Sulfide Oxidation by 2,6-Bis[hydroxyl(methyl)amino]-4-morpholino-1,3,5-triazinatodioxomolybdenum(VI): Mechanistic Implications with DFT Calculations for a New Class of Molybdenum(VI) Complex.

Sulfide oxidation is accomplished by a new class of dioxomolybdenum(VI) catalyst (1) that uses the tridentate 2,6-bis[hydroxyl(methyl)amino]-4-morpholino-1,3,5-triazine ligand to form a five-coordinate molybdenum(VI) center. Resonance Raman spectra show that the dioxo groups on the Mo(VI) oxygens readily exchange with water in an acetonitrile media that allows 18O labeling of catalyst 1. The model oxidation reaction was the conversion of thioanisole (2) to the corresponding sulfoxide with 4% of 1 using an equimolar amount of H2O2 in MeCN-d3. Oxygen-18 labeling experiments with either 18O-labeled 1 or 18O-labeled H2O2 are consistent with a sulfide oxygenation pathway that uses a η1-Mo(OOH) hydroxoperoxyl species (3). The hypothesized intermediate 3 is initially formed in a proton transfer reaction between 1 and H2O2. Oxidation is hypothesized via nucleophilic attack of the sulfide on 3 that is supported from a Hammett linear free-energy relationship for para-derivatives of 2. A Hammett reactivity constant (ρ) of -1.2 ± 0.2 was obtained, which is consistent with other ρ values found in prior sulfide oxidation reactions by group 6 complexes. An Eyring plot of the 2 oxidation by 1 gives an Ea of 63.0 ± 5.2 kJ/mol, which is slightly higher than that of a similar oxidation of 2 by the molybdenum(VI) complex, oxodiperoxo (pyridine-2-carboxylato)molybdate(VI) bis(pyridine-2-carboxylic acid) monohydrate (5). Computational modeling with density functional theory (DFT) of the complete reaction profile gave enthalpy and entropy of activations (64 kJ/mol and -120 J/mol·K, respectively) within 1 standard deviation of the experimental values, further supporting the hypothesized mechanism.

Heterogeneous Organophosphate Ethanolysis: Degradation of Phosphonothioate Neurotoxin by a Supported Molybdenum Peroxo Polymer.

A polystyrene-supported molybdenum peroxo material [Mo-Y(s)] was applied toward the oxidative degradation of the organophosphate neurotoxin O,S-diethylphenyl phosphonothioate (1) through ethanolysis. In addition to the operational advantages of the heterogeneous reactivity, oxidative ethanolysis with a 10-fold excess of hydrogen peroxide yields only P-S bond scission to produce diethylphenyl phosphonate and ethyl sulfate. This is the first report of a molybdenum solid support that promotes the degradation of sulfur-containing organophosphate with the turnover benefits of heterogeneous catalysis. The activation parameters of 1 ethanolysis by Mo-Y(s) (Ea = 57 ± 6 kJ/mol and ΔS⧧ = -124 ± 21 J/mol·K) and by the model compound oxodiperoxo(pyridine-2-carboxylato)molybdate(VI) bis(pyridine-2-carboxylic acid) monohydrate (3; Ea = 55 ± 5 kJ/mol and ΔS⧧ = -154 ± 15 J/mol·K) are almost identical for the oxidation of thioanisole by 3. This suggests that the rate-determining step for 1 ethanolysis is sulfur oxidation to form an intermediate phosphonothioate S-oxide, which subsequently undergoes nucleophilic attack by the ethanol solvent to form diethylphenyl phosphonate and ethyl sulfate. Evidence for the formation of this S-oxide intermediate and the postulated ethanolysis mechanism is provided.

Stereochemical inversion of phosphonothioate methanolysis by La(III) and Zn(II): mechanistic implications for the degradation of organophosphate neurotoxins.

The utility of phosphonothioate methanolysis to degrade organophosphate neurotoxins has prompted the stereochemical investigation of this useful transformation. The methanolysis of enantiomerically pure O,S-diethyl phenylphosphonothioate (5) was studied both in the presence and in the absence of metal ions known to catalyze the phosphonothioate → phosphonate transformation. This report outlines the syntheses of enantiomerically pure 5 and its methanolysis product O-ethyl O-methyl phenylphosphonate (7). Compound 7 results from exclusive P-S scission of 5, which is the desired mode of phosphonothioate methanolysis (E(a) = 14.5 ± 0.5 kcal/mol). The stereochemical analysis of the phosphonothioate methanolysis was done for the first time with ß-cyclodextrin, and it shows complete inversion on the phosphorus center upon methoxide displacement of ethanethiolate. The presence of La(III) or Zn(II) complexes do not alter this S(N)2-like substitution which sheds new light on the mechanism of methanolysis of phosphonothioates.

Accommodation of Ca(II) ions for catalytic activity by a group I ribozyme.

The wildtype Tetrahymena ribozyme cannot catalyze detectable levels of phosphotransfer activity in vitro on an exogenous RNA substrate oligonucleotide when calcium(II) is supplied as the only available divalent ion. Nevertheless, low-error mutants of this ribozyme have been acquired through directed evolution that do have activity in 10mM CaCl(2). The mechanisms for such Ca(II) accommodation are not known. Here, we assayed the entire molecule in an effort to identify the roles of the mutations in allowing catalytic activity in Ca(II). We used four biochemical probing techniques - native-gel electrophoresis, hydroxyl radical footprinting, terbium(III) cleavage footprinting, and phosphorothioate interference mapping - to compare the solution structure of the wildtype ribozyme with that of a Ca(II)-active five-site mutant. We compared the gross folding patterns and specific metal-binding sites in both MgCl(2) and CaCl(2) solutions. We detected no large-scale folding differences between the two RNAs in either metal. However, we did discover a limited number of local folding differences, involving regions of the RNA affected by positions 42, 188, and 270. These data support the notion that Ca(II) is accommodated by the Tetrahymena ribozyme by a slight breathing at the active site, but that alterations at, near to, and distal from the active site can all contribute to Ca(II)-based activity.

P-S Bond scission by bis(cyclopentadienyl)molybdenum(IV) dichloride, Cp(2)MoCl(2)(aq): first documented example of an organometallic complex hydrolyzing thiophosphinates.

Thiophosphinate hydrolysis involving P-S bond scission is desirable for the degradation of organophosphate neurotoxins, and we report the first case for such a hydrolytic process by an organometallic compound. The metallocene, bis(cyclopentadienyl)molybdenum(IV) dichloride, Cp(2)MoCl(2) (Cp = eta(5)-C(5)H(5)), hydrolyzes a variety of thioaryl diphenylphosphinates in an aqueous THF solution. P-S scission of p-methoxythiophenyl diphenylphosphinate has a 500-fold rate of acceleration in the presence of Cp(2)MoCl(2)(aq) with activation parameters of 20(3) kcal mol(-)(1) and -15(3) cal mol(-)(1) K(-)(1) for DeltaH(double dagger) and DeltaS(double dagger), respectively. These activation parameters and the rate acceleration are consistent with an intermolecular hydrolytic process in which the Cp(2)Mo serves as a Lewis acid to activate the phosphinate for nucleophilic attack. Furthermore, rho = 2.3 (25 degrees C) which indicates a single nonconcerted mechanism in which the rate determining step is the nucleophilic attack on the activated phosphinate.