐Laser‐Polymerization: Simultaneous Determination of Backbiting,Secondary, and Tertiary Radical Propagation Rate Coefficients for tert‐Butyl Acrylate

For the first time, a 1000 Hz pulse laser has been applied to determine detailed kinetic rate coefficients from pulsed laser polymerization–size exclusion chromatography experiments. For the monomer tert‐butyl acrylate, apparent propagation rate coefficients k_p^app have been determined in the temperature range of 0–80 °C. k_p^app in the range of few hundreds to close to 50 000 L·mol^–1·s^–1 are determined for low and high pulse frequencies, respectively. The apparent propagation coefficients show a distinct pulse‐frequency dependency, which follows an S‐shape curve. From these curves, rate coefficients for secondary radial propagation (k_p^SPR), backbiting (k_bb), midchain radical propagation (k_p^tert), and the (residual) effective propagation rate (k_p^eff) can be deduced via a herein proposed simple Predici fitting procedure. For k_p^SPR, the activation energy is determined to be (17.9 ± 0.6) kJ·mol^–1 in excellent agreement with literature data. For k_bb, an activation energy of (25.9 ± 2.2) kJ·mol^–1 is deduced.

     

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.     

Reactivity of dpph• in the oxidation of catechol and catechin

A kinetic study of the reduction of pyrocatechol and catechin by dpph^? radical has been carried out in various ratios of CH₃OH/H₂O mixed solvent at pH 5.5–7.5, μ = 0.10 M [(n‐Bu)₄N]ClO₄, and T = 25°C. The rate constants of oxidation in aqueous solvent, k, were obtained from the extrapolation of the linear plots of the specific rate constants k vs. % H₂O plots at each pH value. A linear relationship between k and 1/[H⁺] was observed for both flavonoids with k = k₁K_a1/[H⁺], where K_a1 was the first acid dissociation constant on the catechol ring and k₁ is the rate constant of the oxidation of the mononegative species HX^?. The values of k₁ obtained from the slopes of the plots are (8.2 ± 0.2) × 10⁵ and (6.1 ± 0.1) × 10⁵ M^?1 s^?1 for pyrocatechol and catechin, respectively. The analysis of the reaction on the basis of Marcus theory for an outer‐sphere electron transfer reaction yielded a value of 3.7 × 10³ M^?1 s^?1 for the self‐exchange rate constant of dpph^?/dpphH couple. © 2011 Wiley Periodicals, Inc. Int J Chem Kinet 43: 147–153, 2011     

Effects of CH3OH‐H2O and CH3OH solvents on rate of reaction of phthalimide with piperidine

Pseudo‐first‐order rate constants (k_obs) for the cleavage of phthalimide in the presence of piperidine (Pip) vary linearly with the total concentration of Pip ([Pip]_T) at a constant content of methanol in mixed aqueous solvents containing 2% v/v acetonitrile. Such linear variation of k_obs against [Pip]_T exists within the methanol content range 10%–∼80% v/v. The change in k_obs with the change in [Pip]_T at 98% v/v CH₃OH in mixed methanol‐acetonitrile solvent shows the relationship: k_obs = k[Pip]_T + k[Pip], where respective k and k represent apparent second‐order and third‐order rate constants for nucleophilic and general base‐catalyzed piperidinolysis of phthalimide. The values of k_obs, obtained within [Pip]_T range 0.02–0.40 M at 0.03 M NaOH and 20 as well as 50% v/v CH₃OH reveal the relationship: k_obs = k₀/(1 + {k_n[Pip]/k_OX[⁻OX]_T}), where k₀ is the pseudo‐first‐order rate constant for hydrolysis of phthalimide, k_n and k_OX represent nucleophilic second‐order rate constants for the reaction of Pip with phthalimide and for the XO⁻‐catalyzed cyclization of N‐piperidinylphthalamide to phthalimide, respectively, and [⁻OX]_T = [NaOH] + [⁻OX_re], where [⁻OX_re] = [⁻OH_re] + [CH₃O_re⁻]. The reversible reactions of Pip with H₂O and CH₃OH produce ⁻OH_re and CH₃O_re⁻ ions. The effects of mixed methanol‐water solvents on the rates of piperidinolysis of PTH reveal a nonlinear decrease in k with the increase in the content of methanol. © 2000 John Wiley & Sons, Inc. Int J Chem Kinet 33: 29–40, 2001     

Kinetics and mechanism of adducts formation of tetraaza cobalt(II) complexes with some organic bases in DMF solvent

The kinetics and mechanism of the adduct formation of two Co(II) tetraaza complexes, [Co(ampen)] {[(N,N′‐ethylenebis‐(o‐amino‐α‐phenylbenzylideneiminato)cobalt(II)]} and [Co(campen)] {[(N,N′‐ethylenebis‐(5‐chloro‐o‐amino‐α‐phenylbenzylideneiminato)cobalt(II)]}, with four organic bases, 4‐nitro imidazole (4‐NO₂Imid), 4‐methyl imidazole (4‐MeImid), imidazole (Imid), and 1‐methyl imidazole (1‐MeImid), in DMF were studied spectrophotometrically. The kinetic parameters and the second‐order k₂ rate constants show the following nucleophilicity trend of the bases toward the given substrate: 4‐NO₂Imid > 4‐MeImid > Imid > 1‐MeImid. The linear plots of k_obs vs. the molar concentration of the base, the high span of k₂ values, and the large negative values of ΔS^≠ suggest an associative (A) mechanism. © 2007 Wiley Periodicals, Inc. 39: 137–144, 2007     

New palladium (II) complexes with 1-phenyl-1H-tetrazole-5-thiol and diphosphine Synthesis,characterization, biological,theoretical calculations and molecular docking studies

This paper reports the syntheses and spectral investigations of the new complexes [Pd(k¹-S-ptt)₂(k²-dppmS₂)] ( 1 ), [Pd(k¹-S-ptt)₂(k²-dppp)] ( 2a ), [Pd(k¹-N-ptt)₂(k²-dppp)] ( 2b ) , [Pd(k¹-S-ptt)₂(k²-dpppS₂)] ( 3 ) , [Pd(k¹-S-ptt)₂(k²-dppb)] ( 4 ), [Pd(k¹-S-ptt)₂(k²-dppf)] ( 5a ) and [Pd(k¹-N-ptt)₂(k²-dppf)] ( 5b ) , derived from 1-phenyl-5-thiol-1H-tetrazole (Hptt) and diphosphine (dppmS₂, dppp, dpppS₂, dppb and dppf) as co-ligand. The Hptt ligand acts as monodentate through the thiolato sulfur atom in complexes 1 , 3 and 4 . While in complexes 2 and 5 , the Hptt ligand also acts as monodentate through the nitrogen of heterocyclic ring, or sulfur of thiol group after deprotonation, as two linkage isomers. Theoretical calculations on the all complexes were performed, isomers based on 2a, 2b and 5a, 5b reveal that each pair of isomers is isoenergetic. For the 2a and 2b complexes the energy difference was 19.92 kcal mol⁻¹, while for the 5a and 5b complexes the difference was 11.78 kcal mol⁻¹. These differences are relatively small and suggest that the linkage isomers may be in equilibrium in solution. The reasons for the adoption of these different coordination modes are not clear but steric factors are likely to be a major contributory factor. Further, in vitro anti-bacterial activity and molecular docking analysis has been carried out to study the activity of the compound.     

Kinetics and mechanism of the aminolysis of O‐phenyl 4‐nitrophenyl dithiocarbonate in aqueous ethanol

The reactions of the title substrate (1) with a series of secondary alicyclic amines are subjected to a kinetic investigation in 44 wt% ethanol‐water, at 25.0°C, ionic strength 0.2 M (KCl). Under amine excess over the substrate, pseudo‐first‐order rate coefficients (k_obs) are obtained. Plots of k_obs against [NH], where NH is the free amine, are nonlinear upwards, except the reactions of piperidine, which show linear plots. According to the kinetic results and the analysis of products, a reaction scheme is proposed with two tetrahedral intermediates, one zwitterionic (T^±) and another anionic (T⁻), with a kinetically significant proton transfer from T^± to an amine to yield T⁻ (k₃ step). By nonlinear least‐squares fitting of an equation derived from the scheme to the experimental points, the rate microcoefficients involved in the reactions are determined. Comparison of the kinetics of the title reactions with the linear k_obs vs. [NH] plots found in the same aminolysis of O‐ethyl 4‐nitrophenyl dithiocarbonate (2) in the same solvent shows that the rate coefficient for leaving group expulsion from T^± (k₂) is larger for 2 due to a stronger push by EtO than PhO. The k₃ value is the same for both reactions since both proton transfers are diffusion controlled. Comparison of the title reactions with the same aminolysis of phenyl 4‐nitrophenyl thionocarbonate (3) in water indicates that (i) the k₂ value is larger for the aminolysis of 1 due to the less basic nucleofuge involved and the small solvent effect on k₂, (ii) the k₃ value is smaller for the reactions of 1 due to the more viscous solvent, (iii) the rate coefficient for amine expulsion from T^± (k₋₁) is larger for the aminolysis of 1 than that of 3 due to a solvent effect, and (iv) the value of the rate coefficient for amine attack (k₁) is smaller for the aminolysis of 1 in aqueous ethanol, which can be explained by a predominant solvent effect relative to the electron‐withdrawing effect from the nucleofuge. © 1999 John Wiley & Sons, Inc. Int J Chem Kinet 31: 839–845, 1999     

Highly Active,Low‐Valence Molybdenum‐ and Tungsten‐Amide Catalysts for Bifunctional Imine‐Hydrogenation Reactions

The reactions of [M(NO)(CO)₄(ClAlCl₃)] (M=Mo, W) with (iPr₂PCH₂CH₂)₂NH, (PN^HP) at 90 °C afforded [M(NO)(CO)(PN^HP)Cl] complexes (M=Mo, 1a ; W, 1b ). The treatment of compound 1a with KOtBu as a base at room temperature yielded the alkoxide complex [Mo(NO)(CO)(PN^HP)(OtBu)] ( 2a ). In contrast, with the amide base Na[N(SiMe₃)₂], the PN^HP ligand moieties in compounds 1a and 1b could be deprotonated at room temperature, thereby inducing dehydrochlorination into amido complexes [M(NO)(CO)(PNP)] (M=Mo, 3a ; W, 3b ; PNP=(iPr₂PCH₂CH₂)₂N)). Compounds 3a and 3b have pseudo‐trigonal‐bipyramidal geometries, in which the amido nitrogen atom is in the equatorial plane. At room temperature, compounds 3a and 3b were capable of adding dihydrogen, with heterolytic splitting, thereby forming pairs of isomeric amine‐hydride complexes [Mo(NO)(CO)H(PN^HP)] ( 4a(cis) and 4a(trans) ) and [W(NO)(CO)H(PN^HP)] ( 4b(cis) and 4b(trans) ; cis and trans correspond to the position of the H and NO groups). H₂ approaches the Mo/W?N bond in compounds 3a , 3b from either the CO‐ligand side or from the NO‐ligand side. Compounds 4a(cis) and 4a(trans) were only found to be stable under a H₂ atmosphere and could not be isolated. At 140 °C and 60 bar H₂, compounds 3a and 3b catalyzed the hydrogenation of imines, thereby showing maximum turnover frequencies (TOFs) of 2912 and 1120 h^?1, respectively, for the hydrogenation of N‐(4 ‐ methoxybenzylidene)aniline. A Hammett plot for various para‐substituted imines revealed linear correlations with a negative slope of ?3.69 for para substitution on the benzylidene side and a positive slope of 0.68 for para substitution on the aniline side. Kinetics analysis revealed the initial rate of the hydrogenation reactions to be first order in c(cat.) and zeroth order in c(imine). Deuterium kinetic isotope effect (DKIE) experiments furnished a low k_H/k_D value (1.28), which supported a Noyori‐type metal–ligand bifunctional mechanism with H₂ addition as the rate‐limiting step.     

Synthesis,Spectroscopic Studies,and Crystal Structures of Phenylorganotin Derivatives with [Bis(2,6‐dimethylphenyl)amino]benzoic Acid: Novel Antituberculosis Agents

The novel triphenyl adduct of 2‐[(2,6‐dimethylphenyl)amino]benzoic acid (HDMPA; 1 ), i.e., [SnPh₃(DMPA)] ( 2 ), the dimeric tetraorganostannoxane [Ph₂(DMPA)SnOSn(DMPA)Ph₂]₂ ( 3 ), and the monomeric adduct [SnPh₂(DMPA)₂] ( 4 ), where DMPA is monodeprotonated HDMPA, have been prepared and structurally characterized by means of IR, ¹H‐NMR, and ¹³C‐NMR spectroscopy. The structures of 1 and 2 have been determined by X‐ray crystallography. Single‐crystal X‐ray‐diffraction analysis of 1 revealed that there are two molecules in the asymmetric unit, HD1 and HD2 , differing in conformation, both forming centrosymmetric dimers linked by H‐bonds between the carboxylic O‐atoms. X‐Ray analysis of 2 revealed a pentacoordinate structure containing Ph₃Sn coordinated to the carboxylato group. Significant C? H/π interactions and intramolecular H‐bonds stabilize the structures of 1 and 2 , which self‐assembled via C? H/π and π/π‐stacking interactions. The Ph₃Sn adduct 2 was found to be a promising antimycobacterial lead compound, displaying activity against Mycobacterium tuberculosis H37Rv. The cytotoxiciy in the Vero cell line is also reported.     

Synthesis,asymmetric aldol reactions,and x‐ray crystallography of some oxadiazinanone derivatives

A series of N₄‐substituted oxadiazinanones have been synthesized from (1R,2S)‐norephedrine by a process of either reductive alkylation or arylation, N‐nitrosation, reduction and cyclization. These derivatives (R = ‐CH₂Ph, ‐CH₂C(CH₃)₃, ‐cyclo‐C₆H₁₁, ‐C₆H₅) have been acylated with propanoyl chloride and employed in the asymmetric Aldol reaction. The observed diastereoselectivities for the formation of the “non‐Evans” syn‐adduct ranged from 88:12 to 99:1. The hydrolysis of the Aldol adducts varied with the nature of the nitrogen substituent.