Method of decomposing organophosphorus compounds

FIELD OF THE INVENTION

0001This invention relates to methods of decomposing organophosphorus compounds. The invention more particularly relates to metal ion and metal species catalysis of an alcoholysis reaction which converts toxic organophosphorus compounds into non-toxic compounds. The invention further relates to lanthanum ion catalyzed degradation of chemical warfare agents, insecticides and pesticides.

BACKGROUND OF THE INVENTION

0002The Chemical Weapons Convention was adopted by the Conference on Disarmament in Geneva on September 3, 1992, entered into force on April 29, 1997, and calls for a prohibition of the development, production, stockpiling and use of chemical weapons and for their destruction under universally applied international control. Eliminating the hazard of chemical warfare agents is desirable both in storage sites and on the battlefield. Decontamination of battlefields requires speed and ease of application of decontaminant. Surfaces involved pose a challenge for decontamination techniques since some surfaces absorb such agents, making decontamination difficult. Examples of surfaces that could be involved include those of tanks, ships, aircraft, weapons, electronic devices, ground, protective clothing and human skin. The decontaminants should not be corrosive, so that surfaces are not damaged during/following decontamination. An optimum solvent of a decontaminating method should provide ease of application, solubility of the chemical warfare agent, non-corrosiveness, and minimal environmental contamination. Since the establishment of the Convention, considerable effort has been directed toward methods of facilitating the controlled decomposition of organophosphorus compounds.

0003Aqueous decontamination systems, such as hydrolysis systems, have been used in the past, most notably for nerve agents, particularly for the G-agents tabun (GA), sarin (GB), soman (GD) and GF. However, hydrolysis reactions are not suitable for all chemical warfare nerve agents such as V-agents VX (S-2-(diisopropylamino)ethyl O-ethylmethylphosphonothiolate) and Russian-VX (S-2-(diethylamino)ethyl O-isobutylmethylphosphonothiolate), whose decontamination chemistries are very similar to one another (Yang, 1999). The V-agents are about 1000-fold less reactive with hydroxide than the G-agents (due to their poor solubility in water under basic conditions), and they produce product mixtures containing the hydrolytically stable, but toxic, thioic acid byproduct. <chemistry id="chem0001" num="0001"><img file="EP1613402B1_D0001.tif" /></chemistry><chemistry id="chem0002" num="0002"><img file="EP1613402B1_D0002.tif" /></chemistry><chemistry id="chem0003" num="0003"><img file="EP1613402B1_D0003.tif" /></chemistry>

0004Although some chemical warfare agents are water soluble, they may be applied in combination with a polymer so that, being thickened, they adhere well to surfaces. These "thickened" agents are only minimally soluble in water. In the case of decomposition using a hydrolysis reaction, products in which a phosphorus-sulfur bond is preserved are common; these are toxic in their own right and are relatively resistant to further reaction. Another disadvantage of an aqueous decontamination system is that hydrolysis reactions are not catalytic, and therefore require stoichiometric amounts of reagents. Furthermore, commonly used aqueous methods, due to their alkaline pH, are not suitable for decontamination of human skin. Yet another disadvantage of aqueous decontamination methods is the caustic wastewater produced as an end product, which poses a challenge for disposal.

0005Historically, decontamination of chemical warfare agents has been effected using hydrolysis or oxidation using bleach or alkali salts. Bleach is corrosive to skin, rubber, and metal surfaces and is ineffective in cold weather conditions. Alkali salts require excess hydroxide ion in order for the reaction to go to completion rapidly, thus resulting in a caustic product. Non-catalytic methanolysis of V-agents has been studied, wherein the reaction of VX with alkoxide leads primarily to a displacement of the SR^- group (Yang <i>et al.,</i> 1997).

0006Transition metal ions and lanthanide series ions and certain mono- and dinuclear complexes thereof are known to promote hydrolysis of neutral phosphate and/or phosphonate esters. However, the available literature on the hydrolysis of phosphothiolate (P=S) esters and phosphothiolates is quite sparse with only the softer ions such as Cu²⁺, Hg²⁺ and Pd²⁺ showing significant catalysis. The lack of examples may be due to reduced activity of P=S esters, their poor aqueous solubility and the fact that anionic hydrolytic products bind to the metal ions thereby inhibiting further catalysis.

0007There is a need for a viable catalytic decontamination method which is inexpensive, has high catalyst turnover, and occurs at relatively neutral pH and ambient temperature, and most importantly, proceeds rapidly, e.g. t_1/2 &lt; 1 min.

BRIEF STATEMENT OF THE INVENTION

0008According to one aspect of the invention there is provided a method for decomposing an organophosphorus compound comprising subjecting said organophosphorus compound to an alcoholysis reaction in a medium comprising non-radioactive metal ions and at least a trace amount of alkoxide ions, wherein, through said alcoholysis reaction, said organophosphorus compound is decomposed.

0009In one embodiment of the invention, said organophosphorus compound has the following formula (10): <chemistry id="chem0004" num="0004"><img file="EP1613402B1_D0004.tif" /></chemistry> where: <ul id="ul0001" list-style="none" compact="compact"><li>J is O or S;</li><li>X, G, Z are the same or different and are selected from the group consisting of Q, OQ, QA, OA, F, Cl, Br, I, QS, SQ and C≡N;</li><li>Q is hydrogen or a substituted or unsubstituted branched, straight-chain or cyclic alkyl group having 1-100 carbon atoms; and</li><li>A is a substituted or unsubstituted aryl group selected from the group consisting of phenyl, biphenyl, benzyl, pyridyl, naphthyl, polynuclear aromatic, and aromatic and non-aromatic heterocyclic;</li><li>wherein, when X, G, Z are the same, <ol id="ol0001" compact="compact"><li>(i) X, G, Z are not Q; or</li><li>(ii) Q is not H; and</li></ol></li><li>wherein said substituents are selected from the group consisting of CI, Br, I, F, nitro, nitroso, Q, alkenyl, OQ, carboxyalky acyl, SO₃H, SO₃Q, S=O(Q), S(=O)₂Q, amino, alkylamino (NHQ), arylamino (NHA), alkylarylamino, dialkylamino and diarylamino.</li></ul>

0010In some embodiments, said medium is a solution further comprising a solvent selected from the group consisting of methanol, substituted and unsubstituted primary, secondary and tertiary alcohols, alkoxyalkanol, aminoalkanol, and combinations thereof.

0011In a preferred embodiment, said organophosphorus compound has at least one phosphorus atom double bonded to an oxygen or a sulfur atom.

0012In another embodiment, said medium further comprises a non-inhibitory buffering agent.

0013In yet another embodiment said buffering agent is selected from the group consisting of anilines, N-alkylanilines, N,N-dialkylanilines, N-alkylmorpholines, N-alkylimidazoles, 2,6-dialkylpyridines, primary, secondary and tertiary amines, trialkylamines, and combinations thereof.

0014In another embodiment, said medium is a solution further comprising a solvent selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, 2-butanol, methoxyethanol, and combinations thereof.

0015In further embodiments, said solution further comprises a solvent selected from the group consisting of nitriles, esters, ketones, amines, ethers, hydrocarbons, substituted hydrocarbons, unsubstituted hydrocarbons, chlorinated hydrocarbons, and combinations thereof.

0016In further embodiments, said medium further comprises alkoxide ions in addition to said at least a trace amount of alkoxide ions.

0017In further embodiments, the concentration of said alkoxide ions is about 0.1 to about 2 equivalents of the concentration of the metal ions.

0018In further embodiments, the concentration of said alkoxide ions is about 1 to about 1.5 equivalents of the concentration of the metal ions.

0019In further embodiments, said medium is prepared by combining a metal salt and an alkoxide salt with at least one of alcohol, alkoxyalkanol and aminoalkanol.

0020In further embodiments, said metal ions are selected from the group consisting of lanthanide series metal ions, transition metal ions, and combinations thereof.

0021In further embodiments, said metal ions are selected from the group consisting of lanthanide series metal ions, copper, platinum, palladium, zinc, nickel, yttrium, scandium ions, and combinations thereof.

0022In further embodiments, said metal ions are selected from the group consisting of Cu²⁺, Pt²⁺, Pd²⁺, Zn²⁺, Y³⁺, Sc³⁺, Ce³⁺, La³⁺, Pr³⁺, Nd³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺, Dy³⁺, Ho³⁺, Er³⁺, Tm³⁺, Yb³⁺, and combinations thereof.

0023In further embodiments, said metal ions are lanthanide series metal ions.

0024In further embodiments, said lanthanide series metal ions are selected from the group consisting of Ce³⁺, La³⁺, Pr³⁺, Nd³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺, Dy³⁺, Ho³⁺, Er³⁺, Tm³⁺, Yb³⁺, and combinations thereof.

0025In further embodiments, said metal ions are selected from the group consisting of Cu²⁺ Pt²⁺, Pd²⁺, Zn²⁺, and combinations thereof.

0026In further embodiments, said metal ions are selected from the group consisting of Y³⁺, Sc³⁺, and combinations thereof.

0027In further embodiments, said metal ion is La³⁺.

0028In further embodiments, said organophosphorus compound is a pesticide.

0029In further embodiments, said organophosphorus compound is an insecticide.

0030In further embodiments,said organophosphorus compound is paraoxon.

0031In further embodiments, said organophosphorus compound is a chemical warfare agent.

0032In further embodiments, said organophosphorus compound is a G-agent.

0033In further embodiments, said organophosphorus compound is selected from the group consisting of VX and Russian-VX.

0034In further embodiments, said organophosphorus compound is a nerve agent.

0035In further embodiments, said chemical warfare agent is combined with a polymer.

0036In further embodiments, said medium further comprises one or more ligands.

0037In further embodiments, said ligand is selected from the group consisting of 2,2'-bipyridyl, 1,10-phenanthryl, 2,9-dimethylphenanthryl, crown ether, and 1,5,9-triazacyclododecyl.

0038In further embodiments, said ligand further comprises solid support material.

0039In further embodiments, said solid support material is selected from a polymer, silicate, aluminate, and combinations thereof.

0040In further embodiments, said medium is a solid.

0041In further embodiments, said medium is a solution.

0042In further embodiments, said solution is disposed on an applicator.

0043In further embodiments, the concentration of said alkoxide ions is about 0.5 to about 1.5 equivalents of the concentration of the metal ions.

0044In another broad aspect, the invention provides a kit for decomposing an organophosphorus compound comprising a substantially non-aqueous medium for an alcoholysis reaction, said medium comprising non-radioactive metal ions and at least a trace amount of alkoxide ions.

0045In a first embodiment, said medium is contained in an ampule.

0046In a second embodiment, the kit comprises an applicator bearing the medium, said applicator being adapted so that the medium is applied to the organophosphorus compound and the compound decomposes.

0047In some embodiments, the kit further comprises written instructions for use.

BRIEF DESCRIPTION OF THE DRAWINGS

0048For a better understanding of the invention and to show more clearly how it may be carried into effect, reference will now be made by way of example to the accompanying drawings, which illustrate aspects and features according to preferred embodiments of the present invention, and in which: <ul id="ul0002" list-style="none"><li><figref idref="f0001">Figure 1A</figref> shows a proposed mechanism for catalysis by a lanthanum methoxide dimer of the methanolysis of an aryl phosphate.</li><li><figref idref="f0001">Figure 1B</figref> shows a proposed mechanism for catalysis by a zinc methoxide complex of the methanolysis of an aryl phosphate.</li><li><figref idref="f0002">Figure 1C</figref> shows the reaction scheme for Cu:[12]aneN₃ catalyzing the methanolysis of fenitrothion.</li><li><figref idref="f0002">Figure 2</figref> shows a plot of k_obs vs. concentration of La(OTf)₃ for the La³⁺-catalyzed methanolysis of paraoxon (2.04 x 10^-5 M) at 25 °C, where <ul id="ul0003" list-style="none"><li>■, <maths id="math0001"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0005.tif" /></maths> 8.96;</li><li>○, <maths id="math0002"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0006.tif" /></maths> 8.23; and</li><li>●, <maths id="math0003"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0007.tif" /></maths> 7.72.</li></ul></li><li><figref idref="f0003">Figure 3</figref> shows a plot of the log k₂^obs (M^-1s^-1) vs. <maths id="math0004"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0008.tif" /></maths> for La³⁺ -catalyzed methanolysis of paraoxon at 25 °C. The dotted line through the data was computed on the basis of a fit of the k_obs data to equation 3, the two dominant forms being La₂(OCH₃)₂ and La₂(OCH₃)₃.</li><li><figref idref="f0004">Figure 4</figref> shows a speciation diagram for the distribution of La₂(OCH₃)_n forms in methanol, n = 1-5, as a function of <maths id="math0005"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>,</mo></math><img file="EP1613402B1_D0009.tif" /></maths> calculated for [La(OTf)_3] = 2 x 10^-3 M. Data represented as (●) correspond to second order rate constants (k₂^obs) for La³⁺-catalyzed methanolysis of paraoxon presented in Table 13.</li><li><figref idref="f0005">Figure 5</figref> shows a plot of the predicted k₂^obsvs. <maths id="math0006"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0010.tif" /></maths> rate profile for La³⁺-catalyzed methanolysis of paraoxon (-------) based on the kinetic contributions of La₂(OCH₃)₁, (······); La₂(OCH₃)₂ (solid line) and La₂(OCH₃)₃, (·-·-·-) computed from the k₂^2:1, k₂^2:2 and k₂^2:3 rate constants (Table 14), and their speciation (<figref idref="f0004">Figure 4</figref>); data points (■) are experimental k₂^obs rate constants from Table 13.</li><li><figref idref="f0005">Figure 6</figref> shows the effect of copper triflate (in the presence of equimolar ligand and 0.5 equivalents of methoxide) on the rate of methanolysis of fenitrothion as a plot of the k_obs vs. total concentration of Cu(OTf)₂ for the methanolysis of fenitrothion catalyzed by various species at T = 25 °C and [^-OCH₃]/[Cu²⁺]_t = 0.5, when ligand is used, [Cu²⁺]_t = [Ligand], where <ul id="ul0004" list-style="none"><li>●,{Cu²⁺:no ligand:(^-OCH₃)};</li><li>◆, (Cu²⁺:phen:(^-OCH₃)}; and</li><li>■, {Cu²⁺:bpy:(^-OCH₃)}.</li></ul></li><li><figref idref="f0006">Figure 7</figref> shows the effect of Cu²⁺:[12]aneN₃:(^-OCH₃) (copper triflate in the presence of equimolar ligand and 0.5 equivalents of methoxide) on the rate of methanolysis of paraoxon (●) and fenitrothion (■) as a plot of the k_obs vs. total concentration of Cu(OTf)₂ conducted at T = 25 °C.</li><li><figref idref="f0006">Figure 8</figref> shows the effect of methoxide ion concentration on the rate of Zn²⁺-catalyzed methanolysis of paraoxon as plots of k_obs vs added NaOCH₃ for the methanolysis of paraoxon in the presence of 1 mM Zn(ClO₄), where: <ul id="ul0005" list-style="none" compact="compact"><li>●, no added ligand;</li><li>◊, 1 mM phen;</li><li>■, 1mM diMephen; and</li><li>□, 1 mM [12]aneN₃</li></ul> (lines through the data drawn as visual aid only).</li><li><figref idref="f0007">Figure 9A</figref> shows the catalyzed methanolysis of fenitrothion as a plot of k_obs vs. concentration of zinc ion (Zn(OTf)₂) alone, and in the presence of equimolar ligand at constant [(^-OCH₃)]/[Zn²⁺]_total ratios, where: <ul id="ul0006" list-style="none"><li>●, no ligand, [(^-OCH₃)]/[Zn²⁺]_total = 0.3; ○, phen, [(^-OCH₃)]/[Zn²⁺]_total = 0.5; and</li><li>■, diMephen, [(^-OCH₃)]/[Zn²⁺]_total = 1.0.</li></ul></li><li><figref idref="f0007">Figure 9B</figref> shows the catalyzed methanolysis of paraoxon as a plot of k_obs vs. concentration of zinc ion (Zn(OTf)₂) alone and in the presence of equimolar ligand at constant [(^-OCH₃)]/[Zn²⁺]_total ratios, where: <ul id="ul0007" list-style="none" compact="compact"><li>●, no ligand, [(^-OCH₃)]/[Zn²⁺]_total = 0.3;</li><li>○, phen, [(^-OCH₃)]/[Zn²⁺]_total = 0.5; and</li><li>dimephen, [(^-OCH₃)]/[Zn²⁺]_total = 1.0.</li></ul></li><li><figref idref="f0008">Figure 10</figref> shows the disappearance of paraoxon (●) and appearance of diethyl methyl phosphate (■) product over time for a methanolysis reaction in the presence of zinc ion, methoxide, and ligand in deuterated methanol in a plot of relative signal integration of 31 the reagent and product P NMR signals for a system containing 15 mM paraoxon, 1 mM Zn(OTf)₂, 1mM NaOCH₃ and 1 mM diMephen at T = 25 C.</li><li><figref idref="f0008">Figure 11</figref> shows the effect of increasing concentration of methoxide on the rate of Zn²⁺-catalyzed methanolysis of paraoxon in a plot of the pseudo-first order rate constants (k_obs) for methanolysis of paraoxon in the presence of 1 mM Zn(OTf)₂ and absence of added ligand as a function of added NaOCH₃.</li><li><figref idref="f0009">Figure 12</figref> shows the effect of zinc ion concentration on the rate of Zn²⁺-catalyzed methanolysis of paraoxon as plots of the k_obs for the methanolysis of fenitrothion (●), paraoxon (○) and p-nitrophenyl acetate (■) vs. [Zn(ClO₄)₂] at a constant [Zn²⁺(^-OCH₃)]/[Zn²⁺]_total ratio of 0.3, T = 25 °C. Lines through the data are calculated on the basis of fits to equation (6).</li><li><figref idref="f0010">Figure 13A</figref> shows the effect of Zn²⁺:[12]aneN₃ on the rate of Zn²⁺-catalyzed methanolysis of paraoxon as a plot of k_obs for methanolysis of paraoxon as a function of [Zn(OTf)₂]_total containing equimolar [12]aneN₃ and NaOCH₃, T = 25 °C. Right axis gives [Zn²⁺:[12]aneN₃:(^-OCH₃)] determined by Hyperquad™ fitting of titration data. The arrows are presented as a visual aid to connect the various species concentrations with the kinetic rate constant.</li><li><figref idref="f0010">Figure 13B</figref> shows the effect of Zn²⁺:phen on the rate of Zn²⁺-catalyzed methanolysis of paraoxon as a plot of k_obs for methanolysis of paraoxon as a function of [Zn(OTf)₂]_total containing equimolar phen and NaOCH₃, T = 25 °C. Right axis gives [Zn²⁺:phen:(^-OCH₃)] determined by Hyperquad™ fitting of titration data. The arrows are presented as a visual aid to connect the various species concentrations with the kinetic rate constant.</li><li><figref idref="f0009">Figure 14</figref> shows the titration profiles obtained by potentiometric titration of 2mM Zn(OTf)₂ with no added ligand (●), with 2 mM phen (◆), with 2 mM diMephen (■), with 2 mM [12]aneN₃ (□) and with 1.2 mM added HClO₄ Lines through the titration curves with phen and [12]aneN₃ were derived from Hyperquad™ fitting of the data.</li></ul>

DETAILED DESCRIPTION OF THE INVENTION

0049According to a broad aspect of the invention there is provided a method of decomposing an organophosphorus compound by combining the organophosphorus compound with a substantially non-aqueous medium comprising alcohol, alkoxyalkanol or aminoalkanol, metal ions and at least a trace amount of alkoxide ions. When so combined the organophosphorus compound undergoes an alcoholysis reaction and forms a less toxic or non-toxic compound.

0050More particularly, the invention provides a method of increasing the rate of decomposition of an organophosphorus compound by combining the compound with a catalytic species formed in a substantially non-aqueous medium comprising metal ions; alcohol, alkoxyalkanol or aminoalkanol; and alkoxides ions. In some embodiments, the medium is a solution.

0051As used herein, the term "alcohol" means a compound which comprises an R-OH group, for example, methanol, primary alcohols, and substituted or unsubstituted secondary alcohols, tertiary alcohols, alkoxyalkanol, aminoalkanol, or a mixture thereof.

0052As used herein, "substantially non-aqueous medium" means an organic solvent, solution, mixture or polymer. As it is very difficult to obtain anhydrous alcohol, a person of ordinary skill in the art would recognize that trace amounts of water may be present. For example, absolute ethanol is much less common than 95% ethanol. However, the amount of alcohol present in a medium or solution according to the invention should not have so much water present as to inhibit the alcoholysis reaction, nor should a substantial amount of hydrolysis occur.

0053As used herein, the term "organophosphorus compound" includes compounds which comprise a phosphorus atom doubly bonded to an oxygen or a sulfur atom. In preferred embodiments such organophosphorus compounds are deleterious to biological systems, for example, a compound may be an acetylcholine esterase inhibitor, a pesticide or a chemical warfare agent.

0054As used herein, the term "decomposing an organophosphorus compound" refers to rendering a deleterious organophosphorus compound into a less toxic or non-toxic form.

0055Decomposition of an organophosphorus compound according to the invention may be carried out in solution form, or in solid form. Examples of such decomposition include, applying catalyst as a solution directly to a solid chemical warfare agent or pesticide. Such a solution would be for example, an appropriately buffered alcoholic, alkoxyalkanolic or aminoalkanolic solution comprising metal ions and alkoxide ions, in which one or more catalytic species forms spontaneously, which may be applied to a surface which has been contacted with an organophosphorus agent.

0056As used herein, the term "catalytic species" means a molecule or molecules, comprising metal ions and alkoxide ions, whose presence in an alcoholic, alkoxyalkanolic or aminoalkanolic solvent containing an organophosphorus compound increases the rate of alcoholysis of the organophosphorus compound relative to its rate of alcoholysis in the solvent without the catalytic species.

0057As used herein, the term "appropriately buffered" means that the <maths id="math0007"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0011.tif" /></maths> of a solution is controlled by adding non-inhibitory buffering agents, or by adding about 0.1 to about 2.0 equivalents of alkoxide ion per equivalent of metal ion.

0058As used herein, the term <maths id="math0008"><math display="inline"><mi>ʺ</mi><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mi>ʺ</mi></math><img file="EP1613402B1_D0012.tif" /></maths> is used to indicate pH in a non-aqueous solution (Bosch et al., 1999, Rived et al.,1998, Bosch <i>et</i> al.,1996). One skilled in the art will recognize that if a measuring electrode is calibrated with aqueous buffers and used to measure pH of an aqueous solution, the term <maths id="math0009"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">w</mi><mi mathvariant="normal">w</mi></mmultiscripts></math><img file="EP1613402B1_D0013.tif" /></maths> is used. If the electrode is calibrated in water and the 'pH' of a neat methanol solution is then measured, the term <maths id="math0010"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">w</mi></mmultiscripts></math><img file="EP1613402B1_D0014.tif" /></maths> is used, and if the latter reading is made, and a correction factor of 2.24 (in the case of methanol) is added, then the term <maths id="math0011"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0015.tif" /></maths> is used.

0059As used herein, the term "non-inhibitory agent or compound" means that the agent or compound does not substantially diminish the rate of a catalyzed reaction when compared to the rate of the reaction in the absence thereof.

0060As used herein, the term "inhibitory agent or compound" means that the agent or compound does substantially diminish the rate of a catalyzed reaction when compared to the rate of the reaction in the absence thereof.

0061As used herein, the term "metal species" means a metal in an oxidation state of zero to 9.

0062As used herein, the term "mononuclear" or "monomeric" means a species comprising one metal atom.

0063In an embodiment of the invention, the catalytic species is a metal alkoxide species of the stoichiometry {M^<i>n</i>+(-OR)<i>_m</i>L<i>_g</i>}<i>_s</i> where M is a metal selected from lanthanide series metals or transition metals; n is the charge on the metal which may be 1 to 9, most preferably 2 to 4; ^-OR is alkoxide; <i>m</i> is the number of associated alkoxide ions and may be 1, 2, ..., <i>n</i> -<i>1</i>, <i>n, n</i>+1, <i>n</i>+2, ...<i>n</i>+6, most preferably 1 to <i>n</i>-1; s is 1 to 100; L is ligand; <i>g</i> is the number of ligands complexed to the metal ion, and may be 0 to 9; where <i>g</i> is greater than 1, the ligands may be the same or different. Examples of this embodiment include the lanthanum dimer {La³⁺COMe)}₂ and copper monomer {Cu²⁺(^-OMe)L}.

0064The inventors contemplate an embodiment wherein the oxidation state of the metal atom is zero. For example, it is well known in the art that transition metals having an oxidation state of zero may be reactive and may form complexes. Copper is an example of such a metal, and it is expected that Cu⁰ may catalyze alcoholysis of organophosphorus compounds according to the invention.

0065As used herein, the term "ligand" means a species containing a donor atom or atoms that has a non-bonding lone pair or pairs of electrons which are donated to a metal centre to form one or more metal-ligand coordination bonds. In this way, ligands bond to coordination sites on a metal and thereby limit dimerization and prevent further oligomerization of the metal species, thus allowing a greater number of active mononuclear species to be present than is the case in the absence of ligand or ligands.

0066As used herein, the term "{Mⁿ⁺:L:^-OR}" (which differs from the above described system, {M^<i>n</i>+(^-OR)<i>_m</i>L<i>_g</i>}<i>_s</i>, by the use of the symbol ":" between constituents of the brace "{}") is used when no stoichiometry is defined for a system comprising metal ions (M^<i>n</i>+), ligand (L), and alkoxide (^-OR). This technique is meant to encompass any and all catalytically active stoichiometries thereof including but not limited to dimers, trimers and longer oligomers, monoalkoxides, dialkoxides, polyalkoxides, etc.

0067In another embodiment of the invention, the catalytic species has the general formula 20: <chemistry id="chem0005" num="0005"><img file="EP1613402B1_D0016.tif" /></chemistry> where Z¹ and Z² are the same or different non-radioactive lanthanide, copper, platinum or palladium ions; R¹, R², R³ and R⁴ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms; p is a number from 1-6; and m and q are each independently zero or 1 or more, preferably 1-5, such that the dimer has a net charge of zero.

0068In another embodiment of the invention, the catalytic species has the general formula 20: <ul id="ul0008" list-style="none" compact="compact"><li>where Z¹ and Z² are the same or different non-radioactive lanthanide series metal ions, copper, platinum or palladium ions;</li><li>R¹, R², R³ and R⁴ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms;</li><li>p is a number from 1-6; and</li><li>m and q are each independently zero or 1 or more, preferably 1-5, such that the dimer has a net charge of zero.</li></ul>

0069In another embodiment of the invention, the catalytic species has the general formula 20: <ul id="ul0009" list-style="none" compact="compact"><li>where Z¹ and Z² are the same or different non-radioactive lanthanide series metal ions, and/or transition metal ions;</li><li>R¹, R², R³ and R⁴ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms;</li><li>p is a number from 0-6; and</li><li>m and q are each independently zero or 1 or more, preferably 1-5, such that the dimer has a net positive charge.</li></ul>

0070In another embodiment of the invention, the catalytic species has the general formula 20: <ul id="ul0010" list-style="none" compact="compact"><li>where Z¹ and Z² are the same or different non-radioactive lanthanide series metal ions, and/or transition metal ions;</li><li>R¹, R², R³ and R⁴ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms;</li><li>p is a number from 1-6; and</li><li>m and q are each independently zero or 1 or more, preferably 1-5, such that the dimer has a net positive charge.</li></ul>

0071In another embodiment of the invention, the catalytic species has the general formula 30:         _a(R²O)-Z¹-(OR³)_b     (30) where Z¹ is a non-radioactive lanthanide, copper, platinum or palladium ion; R² and R³ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms; a is a number from 1-3; and b is zero or 1 or more, such that the catalytic species has a net charge of zero.

0072In another embodiment of the invention, the catalytic species has the general formula 30: <ul id="ul0011" list-style="none" compact="compact"><li>where Z¹ is a non-radioactive lanthanide series metal ion or a transition metal ion;</li><li>R² and R³ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms;</li><li>a is a number from 1-3; and</li><li>b is zero or 1 or more, such that the catalytic species has a net positive charge.</li></ul>

0073Another embodiment of the invention, the catalytic species has the general formula 30: <ul id="ul0012" list-style="none" compact="compact"><li>where Z¹ is a non-radioactive lanthanide series metal ion or a transition metal ion;</li><li>R² and R³ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms;</li><li>a is a number from 1-3; and</li><li>b is zero or 1 or more, such that the catalytic species has a net positive charge;</li><li>wherein unoccupied coordination sites on the metal may be occupied by one or more ligands.</li></ul>

0074In another embodiment of the invention, the catalytic species has the general formula 40: <chemistry id="chem0006" num="0006"><img file="EP1613402B1_D0017.tif" /></chemistry> where Z¹, Z² and Z³ are the same or different non-radioactive lanthanide, copper, platinum or palladium ions; R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms; p is a number from 1-4; m, d, q and t are each independently zero or 1 or more, preferably 1-5, such that the oligomer has a net charge of zero; and r is a number from 0 to 100, or in the case of polymeric material may be greater than 100.

0075In yet another embodiment of the invention, the catalytic species has the general formula 40: <ul id="ul0013" list-style="none" compact="compact"><li>where Z¹, Z² and Z³ are the same or different non-radioactive lanthanide series metal ions, or transition metal ions or combinations thereof;</li><li>R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms;</li><li>p is a number from 1-4;</li><li>m, d, q and t are each independently zero or 1 or more, preferably 1-5, such that the oligomer has a net positive charge; and</li><li>r is a number from 0-100, or in the case of polymeric material may be greater than 100.</li></ul>

0076The alcoholic solution comprises a primary, secondary or tertiary alcohol, an alkoxyalkanol, an aminoalkanol, or a mixture thereof. In one embodiment, a non-inhibitory buffering agent is added to the solution to maintain the <maths id="math0012"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0018.tif" /></maths> at the optimum range of <maths id="math0013"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>,</mo></math><img file="EP1613402B1_D0019.tif" /></maths> for example in the case of La³⁺ in methanol, <maths id="math0014"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0020.tif" /></maths> 7 to 11 (see <figref idref="f0003">Figure 3</figref>). Examples of non-inhibitory buffering agents include: anilines; N-alkylanilines; N,N-dialkylanilines; N-alkylmorpholines; N-alkylimidazoles; 2,6-dialkylpyridines; primary, secondary and tertiary amines such as trialkylamines; and their various derivatives.

0077In another embodiment, non-inhibitory buffering agents are not added, but additional alkoxide ion is added in the form of an alkoxide salt to obtain metal ions and alkoxide ions in a metal:alkoxide ratio of about 1:0.01 to about 1:2, for some embodiments preferably about 1:1 to about 1:1.5, for other embodiments preferably about 1:0.5 to about 1:1.5. A person skilled in the art will recognize that an alcoholic solution contains trace amounts of alkoxide ions. This concept is analogous to water containing a trace amount of hydrogen ions and hydroxide ions, thus water of pH 7 contains, by definition, [H⁺] = 1 x 10^-7 M and [OH^-] = 1 x 10^-7 M. For this reason, when alkoxide salts are added according to this embodiment of the invention, they are referred to as "additional" alkoxide ions. Suitable non-inhibitory cations for the alkoxide salts include monovalent ions such as, for example, Na⁺, K⁺, Cs⁺, Rb⁺, NR₄⁺ and NR'R"R"'R""⁺ (where R', R", R"', and R"" may be the same or different and may be hydrogen or substituted or unsubstituted alkyl or aryl groups) and divalent ions such as the alkali earth metals, and combinations thereof. In some instances such ions may prolong the life of a catalyst by bonding to and, for example, precipitating, an inhibitory product of organophosophorus decomposition, an example of which is Ca²⁺ bonding to fluoride.

0078To obtain the metal ions, metal salts are added to the solution. Preferably, the metal ion is a non-radioactive lanthanide series metal ion. Suitable lanthanide series metal ions include, for example, Ce³⁺, La³⁺, Pr³⁺, Nd³⁺, Sm³⁺, Eu³⁺,Gd³⁺, Tb³⁺, Dy³⁺, Ho³⁺, Er³⁺, Tm³⁺ and Yb³⁺ and combinations thereof or complexes thereof. Suitable non-lanthanide series metal ions include, for example, divalent transition metal ions such as, for example, Cu²⁺, Pd²⁺, Pt²⁺, Zn²⁺, and trivalent transition metal ions such as, for example, Sc³⁺ and Y³⁺, as well as combinations thereof or complexes thereof, including combinations/complexes of those with non-radioactive lanthanide series metal ions. While La³⁺<maths id="math0015"><math display="inline"><mfenced><msup><mmultiscripts><mi>pKa</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts><mn>1</mn></msup><mo>=</mo><mn>7.8</mn></mfenced></math><img file="EP1613402B1_D0021.tif" /></maths> has good catalytic efficacy from <maths id="math0016"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0022.tif" /></maths> 7.3 to 10.3, other metal ions which have lower <maths id="math0017"><math display="inline"><mmultiscripts><mi>pKa</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0023.tif" /></maths> values (for example Ho³⁺ and Eu³⁺ have <maths id="math0018"><math display="inline"><msub><mmultiscripts><mi>pKa</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts><mn>1</mn></msub></math><img file="EP1613402B1_D0024.tif" /></maths> values of 6.6, while Yb³⁺ has a <maths id="math0019"><math display="inline"><msub><mmultiscripts><mi>pKa</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts><mn>1</mn></msub></math><img file="EP1613402B1_D0025.tif" /></maths> value of 5.3, Gibson <i>et al.</i> 2003) may be efficacious at lower <maths id="math0020"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mn>.</mn></math><img file="EP1613402B1_D0026.tif" /></maths>

0079An embodiment of the invention is a catalytic system comprising mixtures of metal ions, for example, mixtures of lanthanide series metal ions which would be active between the wide <maths id="math0021"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0027.tif" /></maths> range of 5 to 11. Lanthanide series metal ions and alkoxide may form several species in solution, an example of which, species forming from La³⁺ and methoxide is shown in the figures. In the case of La³⁺, a dimer containing 1 to 3 alkoxides is a particularly active catalyst for the degradation of organophosphorus compounds. In the case of non-lanthanide series metal ions, such as, for example Zn²⁺ and Cu²⁺, a mononuclear complex containing alkoxides is an active catalyst for the degradation of organophosphorus compounds.

0080In some embodiments, the invention provides limiting of dimerization and prevention of further oligomerization by addition of ligand such as, for example, bidentate and tridentate ligands. By coordination at one or more sites on a metal, a ligand limits dimerization and prevents further oligomerization of a metal species, thus allowing a greater number of active mononuclear species than is the case in the absence of ligand. Although not meant to be limiting, examples of such ligands are 2,2'-bipyridyl ("bpy"), 1,10-phenanthryl ("phen"), 2,9-dimethytphenanthryl ("diMephen") and 1,5,9-triazacyclododecyl ("[12]aneN₃"), crown ether, and their substituted forms. Such ligands may be attached via linkages to solid support structures such as polymers, silicates or aluminates to provide solid catalysts for the alcoholysis of organophosphorus compounds which are decomposed according to the invention. The point of attachment of the metal:ligand:alkoxide complex to the solid support is preferably at the 3 or 4 position in the case of bipyridyl or the 3, 4 or 5 position in the case of phenanthrolines using linking procedures and connecting spacers which are known in the art. In the case of aza ligands, such as, for example, [12]aneN₃, the point of attachment of the complex to the solid support would preferably be on one of the nitrogens of the macrocycle, using methods and connecting spacers known in the art. Such attachment to solid supports offers advantages in that the solid catalysts may be conveniently recovered from the reaction media by filtration or decantation. In an embodiment of the invention wherein ligands are attached to solid support structures, organophosphorus compounds may be decomposed by running a solution through a column such as a chromatography column. In another embodiment of the invention wherein ligands are attached to solid support structures, organophosphorus compounds may be decomposed by contact with a polymer comprising metal species and alkoxide ions.

0081Suitable anions of the metal salts are non-inhibitory or substantially non-inhibitory and include, for example, ClO₄^-, BF₄^-, BR₄^- I^-, Br^-, CF₃SO₃^- (also referred to herein as"triflate" or "OTf") and combinations thereof. Preferred anions are ClO₄^- and CF₃SO₃^-. In the case of BF₄^-, a solvent other than methanol is preferred.

0082The solution comprises solvents, wherein preferred solvents are alcohols, including primary and secondary alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, 2-butanol and methoxyethanol, and combinations thereof. Most preferably the solution is all alcohol or all alkoxyalkanol or all aminoalkanol; however, combinations with non-aqueous non-inhibitory solvents can also be used, including, for example, nitriles, ketones, amines, ethers, hydrocarbons including chlorinated hydrocarbons and esters. In the case of esters, it is preferable that the alkoxy group is the same as the conjugate base of the solvent alcohol. In some embodiments, esters may cause side reactions which may be inhibitory.

0083Initial studies have been undertaken in methanol since methanol is closest to water in terms of structure and chemical properties and is readily available. However, methanol is less desirable than other solvents due to its toxicity and its relatively low boiling point of 64.7 °C which makes it volatile and prone to evaporation from open vessels. For these reasons, use of higher alcohols such as ethanol, n-propanol and iso-propanol has been explored (see Examples 1 and 2). Ethanol, n-propanol and iso-propanol are substantially less volatile (boiling points 78, 97.2 and 82.5 °C respectively), are less toxic, and have better solubilizing characteristics for hydrophilic substrates. The higher boiling points mean that these solvents are more amenable to field conditions since there would conveniently be less evaporation and thus less solvent would be lost to the atmosphere.

0084Other preferred solvents include n-butanol and 2-butanol since they have higher boiling points than the lower alcohols.

0085In accordance with the invention, the metal ion species catalyzes an alcoholysis reaction of an organophosphorus compound or a mixture of organophosphorus compounds represented by the following general formula (10): <chemistry id="chem0007" num="0007"><img file="EP1613402B1_D0028.tif" /></chemistry> where P is phosphorus; J is O (oxygen) or S (sulfur); X, G, Z are the same or different and are selected from the group consisting of Q, OQ, QA, OA, F (fluoride), Cl (chloride), Br (bromide), I (iodide), QS, SQ and C≡N; where Q is hydrogen or a substituted or unsubstituted branched, straight-chain or cyclic alkyl group consisting of 1-100 carbon atoms; wherein when X, G, Z are the same, X, G, Z are not Q, and when X, G, Z are the same Q is not H; A is a mono-, di-, or poly-substituted or unsubstituted aryl group selected from phenyl, biphenyl, benzyl, pyridine, naphthyl, polynuclear aromatics, and 5- and 6-membered aromatic and non-aromatic heterocycles; wherein each said substituent is selected from Cl, Br, I, F, nitro, nitroso, Q, alkenyl, OQ, carboxyalkyl, acyl, SO₃H, SO₃Q, S=O(Q), S(=O)₂Q, amino, alkylamino (NHQ), arylamino (NHA), alkylarylamino, dialkylamino and diarylamino.

0086Most preferably, the phosphorus atom of <figref idref="f0008">figure 10</figref> has at least one good leaving group attached. For this reason, organophosphorus compounds which are decomposed according to the invention do not have three alkyl groups, nor three hydrogens, nor three hydroxyl groups attached. One skilled in the art will recognize that a "good leaving group" is a substituent with an unshared electron pair that readily departs from the substrate in a nucleophilic substitution reaction. The best leaving groups are those that become either a relatively stable anion or a neutral molecule when they depart, because they cause a stabilization of the transition state. Also, leaving groups that become weak bases when they depart are good leaving groups. Good leaving groups include halogens, alkanesulfonates, alkyl sulfates, and p-toluenesulfonates.

0087As used herein, the term "heterocycle" means a substituted or unsubstituted 5- or 6-membered aromatic or non-aromatic hydrocarbon ring containing one or more O, S or N atoms, or polynuclear aromatic heterocycle containing one or more N, O, or S atoms.

0088An advantage of the decomposition method of the invention is that the solvent, being hydrophobic, relative to water, permits good solubility of organophosphorus agents such as VX, Russian-VX, tabun (GA), soman (GD), sarin (GB), GF, hydrophobic polymers, insecticides and pesticides.

0089Another advantage of the invention is that it provides a non-aqueous solution and reaction products that can be easily and safely disposed of by incineration. It will thus be appreciated that the decontamination method of the invention can be used for a broad range of chemical warfare agents, or mixtures of such agents, or blends of such agents with polymers, as well as other toxic compounds such as insecticides, pesticides and related organophosphorus agents in general.

0090A further advantage of the invention is that destruction of organophosphorus agents occurs with or without the addition of heat. An ambient temperature reaction is cost-efficient for large scale destruction of stockpiled organophosphous material such as chemical weapons, insecticides or pesticides. The catalyst species can catalyze the alcoholysis over the full temperature range between the freezing and boiling points of the solvents or mixture of solvents used. <chemistry id="chem0008" num="0008"><img file="EP1613402B1_D0029.tif" /></chemistry><chemistry id="chem0009" num="0009"><img file="EP1613402B1_D0030.tif" /></chemistry>

0091The G-type and V-type classes of chemical warfare agents are too toxic to be handled without specialized facilities and are often modeled by simulants such as, for the G-agents: paraoxon and <i>p</i>-nitrophenyl diphenyl phosphate, and for the V-agents: <i>O,S</i>-dialkyl- or <i>O,S</i>-arylalkyl-phosphonothioates or <i>S</i>-alkyl-phosphinothioates or <i>S</i>-aryl-phosphinothioates (Yang, 1999). We have used three such simulants and report herein, degradation of paraoxon as a model of G-agents, degradation of O,O'-diethyl-S-p-nitrophenylphosphorothioate as a model of V-agents, and degradation of fenitrothion as a model of (P=S)-containing pesticides. Structures for these model compounds are shown below. These three compounds were chosen because each possess a chromophore which makes the UV-vis kinetics simpler to study with low concentrations of materials. It is expected that this invention has wide applicability for other organophosphorus compounds including chemical warfare agents and other pesticides such as, for example, parathion and malathion.

0092In our studies, which are detailed in the following examples, we have: confirmed the degradation of paraoxon, O,O'-diethyl-S-p-nitrophenylphosphorothioate and fenitrothion when placed in an alcoholic solution of metal ions and at least a trace amount of alkoxide ions; determined the rate of the decomposition of paraoxon in a methanol solution containing La³⁺ and additional methoxide ions; characterized stoichiometry and proposed a structure of active {La³⁺(^-OCH₃)}₂ dimers; studied catalyzed alcoholysis in the presence of ligand and determined that faster rates are possible in some such systems relative to catalysis in the absence of ligand; and confirmed the complete destruction of paraoxon and O,O'-diethyl-S-p-nitrophenylphosphorothioate relative to catalyst in {La³⁺:'OMe}, {Cu²⁺:^-OMe}, and {Zn²⁺:^-OMe} systems thus confirming the true catalytic nature of this method.

0093The data presented in the following examples support the following conclusions: <ul id="ul0014" list-style="none"><li><b>Destruction of Paraoxon (Model G Agent):</b> A preferred embodiment for methanolysis of paraoxon is a {La³⁺:^-OCH₃} system according to the invention. The procedure involves preparation of a 2 mM La(OTf)₃ methanolic solution, containing equimolar NaOCH₃ which affords a 10⁹-fold acceleration of the methanolysis of paraoxon relative to the background reaction at the same <maths id="math0022"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0031.tif" /></maths> in the absence of catalyst (t_1/2 ~ 20 sec). A second preferred embodiment for the methanolysis of paraoxon is a {Zn²⁺:diMephen:^-OMe} system. This system affords accelerations of up to 1.8 x 10⁶-fold for the methanolysis of paraoxon and has broader applicability than La³⁺ as Zn²⁺ also catalyzes the decomposition of fenitrothion.</li><li><b>Destruction of O,O'-diethyl-S-p-nitrophenylphosphorothioate (Model V Agent):</b> A preferred embodiment for methanolysis of O,O'-diethyl-S-p-nitrophenylphosphorothioate is a {Cu²⁺:^-OCH₃:[12]andN₃} system. A second preferred embodiment for the methanolysis of O,O'-diethyl-S-p-nitrophenylphosphorothioate is methanolic solution of {Zn²⁺:diMephen:^-OCH₃}. A third preferred embodiment for the methanolysis of O,O'-diethyl-S-p-nitrophenylphosphorothioate is a methanolic solution of {La³⁺:^-OCH₃}.</li><li><b>Destruction of Fenitrothion (Model Pesticide):</b> A preferred embodiment for methanolysis of fenitrothion is a {Cu²⁺:[12]aneN₃:^-OCH₃} system according to the invention. The procedure involves preparation of a 2 mM Cu(OTf)₂ methanolic solution containing 0.5 equivalents of N(Bu)₄OCH₃ and 1 equivalent of [12]aneN₃ which catalyzes the methanolysis of fenitrothion with a t_1/2 of -58 sec accounting for a 1.7 x 10⁹-fold acceleration of the reaction at near neutral <maths id="math0023"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0032.tif" /></maths> (8.75). A second preferred embodiment for the methanolysis of fenitrothion is a {Zn²⁺:diMephen:^-OCH₃} system. This system affords accelerations of 13 x 10⁶-fold for the methanolysis of fenitrothion at 2 mM each of Zn(OTf)₂, ligand diMephen and NaOCH₃ and exhibits broad applicability as it also catalyzes the decomposition of paraoxon. Fenitrothion decomposition is not appreciably accelerated in the presence of a La³⁺ system according to the invention. This points out the importance of matching the relative hard/soft characteristics of catalyst and substrate, and suggests that softer metal ions such as Cu²⁺ and Pd²⁺ could show enhanced catalytic activity toward the methanolysis of sulfur-containing phosphorus species.</li><li><b>Destruction of a Suspected Organophosphorus Compound of Unknown Structure:</b> A preferred embodiment of the invention for catalyzed alcoholysis of an unknown agent which is suspected to be an organophosphorus compound, is a mixture of {M³⁺:'OCH₃} and (M²⁺:L: ^-OCH₃} in an alcohol solution. Examples of such a mixture include {La³⁺:OCH₃} and {Cu²⁺:[12]aneN₃:OCH₃}; and {La³⁺:OCH₃} and {Zn²⁺:diMephen:OCH₃}. Although such a M²⁺ system is less reactive toward paraoxon than the M³⁺ system; unlike M³⁺, the M²⁺ system does catalyze alcoholysis of fenitrothion. This mixture produces an effective method for destruction of both P=S pesticides and P=O chemical warfare agents.</li></ul>

0094The invention also provides a kit for decomposing an organophosphorus compound comprising a substantially non-aqueous medium for an alcoholysis reaction, said medium comprising non-radioactive metal ions and at least a trace amount of alkoxide ions . The kit may include a container, e.g., an ampule, which is opened so that the medium can be applied to the organophosphorus compound. Alternatively, the kit may include an applicator bearing the medium, wherein the applicator is adapted so that the medium is applied to the organophosphorus compound and the compound consequently decomposes. The applicator may comprise a moist cloth, i.e., a cloth bearing a solution according to the invention. The applicator may be a sprayer which sprays medium according to the invention on the organophosphous compound. In some embodiments, the kit comprises written instructions for use to decompose an organophosphorus compound.

0095The following examples further illustrate the present invention and are not intended to be limiting in any respect. All scientific and patent publications cited herein are hereby incorporated by reference in their entirety.

Examples

0096Examples 5 to 8 provide a summary of the La³⁺ ion catalyzed alcoholysis of paraoxon. Example 10 is a prophetic example of an La³⁺ ion catalyzed alcoholysis of VX. Due to the fact that the dimeric lanthanum methoxide catalyst is stable in solution, and the reaction takes place at room temperature and at neutral pH (neutral <maths id="math0024"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0033.tif" /></maths> in methanol is -8.4), we expect that this reaction is amenable to scale-up and to use in the field.

0097In the examples, methanol (99.8 % anhydrous), sodium methoxide (0.5 M solution in methanol), La(CF₃SO₃)₃ and paraoxon were purchased from Sigma-Aldrich (St. Louis, Missouri) and used without any further purification. HClO₄ (70% aqueous solution) was purchased from BDH (Dorset, England). ¹H NMR and ³¹P NMR spectra were determined at 400 MHz and 161.97 MHz. ³¹P NMR spectra were referenced to an external standard of 70% phosphoric acid in water, and up-field chemical shifts are negative.

0098In the examples, the CH₃OH₂⁺ concentration was determined using a Radiometer Vit 90 Autotitrator, equipped with a Radiometer GK2322 combination (glass/calomel) electrode calibrated with Fisher Certified Standard aqueous buffers (pH = 4.00 and 10.00) as described in recent papers (Neverov <i>et al</i> 2000; Neverov <i>et a</i>/., 2001 (a); Neverov <i>et al</i>., 2001 (b); Neverov <i>et al</i>., 2001 (c); Brown <i>et al</i>., 2002; Tsang <i>et al.,</i> 2003). Values of <maths id="math0025"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0034.tif" /></maths> were calculated by adding a correction constant of 2.24 to the experimental meter reading as reported by Bosch <i>et al</i>., 1999.

0099The <maths id="math0026"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0035.tif" /></maths> values of buffers used in the examples were obtained from the literature or measured at half neutralization of the bases with 70% HClO₄ in MeOH.

Example 1. Mⁿ⁺-Catalyzed Ethanolysis Of Paraoxon And Fenitrothion: Reaction Conditions And Rates

0100The ethanolysis of fenitrothion and paraoxon was studied in ethanol using various metal ions with varying amounts of added base. These reactions were followed by UV-vis spectroscopy by observing the rate of disappearance of a starting material signal or the rate of appearance of a product signal such as 4-nitrophenol in the case of paraoxon or 3-methyl-4-nitrophenol in the case of fenitrothion. Reaction conditions and the catalyzed reaction's rate constants are summarized in Table 1. <tables id="tabl0001" num="0001"><table frame="all"><title>Table 1 - Maximum pseudo-first order kinetic rate constants for the ethanolysis of fenitrothion and paraoxon catalyzed by metal ions (0.001 M) in the presence of optimum amount of base (max k_obs) and at equimolar amount (k_obs 1:1 OCH₃/M^x ratio) , T = 25 °C.</title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="41mm" /><colspec colnum="2" colname="col2" colwidth="42mm" colsep="0" /><colspec colnum="3" colname="col3" colwidth="42mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry align="center" valign="top"><b>Metals^a</b></entry><entry namest="col2" nameend="col3" align="center" valign="top"><b>Paraoxon</b></entry><entry align="center" valign="top"><b>Fenitrothion</b></entry></row><row><entry align="center" valign="top" /><entry align="center" valign="top"><b>10⁴ Max k_obs, s^-1</b></entry><entry align="center" valign="top"><b>10⁴ k_obs, s^{-1 b}</b></entry><entry align="center" valign="top"><b>10⁴ k_obs, s^{-1 b}</b></entry></row><row rowsep="0"><entry align="center" valign="top"><b><i>Lanthanides</i></b></entry><entry align="center" valign="top" /><entry align="center" valign="top" /><entry align="center" valign="top" /></row></thead><tbody><row rowsep="0"><entry align="center">La³⁺</entry><entry align="center">544.15 (1:1)</entry><entry align="center">544.15</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Pr³⁺</entry><entry align="center">253.24 (1:1)</entry><entry align="center">253.24</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Nd³⁺</entry><entry align="center">247.59 (1:1)</entry><entry align="center">247.59</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Gd³⁺</entry><entry align="center">220.14 (1:1)</entry><entry align="center">220.14</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Sm³⁺</entry><entry align="center">185.88 (1:1)</entry><entry align="center">185.88</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Eu³⁺</entry><entry align="center">160.0 (1:1)</entry><entry align="center">160</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Tb³⁺</entry><entry align="center">146.34 (1:1)</entry><entry align="center">146.34</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Ho³⁺</entry><entry align="center">99.72 (1:1)</entry><entry align="center">99.72</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Dy³⁺</entry><entry align="center">63.65 (1:1)</entry><entry align="center">63.65</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Er³⁺</entry><entry align="center">62.61 (1:1)</entry><entry align="center">62.61</entry><entry align="center">No catalysis</entry></row><row><entry align="center">Tm³⁺</entry><entry align="center">49.34 (1:1)</entry><entry align="center">49.34</entry><entry align="center">No catalysis</entry></row></tbody></tgroup><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="41mm" /><colspec colnum="2" colname="col2" colwidth="42mm" colsep="0" /><colspec colnum="3" colname="col3" colwidth="42mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row rowsep="0"><entry align="center" valign="top"><b><i>Transition Metals</i></b></entry><entry align="center" valign="top" /><entry align="center" valign="top" /><entry align="center" valign="top" /></row></thead><tbody><row rowsep="0"><entry align="center">Zn²⁺</entry><entry align="center">48.22 (1:0:5)</entry><entry align="center">37.28</entry><entry align="center">5.42</entry></row><row rowsep="0"><entry align="center">Y³⁺</entry><entry align="center">32.56 (1:1)</entry><entry align="center">32.56</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Co²⁺</entry><entry align="center">25.70 (1:0:5)</entry><entry align="center">Catalysis, rate unknown^c</entry><entry align="center">Catalysis, rate unknown^c</entry></row><row rowsep="0"><entry align="center">Yb³⁺</entry><entry align="center">25.73(1:1)</entry><entry align="center">25.73</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Ni²⁺</entry><entry align="center">23.63 (1:0:5)</entry><entry align="center">12.18</entry><entry align="center">No catalysis</entry></row><row rowsep="0"><entry align="center">Cu²⁺</entry><entry align="center">No catalysis</entry><entry align="center">No catalysis</entry><entry align="center">Catalysis, rate unknown^c</entry></row><row><entry align="center">Sc³⁺</entry><entry align="center">No catalysis</entry><entry align="center">No catalysis</entry><entry align="center">No catalysis</entry></row></tbody></tgroup><tgroup cols="4" rowsep="0"><colspec colnum="1" colname="col1" colwidth="41mm" /><colspec colnum="2" colname="col2" colwidth="42mm" /><colspec colnum="3" colname="col3" colwidth="42mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><tbody><row><entry namest="col1" nameend="col4" align="justify">^a Introduced as commercially available triflate salts and used as received ^b 0.001 M in each of Mⁿ⁺ salt and added NaOCH₃^c Product formation was observed by final UV-vis spectra, but determination of exact value of the rate constant was not possible due to high absorbance of the solutions.</entry></row></tbody></tgroup></table></tables>

Example 2. La³⁺ And Zn²⁺-Catalyzed Solvolysis of Paraoxon in Propanols: Kinetics and NMR Studies

0101The solvolysis of paraoxon was studied in two alcohols that are less polar than methanol, namely 1-propanol and 2-propanol. In the case of 1-propanol, kinetics were monitored by UV-vis spectroscopic techniques following the appearance of the product of the solvolysis, 4-nitrophenol, at λ=335 nanometers. For example, at a concentration of La(OTf)₃ = 0.5mM = concentration of NaOCH₃, in the absence of any ligand, catalyzed solvolysis of paraoxon proceeded with a pseudo-first order rate constant of 2.1 x 10^-4 s^-1. At a concentration of Zn(OTf)₂ = 0.5mM = concentration of NaOCH₃, in the presence of equimolar diMephen, the catalyzed solvolysis of paraoxon proceeded with a pseudo-first rate constant of 1.93 x10^-4 s^-1.

0102The true catalytic nature of the system was demonstrated in the following Nuclear Magnetic Resonance (NMR) studies. To 2.5 mL of a solution of 1-propanol containing 5% methanol, and 0.5mM each of Zn(OTf)₂, diMephen and NaQMe was added 8.3 µL of paraoxon so that the latter's total concentration was 15.4 mM. The alcoholic solution was then incubated at room temperature for 72 hours after which the ³¹P NMR spectrum was recorded. This spectrum showed complete disappearance of the paraoxon starting material and complete formation of diethyl methyl phosphate (product of reaction with methanol) (δ = -0.3ppm) and diethyl 1-propyl phosphate (product of reaction with 1-propanol) (δ =-1.23 ppm). This indicates true catalysis with more than 30 turnovers in 72 hr. The solvents were removed, and the residues dissolved in deuterated methanol-d₄ and the ¹H NMR spectra were recorded showing the presence of the products: 4-nitrophenol, diethyl methyl phosphate and diethyl 1-propyl phosphates. Similarly, an NMR study was done such that 2.5 mL of 2-propanol containing 5% methanol, 0.5mM each of Zn(OTf)₂, diMephen and NaOMe was added 8.3 µL of paraoxon so that the latter's total concentration was 15.4 mM. The alcoholic solution was then incubated at room temperature for 72 hours after which the ³¹P NMR spectrum was recorded. This spectrum showed complete disappearance of the paraoxon starting material and complete formation of diethyl methyl phosphate (product of reaction with methanol) (δ = -0.3ppm) and diethyl 2-propyl phosphate (product of reaction with 2-propanol) (δ =-2.4ppm) was observed and formation of the products 4-nitrophenol, diethyl methyl phosphate and diethyl 2-propyl phosphate were confirmed by ¹H NMR.

0103The ratio of the two phosphate products from each of the propanol solvents was determined from their ³¹P NMR spectra and were found to be: MeOH reaction product: Propanol reaction product <tables id="tabl0002" num="0002"><table frame="none"><tgroup cols="2" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="33mm" /><colspec colnum="2" colname="col2" colwidth="14mm" /><tbody><row><entry>1-propanol reaction</entry><entry>1 : 2.8</entry></row><row><entry>2-propanol reaction</entry><entry>2.2 : 1.</entry></row></tbody></tgroup></table></tables>

0104These ratios show that if the medium for catalysis according to the invention is a mixture of alcohol, alkoxyalkanol and aminoalkanol, the reaction will select for the least hindered one. This factor may determine what an "effective amount" of methanol will be for a given system.

Example 3. La³⁺-Catalyzed Methanolysis of Paraoxon: Experimental Details

0105Paraoxon, when placed in an appropriately buffered methanol solution containing La³⁺ ions held in a <maths id="math0027"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0036.tif" /></maths> region between 7 and 11, underwent rapid methanolysis at ambient temperature to produce diethyl methyl phosphate and p-nitrophenol. A detailed reaction scheme is given in Scheme 1. <chemistry id="chem0010" num="0010"><img file="EP1613402B1_D0037.tif" /></chemistry>

0106To two mL of dry methanol at ambient temperature was added N-ethylmorpholine (25.5 µL or 23 mg) half neutralized with 11.4 M HClO4 (8.6µL) so that the final total buffer concentration was 0.1 M. To this was added 16.0 mg of paraoxon. The ³¹P NMR spectrum showed a single signal at δ-6.35 ppm. To the resulting mixture was added 12.9 mg of La(O₃SCF₃)₃ and 40 µL of 0.5 M NaOCH₃ in methanol solution. At this point the concentration of paraoxon was 0.057 M and that of La(O₃SCF₃)₃ was 0.011 M and the measured <maths id="math0028"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0038.tif" /></maths> of the methanol solution was 8.75, essentially neutrality. This solution was allowed to stand for 10 minutes, after which time the ³¹P NMR spectrum indicated complete disappearance of the paraoxon signal and the appearance of a new signal at δ 0.733 ppm corresponding to diethyl methyl phosphate. The ¹H NMR spectrum indicated complete disappearance of the starting material and full release of free p-nitrophenol.

Example 4. La³⁺ -Catalyzed Methanolysis of G-agent: A Prophetic Example

0107To 200 mL of methanol is added 2.55 mL of N-ethylmorpholine (2.3 g) and 0.86 mL of 11.4 M HClO₄ to bring the total buffer concentration to 0.1 M. To this solution is added 1.29 g of La(O₃SCF₃)₃ and 4 mL of a 0.5 M solution of NaOCH₃ in methanol.

0108To the above solution is added 2 g of the G-agent Sarin (0.016 moles, 0.08 M) and the solution is allowed to stand at ambient temperature for 15 minutes. It is expected that analysis of the resulting solution would indicate substantially complete disappearance of Sarin. This reaction may be inhibited by F^- in which case Ca²⁺ may be added to the reaction solution to precipitate this inhibitory product.

Example 5. La³⁺-Catalyzed Methanolysis of Paraoxon: Kinetics

0109The kinetics of the alcoholysis degradation reaction have been thoroughly investigated using the pesticide paraoxon. For methanolysis with dimeric lanthanum catalysts at 25°C, as little as 10^-3 M of the catalytic specie(s) promotes the methanolysis reaction by ~10⁹-fold relative to the background reaction at a neutral <maths id="math0029"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0039.tif" /></maths> of ∼8.5. The uncatalyzed methoxide-promoted reaction of paraoxon proceeds with the second order rate constant, k₂^OCH3 of 0.011 M^-1s^-1 determined from concentrations of NaOCH₃ between 1 x 10^-2 M and 4 x 10^-2 M. Methanolysis of paraoxon is markedly accelerated in the presence of La³⁺ with an observed second order rate constant, k₂^obs of ~17.5 M^-1s^-1 at the near neutral <maths id="math0030"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0040.tif" /></maths> of 8.23. Assuming that the methoxide reaction persists at <maths id="math0031"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0041.tif" /></maths> 8.23, the acceleration afforded to the methanolysis of paraoxon at that <maths id="math0032"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0042.tif" /></maths> by a 2 x 10^-3 M solution of La(O₃SCF₃)₃ is 1.1 x 10⁹-fold giving a half-life time of 20 seconds. The acceleration is 2.3 x 10⁹-fold at <maths id="math0033"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0043.tif" /></maths> 7.72 and 2.7 x 10⁸-fold at <maths id="math0034"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0044.tif" /></maths> 8.96.

0110UV kinetics of the methanolysis of paraoxon were monitored at 25 °C by observing the rate of loss of paraoxon at 268 nm or by the rate of appearance of <i>p</i>-nitrophenol at 313 nm or 328 nm at a concentration of paraoxon = 2.04 x 10^-5 M using an OLIS^® -modified Cary 17 UV-vis spectrophotometer. The concentration of La(O₃SCF₃)₃ was varied from 8 x10^-6 M to 4.8 x 10^-3 M. All reactions were followed to at least three half-times and found to exhibit good pseudo-first order rate behavior. The pseudo-first order rate constants (k_obs) were evaluated by fitting the Absorbance vs. time traces to a standard exponential model.

0111The kinetics were determined under buffered conditions. Buffers were prepared from N, N-dimethylaniline <maths id="math0035"><math display="inline"><mfenced><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo mathvariant="normal">=</mo><mn mathvariant="normal">5.00</mn></mfenced><mo mathvariant="normal">,</mo></math><img file="EP1613402B1_D0045.tif" /></maths> 2,6-lutidine <maths id="math0036"><math display="inline"><mfenced><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo mathvariant="normal">=</mo><mn mathvariant="normal">6.70</mn></mfenced><mo mathvariant="normal">,</mo></math><img file="EP1613402B1_D0046.tif" /></maths> N-methylimidazole <maths id="math0037"><math display="inline"><mrow><mo>(</mo><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></mrow><mo>=</mo></math><img file="EP1613402B1_D0047.tif" /></maths><maths id="math0038"><math display="inline"><mrow><mn>7.60</mn><mo>)</mo></mrow><mo>,</mo></math><img file="EP1613402B1_D0048.tif" /></maths> N-ethylmorpholine <maths id="math0039"><math display="inline"><mfenced><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo mathvariant="normal">=</mo><mn mathvariant="normal">8.60</mn></mfenced></math><img file="EP1613402B1_D0049.tif" /></maths> and triethylamine <maths id="math0040"><math display="inline"><mfenced><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo mathvariant="normal">=</mo><mn mathvariant="normal">10.78</mn></mfenced><mn>.</mn></math><img file="EP1613402B1_D0050.tif" /></maths> Due to the fact that added counterions can ion-pair with La³⁺ ions and affect its speciation in solution, ionic strength was controlled through neutralization of the buffer and not by added salts. The total concentration of buffer varied between 7 x 10^-3 M and 3 x 10^-2 M, and the buffers were partially neutralized with 70 % HClO₄ to keep the concentration of ClO₄^- at a low but constant value of 5 x 10^-3 M which leads to a reasonably constant ionic strength in solution. With the concentration of La³⁺ > 5 x 10^-4 M at <maths id="math0041"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>></mo><mn>7.0</mn><mo>,</mo></math><img file="EP1613402B1_D0051.tif" /></maths> the metal ion was partially neutralized by adding an appropriate amount of NaOMe to help control the <maths id="math0042"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0052.tif" /></maths> at the desired value. <maths id="math0043"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0053.tif" /></maths> measurements were performed before and after each experiment and in all cases the values were consistent to within 0.1 units.

0112Shown in <figref idref="f0002">Figure 2</figref> are three representative plots of the pseudo-first order rate constants (k_obs) for methanolysis of paraoxon as a function of added concentration of La(O₃SCF₃)₃ at <maths id="math0044"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0054.tif" /></maths> 7.72, 8.23 and 8.96. (For original k_obs vs. concentration of La³⁺ kinetic data see Tables 2-12). <tables id="tabl0003" num="0003"><table frame="all"><title>Table 2 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon (2.04 x 10^-5 M) at 25 °C; <maths id="math0045"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0055.tif" /></maths> 5.15 [dimethylaniline buffer] = 1.00 x 10^-2 M, λ = 328 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>3.11 E-07</entry></row><row><entry>6.00E-05</entry><entry>5.46E-07</entry></row><row><entry>8.00E-05</entry><entry>4.90E-07</entry></row><row><entry>2.00E-04</entry><entry>1.17E-05</entry></row><row><entry>4.00E-04</entry><entry>2.46E-05</entry></row><row><entry>6.00E-04</entry><entry>3.78E-05</entry></row><row><entry>8.00E-04</entry><entry>5.34E-05</entry></row><row><entry>1.00E-03</entry><entry>6.13E-05</entry></row><row><entry>1.20E-03</entry><entry>7.72E-05</entry></row></tbody></tgroup></table></tables><tables id="tabl0004" num="0004"><table frame="all"><title>Table 3 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon (2.04 x 10^-5M) at 25 °C; <maths id="math0046"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0056.tif" /></maths> 5.58 [dimethylaniline buffer] = 2.00 x 10^-2M, λ = 328 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">K_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>5.37E-06</entry></row><row><entry>6.00E-05</entry><entry>6.23E-06</entry></row><row><entry>8.00E-05</entry><entry>5.63E-06</entry></row><row><entry>2.00E-04</entry><entry>8.33E-06</entry></row><row><entry>4.00E-04</entry><entry>4.28E-05</entry></row><row><entry>6.00E-04</entry><entry>6.93E-05</entry></row><row><entry>8.00E-04</entry><entry>9.48E-05</entry></row><row><entry>1.00E-03</entry><entry>1.05E-04</entry></row><row><entry>1.20E-03</entry><entry>1.26E-04</entry></row></tbody></tgroup></table></tables><tables id="tabl0005" num="0005"><table frame="all"><title>Table 4 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon (2.04x 10^-5M) at 25 °C; <maths id="math0047"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0057.tif" /></maths> 5.82 [dimethylaniline buffer] = 2.93 x 10^-2 M, λ = 328 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>1.15E-05</entry></row><row><entry>6.00E-05</entry><entry>1.71E-06</entry></row><row><entry>8.00E-05</entry><entry>2.52E-06</entry></row><row><entry>2.00E-04</entry><entry>3.13E-05</entry></row><row><entry>4.00E-04</entry><entry>7.11 E-05</entry></row><row><entry>6.00E-04</entry><entry>1.15E-04</entry></row><row><entry>8.00E-04</entry><entry>1.92E-04</entry></row><row><entry>1.00E-03</entry><entry>2.17E-04</entry></row><row><entry>1.20E-03</entry><entry>3.07E-04</entry></row></tbody></tgroup></table></tables><tables id="tabl0006" num="0006"><table frame="all"><title>Table 5 -</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis ofparaoxon(2.04 x 10^-5M) at 25 °C; <maths id="math0048"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0058.tif" /></maths> 6.69 [2,6-Lutidine buffer] = 6.61 x 10^-3 M, λ = 313 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>1.18E-05</entry></row><row><entry>6.00E-05</entry><entry>3.13E-05</entry></row><row><entry>8.00E-05</entry><entry>4.43E-05</entry></row><row><entry>2.00E-04</entry><entry>1.21 E-04</entry></row><row><entry>4.00E-04</entry><entry>3.04E-04</entry></row><row><entry>6.00E-04</entry><entry>5.24E-04</entry></row><row><entry>8.00E-04</entry><entry>8.00E-04</entry></row><row><entry>1.00E-03</entry><entry>9.31 E-04</entry></row><row><entry>1.20E-03</entry><entry>1.18E-03</entry></row></tbody></tgroup></table></tables><tables id="tabl0007" num="0007"><table frame="all"><title>Table 6 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis ofparaoxon(2.04 x 10^-5M) at 25 °C, <maths id="math0049"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0059.tif" /></maths> 7.10 [2,6-Lutidine buffer] = 1.00 x 10^-2 M, λ = 313 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>2.58E-05</entry></row><row><entry>6.00E-05</entry><entry>4.86E-05</entry></row><row><entry>8.00E-05</entry><entry>6.68E-05</entry></row><row><entry>2.00E-04</entry><entry>2.62E-04</entry></row><row><entry>4.00E-04</entry><entry>7.22E-04</entry></row><row><entry>6.00E-04</entry><entry>1.26E-03</entry></row><row><entry>8.00E-04</entry><entry>1.88E-03</entry></row><row><entry>1.00E-03</entry><entry>2.14E-03</entry></row><row><entry>1.20E-03</entry><entry>2.67E-03</entry></row></tbody></tgroup></table></tables><tables id="tabl0008" num="0008"><table frame="all"><title>Table 7 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis ofparaoxon(2.04 x 10^-5M) at 25 °C; <maths id="math0050"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0060.tif" /></maths> 7.30 [<i>N</i>-methyimidazole buffer] = 6.67 x 10^-3 M, λ = 268 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>8.00E-06</entry><entry>3.83E-05</entry></row><row><entry>2.00E-05</entry><entry>1.50E-05</entry></row><row><entry>8.00E-05</entry><entry>7.95E-05</entry></row><row><entry>2.00E-04</entry><entry>7.17E-04</entry></row><row><entry>4.00E-04</entry><entry>1.58E-03</entry></row><row><entry>8.00E-04</entry><entry>3.97E-03</entry></row><row><entry>1.60E-03</entry><entry>8.45E-03</entry></row><row><entry>3.20E-03</entry><entry>1.70E-02</entry></row><row><entry>4.80E-03</entry><entry>2.28E-02</entry></row></tbody></tgroup></table></tables><tables id="tabl0009" num="0009"><table frame="all"><title>Table 8 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon(2.04 x 10^-5M) at 25 °C.; <maths id="math0051"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0061.tif" /></maths> 7.72 [<i>N</i>-methyimidazole buffer] = 1.00 x 10^-2 M, λ = 268 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>2.00E-05</entry><entry>2.83E-06</entry></row><row><entry>8.00E-05</entry><entry>1.18E-04</entry></row><row><entry>2.00E-04</entry><entry>9.30E-04</entry></row><row><entry>4.00E-04</entry><entry>3.49E-03</entry></row><row><entry>6.00E-04</entry><entry>6.10E-03</entry></row><row><entry>8.00E-04</entry><entry>8.46E-03</entry></row><row><entry>1.20E-03</entry><entry>1.22E-02</entry></row><row><entry>1.60E-03</entry><entry>1.51 E-02</entry></row></tbody></tgroup></table></tables><tables id="tabl0010" num="0010"><table frame="all"><title>Table 9 -</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis ofparaoxon(2.04 x 10^-5M) at 25 °C; <maths id="math0052"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0062.tif" /></maths> 8.23 [<i>N</i>-methyimidazole buffer] = 2.00 x 10^-2 M, λ = 268 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>5.08E-05</entry></row><row><entry>6.00E-05</entry><entry>9.74E-05</entry></row><row><entry>8.00E-05</entry><entry>1.63E-04</entry></row><row><entry>2.00E-04</entry><entry>1.94E-03</entry></row><row><entry>4.00E-04</entry><entry>5.65E-03</entry></row><row><entry>6.00E-04</entry><entry>1.01 E-02</entry></row><row><entry>8.00E-04</entry><entry>1.26E-02</entry></row><row><entry>1.00E-03</entry><entry>1.66E-02</entry></row><row><entry>1.20E-03</entry><entry>1.98E-02</entry></row></tbody></tgroup></table></tables><tables id="tabl0011" num="0011"><table frame="all"><title>Table 10 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon (2.04 x 10^-5M) at 25 °C; <maths id="math0053"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0063.tif" /></maths> 8.96 [<i>N</i>-ethylmorpholine buffer] = 2.00 x 10^-2 M, λ = 268 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>8.50E-05</entry></row><row><entry>6.00E-05</entry><entry>2.03E-04</entry></row><row><entry>8.00E-05</entry><entry>3.75E-04</entry></row><row><entry>2.00E-04</entry><entry>2.70E-03</entry></row><row><entry>4.00E-04</entry><entry>8.25E-03</entry></row><row><entry>6.00E-04</entry><entry>1.38E-02</entry></row><row><entry>8.00E-04</entry><entry>1.76E-02</entry></row><row><entry>1.00E-03</entry><entry>2.14E-02</entry></row><row><entry>1.20E-03</entry><entry>2.65E-02</entry></row></tbody></tgroup></table></tables><tables id="tabl0012" num="0012"><table frame="all"><title>Table 11 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon (2.04 x 10^-5M) at 25 °C; <maths id="math0054"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0064.tif" /></maths> 10.34 [triethythlamine buffer] = 6.67 x 10^-3 M, λ = 268 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>1.75E-04</entry></row><row><entry>6.00E-05</entry><entry>4.52E-04</entry></row><row><entry>8.00E-05</entry><entry>1.43E-03</entry></row><row><entry>2.00E-04</entry><entry>4.75E-03</entry></row><row><entry>4.00E-04</entry><entry>8.08E-03</entry></row><row><entry>6.00E-04</entry><entry>1.10E-02</entry></row><row><entry>8.00E-04</entry><entry>1.28E-02</entry></row><row><entry>1.00E-03</entry><entry>1.42E-02</entry></row><row><entry>1.20E-03</entry><entry>1.66E-02</entry></row></tbody></tgroup></table></tables><tables id="tabl0013" num="0013"><table frame="all"><title>Table 12 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="84mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed pseudo-first order rate constants for La³⁺ catalyzed methanolysis of paraoxon (2.04 x 10^-5M) at 25 °C; <maths id="math0055"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0065.tif" /></maths> 10.97 [triethylamine buffer] = 1.00 x 10^-2 M, λ = 268 nm.</entry></row><row><entry valign="top">La(O₃SCF₃)₃, M</entry><entry valign="top">k_obs, s^-1</entry></row></thead><tbody><row><entry>4.00E-05</entry><entry>1.60E-04</entry></row><row><entry>6.00E-05</entry><entry>3.98E-04</entry></row><row><entry>8.00E-05</entry><entry>5.21E-04</entry></row><row><entry>2.00E-04</entry><entry>3.49E-03</entry></row><row><entry>4.00E-04</entry><entry>5.42E-03</entry></row><row><entry>6.00E-04</entry><entry>6.23E-03</entry></row><row><entry>8.00E-04</entry><entry>7.57E-03</entry></row><row><entry>1.00E-03</entry><entry>8.17E-03</entry></row><row><entry>1.20E-03</entry><entry>9.15E-03</entry></row></tbody></tgroup></table></tables>

0113As was observed in our earlier studies of the La³⁺-catalyzed methanolysis of esters (Neverov <i>et al.,</i> 2001) and acetyl imidazole, (Neverov <i>et al.,</i> 2000 &amp; Neverov <i>et al</i>., 2001) these plots exhibit two domains, a nonlinear one at low concentration of La³⁺ suggestive of a second order behavior in La³⁺, followed by a linear domain at higher concentration of La³⁺. Following the approach we have used before, (Neverov <i>et al.,</i> 2001, Neverov <i>et al.,</i> 2000 &amp; Neverov <i>et al.,</i> 2001) we use the linear portion of these plots to calculate the observed second order rate constants (k₂^obs) for La³⁺-catalyzed methanolysis of paraoxon at the various <maths id="math0056"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0066.tif" /></maths> values. These are tabulated in Table 13 and graphically presented in <figref idref="f0003">Figure 3</figref> as a log k₂^obs vs. <maths id="math0057"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0067.tif" /></maths> plot which is seen to have a skewed bell-shape, maximizing at <maths id="math0058"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>∼</mo><mn>9.</mn></math><img file="EP1613402B1_D0068.tif" /></maths><tables id="tabl0014" num="0014"><table frame="all"><title>Table 13 --</title><tgroup cols="2"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="82mm" /><thead><row><entry namest="col1" nameend="col2" align="left" valign="top">Observed second order rate constants for La³⁺ catalyzed methanolysis of paraoxon at various <maths id="math0059"><math display="inline"><mrow><mmultiscripts><mrow><mi mathvariant="normal">pH</mi></mrow><mprescripts /><mrow><mi mathvariant="normal">s</mi></mrow><mrow><mi mathvariant="normal">s</mi></mrow></mmultiscripts></mrow></math><img file="EP1613402B1_D0069.tif" /></maths> values, T = 25 °C.</entry></row><row><entry valign="top"><maths id="math0060"><math display="block"><mrow><mmultiscripts><mrow><mi mathvariant="normal">pH</mi></mrow><mprescripts /><mrow><mi mathvariant="normal">s</mi></mrow><mrow><mi mathvariant="normal">s</mi></mrow></mmultiscripts></mrow></math><img file="EP1613402B1_D0070.tif" /></maths></entry><entry valign="top">k₂^obs, M^-1 s^-1a</entry></row></thead><tbody><row><entry>5.15</entry><entry>0.065 ± 0.002</entry></row><row><entry>5.58</entry><entry>0.11 ± 0.01</entry></row><row><entry>5.82</entry><entry>0.28 ± 0.02</entry></row><row><entry>6.69</entry><entry>1.07 ± 0.04</entry></row><row><entry>7.10</entry><entry>2.4 ± 0.1</entry></row><row><entry>7.30</entry><entry>5.6 ± 0.1</entry></row><row><entry>7.72</entry><entry>11.3 ± 0.5</entry></row><row><entry>8.23</entry><entry>17.5 ± 0.5</entry></row><row><entry>8.96</entry><entry>23.2 ± 0.9</entry></row><row><entry>10.34</entry><entry>11.4 ± 0.8</entry></row><row><entry>10.97</entry><entry>5.4 ± 0.4</entry></row></tbody></tgroup><tgroup cols="2" rowsep="0"><colspec colnum="1" colname="col1" colwidth="82mm" /><colspec colnum="2" colname="col2" colwidth="82mm" /><tbody><row><entry namest="col1" nameend="col2" align="justify">^a k₂ determined from slope of the k_obs vs. [La³⁺]_total plots at higher [La³⁺] at each <maths id="math0061"><math display="inline"><mrow><mmultiscripts><mrow><mi mathvariant="normal">pH</mi></mrow><mprescripts /><mrow><mi mathvariant="normal">s</mi></mrow><mrow><mi mathvariant="normal">s</mi></mrow></mmultiscripts><mn>.</mn></mrow></math><img file="EP1613402B1_D0071.tif" /></maths></entry></row></tbody></tgroup></table></tables>

Example 6. La³⁺ Catalyst Species: Stoichiometries

0114As shown in <figref idref="f0003">Figure 3</figref>, the reactivity of the catalytic species increases with increasing <maths id="math0062"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0072.tif" /></maths> up to ~9.0. This fact seems to indicate the involvement of at least one methoxide, although the general shape of the plot suggests the catalytic involvement of more than one species. Since the second order k₂^obs values for the La³⁺-catalyzed reactions in the neutral <maths id="math0063"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0073.tif" /></maths> region are some 1000- to 2300-fold larger than the methoxide k₂^OCH3, the role of the metal ion is not to simply decrease the <maths id="math0064"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0074.tif" /></maths> of any bound CH₃OH molecules that act as nucleophiles. This points to a dual role for the metal, such as acting as a Lewis acid and as a source of the nucleophile.

0115Detailed mechanistic evaluation of kinetic data requires additional information such as the stoichiometries and concentrations of various La³⁺-containing species that are formed as a function of both <maths id="math0065"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0075.tif" /></maths> and concentration of La³⁺. A study of the potentiometric titration of La³⁺ was performed under various conditions, with the concentration of La(O₃SCF₃)₃ from 1 x 10^-3 M to 3 x 10^-3 M, which is within the concentration range where the kinetic plots of k_obs vs. concentration of La³⁺ in this study are linear. The potentiometric titration data were successfully analyzed with the computer program Hyperquad™ (Gans <i>et al.,</i> 1996) through fits to the dimer model presented in equation(1) where n assumes values of 1-5, to give the various stability constants <maths id="math0066"><math display="inline"><mfenced><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">n</mi></msub><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></mfenced></math><img file="EP1613402B1_D0076.tif" /></maths> that are defined in equation(2). On the basis of the five computed stability constants, log <maths id="math0067"><math display="inline"><mmultiscripts><msub><mi mathvariant="normal">K</mi><mrow><mn>1</mn><mo>-</mo><mn>5</mn></mrow></msub><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts><mo>=</mo><mn>11.66</mn><mo>±</mo><mn>0.04</mn><mo>,</mo><mspace width="1em" /><mn>20.86</mn><mo>±</mo><mn>0.07</mn><mo>,</mo><mspace width="1em" /><mn>27.52</mn><mo>±</mo><mn>0.09</mn><mo>,</mo><mspace width="1em" /><mn>34.56</mn><mo>±</mo></math><img file="EP1613402B1_D0077.tif" /></maths> 0.20 and 39.32 ± 0.26, we constructed the speciation diagram shown in <figref idref="f0004">Figure 4</figref> which presents the distribution of the various La₂(OCH₃)_n forms as a function of <maths id="math0068"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0078.tif" /></maths> at [La(O₃SCF₃)₃]_total = 2 x 10^-3 M. <chemistry id="chem0011" num="0011"><img file="EP1613402B1_D0079.tif" /></chemistry><chemistry id="chem0012" num="0012"><img file="EP1613402B1_D0080.tif" /></chemistry>

0116Also included on <figref idref="f0004">Figure 4</figref> as data points (•) are the k₂^obs data for La³⁺-catalyzed methanolysis of paraoxon which predominantly coincide with the <maths id="math0069"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0081.tif" /></maths> distribution of La³⁺₂(OCH₃)₂ but with an indication that higher order species such as La³⁺₂(OCH₃)₃ and/or La³⁺₂(OCH₃)₄ have some activity. To determine the activities for the various La³⁺₂(OCH₃)_n we analyzed the k₂^obs data as a linear combination of individual rate constants (equation(3).         k₂^obs = (k₂^2:1[La³⁺₂(OCH₃)₁] + k₂^2:2[La³⁺₂(OCH₃)₂] + ... ...k₂^2:<i>n</i>[La³⁺₂(OCH₃)<i>_n</i>])/[La³⁺ (O₃SCF₃)₃]_total     (3) where k₂^2:1, k₂^2:2,...... ,k₂^2:<i>n</i> are the second order rate constants for the methanolysis of paraoxon promoted by the various dimeric forms. Given in Table 14 are the best-fit rate constants produced by fitting under various assumptions. <tables id="tabl0015" num="0015"><table frame="all"><title>Table 14 -- Computed second order rate constants for various dimeric forms La₂(OCH₃)_n, catalyzing the methanolysis of paraoxon, as determined from fits of k₂^obs data in Table 13 to equation(3), [La(O₃SCF₃)₃]_total = 2 x 10^-3 M, T=25 °C.</title><tgroup cols="6"><colspec colnum="1" colname="col1" colwidth="28mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="27mm" /><colspec colnum="4" colname="col4" colwidth="27mm" /><colspec colnum="5" colname="col5" colwidth="29mm" /><colspec colnum="6" colname="col6" colwidth="30mm" /><thead><row><entry valign="top">Fit #</entry><entry valign="top">K₂^2:1 (M^-1s^-1)</entry><entry valign="top">k₂^2:2 (M^-1s^-1)</entry><entry valign="top">k₂^2:3) (M^-1s^-1)</entry><entry valign="top">k₂^2:4(M^-1s^-1)</entry><entry valign="top">R²</entry></row></thead><tbody><row><entry>1^a</entry><entry>15.9 ± 3.2</entry><entry>49.8 ± 2.2</entry><entry>67.2 ± 36.0</entry><entry>8.8 ± 11.2</entry><entry>0.9976</entry></row><row><entry>2^b</entry><entry>18.4 ± 5.4</entry><entry>47.2 ± 2.4</entry><entry>110.4 ± 11.8</entry><entry>-</entry><entry>0.9861</entry></row><row><entry>3^c</entry><entry>-</entry><entry>51.4 ± 2.8</entry><entry>103.4 ± 17</entry><entry>-</entry><entry>0.9664</entry></row></tbody></tgroup><tgroup cols="6" rowsep="0"><colspec colnum="1" colname="col1" colwidth="28mm" /><colspec colnum="2" colname="col2" colwidth="27mm" /><colspec colnum="3" colname="col3" colwidth="27mm" /><colspec colnum="4" colname="col4" colwidth="27mm" /><colspec colnum="5" colname="col5" colwidth="29mm" /><colspec colnum="6" colname="col6" colwidth="30mm" /><tbody><row><entry namest="col1" nameend="col6" align="justify">^a Including all dimeric forms except La₂(OCH₃)₀ and La₂(OCH₃)₆. Computed value of k₂^2:5 = (-3.4 ± 10.8) M^-1s^-1. ^b Computed without the involvement of k₂^2:4 and k₂^2:5. ^c Computed without the involvement of k₂^2:1, k₂^2:4 and k₂^2:5.</entry></row></tbody></tgroup></table></tables>

0117We have analyzed the titration data to determine speciation for a total La³⁺ concentration of 2 x 10^-3 M which is in the general concentration range where the kinetic behavior of the methanolysis of paraoxon is linearly dependent on concentration of La³⁺, and thus largely controlled by dimeric species. In <figref idref="f0005">Figure 5</figref> are presented kinetic plots for all three species (La³⁺₂(OCH₃)₁, La³⁺₂(OCH₃)₂ and La³⁺₂(OCH₃)₃) based on their second order rate constants for catalyzed methanolysis of paraoxon, and their concentrations as a function of <maths id="math0070"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mn>.</mn></math><img file="EP1613402B1_D0082.tif" /></maths> Their combined reactivities as a function of <maths id="math0071"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0083.tif" /></maths> give the predicted log k₂^obs vs. <maths id="math0072"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0084.tif" /></maths> profile shown as the dashed line on <figref idref="f0005">Figure 5</figref>. The computed line is also presented in the plot in <figref idref="f0002">Figure 2</figref> of log k₂^obs vs. <maths id="math0073"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mn>.</mn></math><img file="EP1613402B1_D0085.tif" /></maths> Included on <figref idref="f0005">Figure 5</figref> as data points (□) are the actual experimentally-determined values which fit on the computed profile with remarkable fidelity, strongly indicating that these three species are responsible for the observed activity. At <maths id="math0074"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0086.tif" /></maths> values below 9, the La³⁺₂(OCH₃)₂ complex accounts for essentially all the activity, while at <maths id="math0075"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0087.tif" /></maths> 10 and above, the dominantly active form is La³⁺₂(OCH₃)₄.

0118Through joint consideration of the k_obs vs. concentration of La³⁺ kinetics and a detailed analysis of the potentiometric titration data for La³⁺ in methanol, we have determined that the dominant species in solution are dimers of the general formula La₂(OCH₃)_n where n = 1-5, and three of these dimers, La³⁺₂(OCH₃)₁, La³⁺₂(OCH₃)₂ and La³⁺₂(OCH₃)₃, account for all the catalytic activity with La³⁺₂(OCH₃)₂ being the most important form at <maths id="math0076"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>&lt;</mo><mn>9.</mn></math><img file="EP1613402B1_D0088.tif" /></maths>

0119The <maths id="math0077"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0089.tif" /></maths> dependence of the metal ion is such that several complexes are present with their individual concentrations maximized at different <maths id="math0078"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0090.tif" /></maths> values. It is only through complementary analyses of the kinetic and potentiometric titration data that one can satisfactorily explain the kinetic behavior of complex mixtures having several <maths id="math0079"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0091.tif" /></maths> dependent forms.

0120Through a series of detailed potentiometric titrations of the {La³⁺:^-OMe} system in methanol, and through studies of the kinetics of methanolysis of paraoxon as a function of La³⁺ concentration and <maths id="math0080"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>,</mo></math><img file="EP1613402B1_D0092.tif" /></maths> it has been determined that in this {La³⁺:^-OMe:paraoxon} system there are two dominant stoichiometries of catalysts, La₂(OCH₃)₂ with a proposed structure of a bis-methoxy bridged dimer between <maths id="math0081"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0093.tif" /></maths> 8 and 10 (maximum concentration of ~80% at <maths id="math0082"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0094.tif" /></maths> 8.9), and La₂(OCH₃)₃ with a proposed structure of tris-methoxy bridged dimer)

0121between <maths id="math0083"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0095.tif" /></maths> 9 and 11 (maximum concentration of ~25% at <maths id="math0084"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0096.tif" /></maths> 10). Above a total [La³⁺] of about 2 x 10^-4 M, these species form spontaneously in solution without any requirement for added ligands, so that in the millimolar concentration range, dimer formation is essentially complete.

0122Given that we know the dominantly active forms are La³⁺₂(OCH₃)₂ and La³⁺₂(OCH₃)₃, we can derive a kinetic expression (equation4) which gives values of k₂^2:2 = 51.4 ± 2.8 and k₂^2:3 = 103 ± 17 M^-1s^-1 for the second order rate constants for methanolysis of paraoxon catalyzed by the bis-methoxy dimer and the tris-methoxy dimer respectively (Table 14).         k₂^obs=k₂^2:2[La³⁺₂(OCH₃)₂]+k₂^2:3[La³⁺₂(OCH₃)₃]     (4)

0123The net effect of this is that a solution containing 2 x 10^-3 M of La(OTf)₃, generating 1 x 10^-3 M of total dimer, will catalyze the methanolysis of paraoxon with t_1/2 values of 30s, 20s, 15s and 30s at respective <maths id="math0085"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0097.tif" /></maths> values of 7.7, 8.2, 9.0 and 10.3. By way of reference, at <maths id="math0086"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0098.tif" /></maths> 7.7 the methoxide background rate constant is (0.011 M^-1s^-1 x 10^-9 M [OCH₃^-]) = 1.1 x 10^-11 s^-1, corresponding to a t_1/2 of 1994 years, so that the acceleration afforded by the La³⁺ catalyst is some two billion-fold at that <maths id="math0087"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mn>.</mn></math><img file="EP1613402B1_D0099.tif" /></maths>

Example 7. La³⁺ Catalysis: Proposed Mechanism

0124We have shown above that La³⁺ in methanol is a remarkably effective catalyst for the decomposition of paraoxon and that there are three forms of dimeric species which have maximal activities at different <maths id="math0088"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0100.tif" /></maths> values. Of these, the highest activity is attributed to La³⁺₂(^-OCH₃)₂ operating most effectively in the neutral <maths id="math0089"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0101.tif" /></maths> region between 7.7 and 9.2 (neutral <maths id="math0090"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0102.tif" /></maths> in methanol is 8.4). Given in <figref idref="f0001">Figure 1A</figref> is a proposed mechanism by which La³⁺₂(^-OCH₃)₂, as a bis methoxy bridged dimer, promotes the methanolysis of paraoxon. Although none of our k_obs vs. [La³⁺] kinetics profiles shows saturation behavior indicative of formation of a strong complex between paraoxon and La³⁺, given the well-known coordinating ability of trialkyl phosphates to lanthanide series metal ions and actinide series metal ions, a first step probably involves transient formation of a {paraoxon:La³⁺₂:(^-OCH₃)₂} complex. Since it is unlikely that the bridged methoxy is sufficiently nucleophilic to attack the coordinated phosphate, in the proposed mechanism, one of the La³⁺-OCH₃-La³⁺ bridges opens to reveal a singly coordinated {La³⁺;^-OCH₃} adjacent to a Lewis acid coordinated phosphate which then undergoes intramolecular nucleophilic addition followed by ejection of the <i>p</i>-nitrophenoxy leaving group. La³⁺₂(OCH³)₂ is regenerated from the final product by a simple deprotonation of one of the methanols of solvation and dissociation of the phosphate product, (EtO)₂P(O)OCH₃.

Example 8. Mⁿ⁺-Catalyzed Ethanolysis of O,O'-diethyl-S-p-nitrophenylphosphorothioate: Experimental Details, Kinetics and NMR Studies

0125O,O- diethyl-S-p-nitrophenyl phosphorothiolate, when placed in an appropriately buffered methanol solution containing La³⁺ and ^-OCH₃ ions held in the <maths id="math0091"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0103.tif" /></maths> region between 7 and 11, underwent rapid methanolysis at ambient temperature to produce diethyl methyl phosphate and 5-mercapto-2-nitrobenzene. A detailed reaction scheme is given in Scheme 2 and reaction conditions are detailed below. <chemistry id="chem0013" num="0013"><img file="EP1613402B1_D0104.tif" /></chemistry>

0126To 4.9 mL of anhydrous methanol at ambient temperature was added N-ethylmorpholine (63.8 µL or 57.7 mg) half neutralized with 11.4 M HClO₄ (21.5 µL), so that the final total buffer concentration was 0.1 M in 4.95mL solution. The measured <maths id="math0092"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0105.tif" /></maths> of the buffer solution was 8.89. To 0.8 mL of this buffer and 0.2 mL deuterated methanol was added 8.8 mg of O,O-diethyl-S-p-nitrophenyl phosphorothiolate. The ³¹P NMR spectrum of this solution showed a single signal at δ 22.39 ppm. Following NMR analysis, a 10 µL aliquot of a lanthanum ion/sodium methoxide/methanol solution was added which had been prepared by dissolving 16.4 mg La(O₃SCF₃)₃ in 56.9 µL of 0.5 M sodium methoxide methanol solution. At this point, the concentrations in the NMR tube were: 0.030 M phosphorothiolate, 0.1 M N-ethylmorpholine, 0.01 M sodium methoxide and 0.0098 M La(O₃SCF₃)₃. The ³¹P NMR spectrum, obtained 103 sec after addition of the aliquot indicated complete disappearance of the phosphorothiolate signal and the appearance of a new signal at δ 3.57 ppm, attributable to diethyl methyl phosphate in the presence of 0.0098 M La³⁺.

0127The absorbance of a 0.5 mL solution of methanol containing 1 mM of Cu(OTf)₂, 1 mM of [12]aneN_3, 0.5 mM of NaOCH₃ and 0.5 mM of O,O'-diethyl-S-p-nitrophenylphosphorothioate was monitored at 280 nm as a function of time. The reaction exhibited first order kinetics with k_obs = 4.3 x 10^-2 s^-1 (t_1/2 = 16 sec) corresponding to a 8.3 x 10⁷-fold acceleration over the background reaction at <maths id="math0093"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>=</mo><mn>8.41.</mn></math><img file="EP1613402B1_D0106.tif" /></maths>

0128The absorbance of a 2.5 mL solution of methanol containing 1 mM of Zn(OTf)₂, 1 mM of [12]aneN₃, 0.5 mM of NaOCH₃ and 0.5 mM of O,O'-diethyl-S-p-nitrophenylphosphorothioate was monitored at 280 nm as a function of time. The reaction exhibited first order kinetics with k_obs = 4.1 x 10^-4 s^-1 (t_1/2 = 28 min) corresponding to a 4.1 x 10⁵-fold acceleration over the background reaction at <maths id="math0094"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi>s</mi></mmultiscripts><mo>=</mo><mn>8.70.</mn></math><img file="EP1613402B1_D0107.tif" /></maths>

Example 9. La³⁺-Catalyzed Methanolysis of VX: A Prophetic Example

0129To 200 mL of methanol is added 2.55 mL of N-ethylmorpholine (2.3 g) and 0.86 mL of 11.4 M HClO₄ to bring the total buffer concentration to 0.1 M. To this solution is added 1.29 g of La(O₃SCF₃)₃ and 4 mL of a 0.5 M solution of NaOCH₃ in methanol.

0130To the above solution is added 2 g of VX (8.33 x 10^-3 moles, 0.041 M) and the solution is allowed to stand at ambient temperature for 15 minutes. It is expected that analysis of the resulting solution would indicate substantially complete disappearance of VX.

Example 10. M²⁺-Catalyzed Methanolysis of Fenitrothion

0131The activity of this system may be increased by adding equimolar amounts of bi- or tri-dentate ligands to complex Zn²⁺(^-OCH₃) and limit oligomerization of Zn²⁺(^-OCH₃)₂ in solution. The systems studied herein used methoxide and the ligands phen, diMephen and [12]aneN₃. The active forms of the metal ions at neutral <maths id="math0095"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0108.tif" /></maths> are Zn²⁺(^-OCH₃) with no added ligand and {Zn²⁺:L:(^-OCH₃)} when ligand (L) is present. In the case of phen ligand, decreasing the oligomerization does not prevent the formation Zn²⁺(^-OCH₃) dimers since the bulk of the material is now present as {LZn²⁺(^-OCH₃)₂Zn²⁺L} which is not catalytically active, but is in equilibrium with an active mononuclear form. The propensity to form the latter inactive dimers can be reduced either by increasing the steric interaction (ligand diMephen) or by changing the coordination number (ligand [12]aneN₃) in which cases the overall activity of the catalytic system increases. In the case of ligand diMephen, the dimerization is definitely reduced but the binding to the metal ion is not as strong as in the case of phen or [12]aneN3_, which means that there is some free Zn²⁺ in solution under the concentrations and <maths id="math0096"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0109.tif" /></maths> region where the catalyst is active.

0132A reaction scheme is given below (Scheme 3) for the methanolysis of fenitrothion where M²⁺ is a transition metal ion, most preferably Zn²⁺ or Cu²⁺. In a preferred embodiment a ligand is present, preferably a bidentate or tridentate ligand, most preferably [12]aneN₃ for Cu²⁺ and diMephen or [12]aneN₃ for Zn²⁺. <chemistry id="chem0014" num="0014"><img file="EP1613402B1_D0110.tif" /></chemistry>

0133As seen in <figref idref="f0005">Figures 6</figref> and <figref idref="f0006">7</figref>, Cu²⁺:(^-OCH₃) at 25 °C either alone or in the presence of equimolar [12]aneN_3, bpy or phen shows both great catalytic efficacy and specificity toward the P=S derivatives.

0134Apparently matching the hard/soft characteristics of the metal ion and the substrate is important in designing an effective catalytic system for P=S substrates. With due consideration for matching the hard/soft characteristics of the substrate and the metal ion, dramatic rate and selectivity can be achieved in the methanolysis of P=O vs. P=S phosphates.

Example 11. Zn²⁺-Catalyzed Methanolysis of Paraoxon and Fenitrothion

0135The methanolyses of paraoxon and fenitrothion were investigated as a function of added Zn(OTf)₂ or Zn(ClO₄)₂ in methanol at 25 °C either alone, or in the presence of equimolar concentration of ligands: phen, diMephen and [12]aneN_3. The catalysis requires the presence of methoxide, and when studied as a function of added [NaOCH₃], the rate constants (k_obs) for methanolysis with Zn²⁺ alone or in the presence of equimolar phen or diMephen, maximize at different [^-OCH₃]/[Zn²⁺]_total ratios of 0.3, 0.5 and 1.0 respectively. Plots of k_obs vs. [Zn²⁺]_t either alone or in the presence of equimolar ligands phen and diMephen at the [^-OCH₃]/[Zn²⁺]_total ratios corresponding to the rate maxima are curved and show a square root dependence on [Zn²⁺]_t. In the cases of phen and diMephen, this is explained as resulting from formation of a non-active dimer, formulated as a bis-µ-methoxide bridged form (L:Zn²⁺(^-OCH₃)₂Zn²⁺:L) in equilibrium with an active mononuclear form, L:Zn²⁺(^-OCH₃). In the case of the Zn²⁺:[12]aneN₃ system, no dimeric forms are present as can be judged by the strict linearity of the plots of k_obs vs. [Zn²⁺]_t in the presence of equimolar [12]aneN₃ and ^-OCH₃. Analysis of the potentiometric titration curves for Zn²⁺ alone and in the presence of the ligands allows calculation of the speciation of the various Zn²⁺ forms and shows that the binding to ligands phen and [12]aneN₃ is very strong, while the binding to ligand diMephen is weaker. This {Zn²⁺:[12]aneN₃:^-OMe} system exhibits excellent turnover of the methanolysis of paraoxon when the substrate is in excess. A mechanism for the catalyzed reactions is proposed (see <figref idref="f0001">Figure 1 B)</figref> which involves a dual role for the metal ion as a Lewis acid and source of nucleophilic Zn²⁺-bound ^-OCH₃.

Example 12. Zn²⁺-Catalyzed Methanolysis of Paraoxon and Fenitrothion and p-nitrophenyl acetate

0136A second set of methanolysis experiments was performed with three substrates, namely paraoxon, fenitrothion and p-nitrophenyl acetate, as a function of total added [Zn(ClO₄)₂] maintaining the [(^-OCH₃)]/[Zn²⁺]_total ratio at 0.3 with added NaOCH₃. The three plots shown in <figref idref="f0009">Figure 12</figref> all exhibit a similar curvature independent of the nature of the substrate. The curvature thus cannot be due to substrate binding and is modeled according to the overall process given in equation(5) where an active mononuclear form (assumed to be [Zn(OCH₃)]⁺ is in equilibrium with a non-active dimer. Given in equation (6) is the appropriate kinetic expression based on equation(5) which includes a possible methoxide dependent term (k_background) which is present for the most reactive substrate (p-nitrophenyl acetate) but not important for the phosphate triesters. This expression shows a square-root dependence on the [M²⁺]_total. Shown in <figref idref="f0007">Figure 9A and 9B</figref> are the concentration dependencies for the methanolysis of fenitrothion (<figref idref="f0007">Figure 9A</figref>) and paraoxon (<figref idref="f0007">Figure 9B</figref>) catalyzed by Zn²⁺ alone and in the presence of ligands phen and diMephen where the ratio of [(^-OCH₃)]/[Zn²⁺]_total is kept at a constant value (i.e. 0.3 for Zn²⁺ alone, 0.5 for phen, and 1.0 for diMephen).

0137These plots are also curved, not due to a saturation binding of the phosphorus triesters to the metal, but due to the monomer:dimer equilibrium given in equation(5). The lines through the <figref idref="f0007">Figure 9A, 9B</figref> data are derived on the basis of NLLSQ fits to equation(6) and yield the kinetic constants given in Table 16. As shown in <figref idref="f0010">Figure 13A</figref>, the kinetic dependence in the presence of ligand [12]aneN₃ is substantially linear and showns no evidence of monomer:dimer equilibrium. <chemistry id="chem0015" num="0015"><img file="EP1613402B1_D0111.tif" /></chemistry><maths id="math0097" num="(6)"><math display="block"><msub><mi mathvariant="normal">k</mi><mi>obs</mi></msub><mo mathvariant="normal">=</mo><mfenced open="{" close="}"><msub><mi mathvariant="normal">k</mi><mi mathvariant="normal">m</mi></msub><mo>⁢</mo><msub><mi mathvariant="normal">K</mi><mi>dis</mi></msub><mo>⁢</mo><mfenced><msqrt><mn mathvariant="normal">1</mn><mo mathvariant="normal">+</mo><mmultiscripts><msub><mo mathvariant="normal">/</mo><msub><mi mathvariant="normal">K</mi><mi>dis</mi></msub></msub><mprescripts /><none /><mrow><mn mathvariant="normal">8</mn><mo>⁢</mo><msub><mfenced open="[" close="]"><msup><mi mathvariant="normal">M</mi><mrow><mn mathvariant="normal">2</mn><mo mathvariant="normal">+</mo></mrow></msup></mfenced><mi>total</mi></msub></mrow></mmultiscripts></msqrt><mo mathvariant="normal">-</mo><mn mathvariant="normal">1</mn></mfenced><mo mathvariant="normal">/</mo><mn mathvariant="normal">4</mn><mo mathvariant="normal">+</mo><msub><mi mathvariant="normal">k</mi><mi>background</mi></msub></mfenced></math><img file="EP1613402B1_D0112.tif" /></maths>

Example 13. Zn²⁺-Catalyst Stoichiometry

0138Potentiometric titration of Zn(OTf)₂ solutions of varying concentrations (0.5-2 mM) in anhydrous methanol were performed in the absence and presence of equimolar amounts of ligands phen, diMephen and [12]aneN₃ in order to determine the speciation of the Zn²⁺ ions under conditions similar to those of the kinetic experiments.

0139Independent titrations of 1 mM solutions of each ligand were performed and the resulting data were analyzed using Hyperquad™ 2000 fitting routine providing the <maths id="math0098"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0113.tif" /></maths> values for the last acid dissociation step, of 5.63 ± 0.01 for phen-H⁺, 6.43 ± 0.01 for diMephen-H⁺ and > 13 for [12]aneN₃-H⁺ respectively.

0140The potentiometric titration curve of Zn(OTf)₂ presented in <figref idref="f0009">Figure 14</figref> shows the consumption of two equivalents of methoxide occuring in one rather steep step. In the presence of ligands phen, diMephen and [12]aneN_3, the titration curve changes due to the formation of complexes. To analyze these titration data, a number of different dissociation schemes were attempted and the final adopted ones were selected based on goodness of fit to the titration profiles along with due consideration of the various species suggested by the kinetic studies.

0141The case of the ligand triazacrown ether [12]aneN₃ is the simplest to analyze since we have no evidence supporting the presence of any species containing more than one Zn²⁺ ion. This fact, coupled with the high <maths id="math0099"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mn>2</mn></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0114.tif" /></maths> of [12]aneN₃-H⁺, allows one to define the relevant species in solution as [12]aneN₃-H⁺, Zn²⁺:[12]aneN₃, Zn²⁺:[12]aneN₃:(^-OCH₃) and Zn²⁺:[12]aneN₃:(^-OCH₃)₂, which, when fit via the Hyperquad™ 2000 program, produces a theoretical titration curve (<figref idref="f0009">Figure 14</figref>) which is in excellent agreement with the observed curve. The best fit formation constants for [12]aneN₃-H⁺, Zn²⁺:[12]aneN₃, Zn²⁺:[12]aneN₃:(^-OCH₃) and Zn²⁺:[12]aneN₃:2(^-OCH₃) are given in Table 15. The Zn²⁺ speciation diagram constructed from these constants (not shown) indicates that in the <maths id="math0100"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0115.tif" /></maths> region used in our kinetic studies, greater than 95% of the total Zn²⁺ is present as Zn²⁺:[12]aneN₃:(^-OCH₃). Shown in <figref idref="f0010">Figure 13A</figref> is a plot of the pseudo-first order rate constants for the methanolysis of paraoxon in the presence of Zn(OTf)₂ with a right hand axis depicting the [Zn²⁺:[12]aneN₃:(^-OCH₃)] as function of total [Zn(OTf)₂]. The very good correlations between the kinetic data and the speciation data strongly supports Zn²⁺:[12]aneN₃:(^-OCH₃) as the catalytically active component, with a derived second order rate constant of 50.4 M^-1 min^-1 for the methanolysis of paraoxon.

0142Potentiometric titration of an equimolar mixture of Zn(OTf)₂ and phen in the presence of 0.6 equivalents of perchloric acid showed that all the added H⁺ was released in the strong acid region below <maths id="math0101"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0116.tif" /></maths> 3 with one additional step consuming a single equivalent of methoxide around <maths id="math0102"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0117.tif" /></maths> 10. The former indicates strong binding between Zn²⁺ and phen even at <maths id="math0103"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts><mo>=</mo><mn>3</mn><mo>,</mo></math><img file="EP1613402B1_D0118.tif" /></maths> but does not allow us to determine an exact value of the Zn²⁺: phen binding constant other than to set a lower limit for its formation constant of 10¹⁰ M^-1 which was used as a fixed value in all subsequent fittings. In the higher <maths id="math0104"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0119.tif" /></maths> region where the kinetic experiments were performed, we employed a model where the Zn²⁺ exists predominantly as {Zn²⁺: phen:(^-OCH₃)}₂ and Zn²⁺: phen:(^-OCH₃)₂, both of these being inferred by the kinetic data. Hyperquad™ 2000 fitting of the full titration profile using the previously determined stability constants for phen-H⁺ and Zn²⁺:phen, produces a good fit and provides respective stability constants for {Zn²⁺: phen:(^-OCH₃)}₂ and Zn²⁺:phen:(^-OCH₃)₂ given in Table 15.

0143In the catalysis of methanolysis of paraoxon and fenitrothion by {Zn²⁺:^-OMe}, either alone or in the presence of complexing ligands,two things are clear: first, Zn²⁺ species are appreciably soluble in solution at all <maths id="math0105"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0120.tif" /></maths> values and all concentrations employed; and second, equilibria consisting of dimeric species in equilibrium with a kinetically active mononuclear species are formed in the case of Zn²⁺, {Zn²⁺:phen} and {Zn²⁺:diMephen}, but not in the case of {Zn²⁺:[12]aneN₃} where only the kinetically active mononuclear form is present. High solubility of Zn²⁺ has been found with triflate and perchlorate counterions. These anions are preferred for their relative kinetic inertness since they give the highest rates for catalyzed reactions relative to other anions such as bromide, chloride or acetate. Methanolysis of paraoxon, catalyzed by 1 mM Zn(OTf)₂ with 0.3 equationof added NaOCH₃ is relatively unaffected by the addition of up to 5 mM NaOTf or NaClO₄, but is significantly inhibited by the addition of 1 mM NaCl, NaBr or Na(O₂CCH₃).

0144The ability of the Zn²⁺ species to methanolyze both the P=O and P=S species with second-order rate constants 50-to 1000-fold larger than the corresponding second-order rate constants for methoxide attack alone may be due to the bifunctional nature of the catalyst and partly due to the reduced dielectric constant of the medium and its reduced solvation of metal ions relative to water.

0145Preparatively useful forms of catalysts can be generated by the addition of known amounts of ligand, Zn(OTf)₂ and methoxide. In the case of a solution comprising 2 mM Zn(OTf)₂, 2 mM diMephen ligand and 2 mM NaOCH₃ which generates a <maths id="math0106"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0121.tif" /></maths> of -9.5, methanolysis of paraoxon is accelerated 1.8 x 10⁶-fold and methanolysis of fenitrothion is accelerated 13 x 10⁶-fold. Likewise, a solution comprising 1 mM of Zn(OTf)₂, 1 mM [12]aneN₃ ligand and 0.5 mM NaOCH₃ generates a <maths id="math0107"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0122.tif" /></maths> of 9.3 and methanolysis of paraoxon is accelerated 1.7 x 10⁶-fold.

0146Unlike the dimeric form of La³⁺, which are effective for methanolyzing paraoxon, dimeric forms of Zn²⁺ are not as effective as its monomers.

Example 14. Zn²⁺-Catalyzed Methanolysis of Paraoxon and Fenitrothion: Kinetic and Potentiometric Studies

0147The kinetics for Zn²⁺-catalyzed methanolysis of paraoxon and fenitrothion fall into two distinct classes depending on what ligand is coordinated to the metal ion and how much methoxide is added. Without any ligand, as shown in <figref idref="f0008">Figure 11</figref>, the k_obs for methanolysis of paraoxon in the presence of 1 mM Zn(OTf)₂ is maximized between 0.1 and 0.4 mM added NaOCH₃. There is an initially very strong dependence on the concentration of methoxide, the slope of which for the first 0.05 equationadded yields a second order rate constant of ~ 34 M^-1 min^-1 for methanolysis of paraoxon. Undoubtedly this methoxide is coordinated to Zn²⁺ to establish the {Zn(OCH₃)}₂²⁺ ⇄ 2 {Zn(OCH₃)}⁺ equilibrium but as additional methoxide is added, the overall rate drops significantly suggesting formation of inactive species having a [(^-OCH₃)]/[Zn²⁺] greater than 1. This agrees with a potentiometric titration of Zn²⁺ in methanol which displayed a steeper-than-normal consumption of 2 methoxides in an apparent single event having a midpoint of - <maths id="math0108"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0123.tif" /></maths> 9.8 which, when analyzed via Hyperquad™ fitting to a model containing only the mononuclear species Zn²⁺(OCH₃^-) and Zn²⁺(OCH₃^-)₂, gives apparent <maths id="math0109"><math display="inline"><mmultiscripts><msub><mi>pK</mi><msup><mi mathvariant="normal">a</mi><mn>1</mn></msup></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0124.tif" /></maths> and <maths id="math0110"><math display="inline"><mmultiscripts><msub><mi>pK</mi><msup><mi mathvariant="normal">a</mi><mn>2</mn></msup></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0125.tif" /></maths> values of 10.66 and 8.94. While our original fitting (Gibson, <i>et al.,</i> 2003) did not include dimer and oligomer formation, the fact that the second apparent <maths id="math0111"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0126.tif" /></maths> is lower than the first indicates some cooperative effect facilitating addition of a second methoxide per Zn²⁺ ion before the first addition is stoichiometrically complete. This fact limits the amount of any forms having a methoxide/Zn²⁺ stoichiometry of 1 and shifts the maximum of the kinetic plot in <figref idref="f0008">Figure 11</figref> to the left. Species where the methoxide/Zn²⁺ ratio >1 probably exist in solution as oligomers of {Zn²⁺(-OCH₃)_1.5,2}<i>_n</i>, held together with methoxide bridges. Added bi- or tridentate ligands could, in principle, disrupt this arrangement by capping one face of the Zn favouring the formation of dimers and monomers of stoichiometry {Zn²⁺:L(^-OCH₃)}₂, Zn²⁺:L(^-OCH₃)(HOCH₃) or Zn²⁺:L(^-OCH₃)₂ depending on the methoxide/Zn²⁺ ratio. Indeed, as shown in <figref idref="f0006">Figure 8</figref>, ligands phen, diMephen and [12]aneN₃ modify the kinetic behaviour in important ways depending on whether the methoxide/Zn²⁺ ratio is less than or greater than 1.

Example 15. Zn²⁺-Catalyzed Methanolysis of Paraoxon: NMR Studies of Catalytic Turnover

0148A ³¹ P NMR experiment was performed to determine a turnover rate for the methanolysis of paraoxon using Zn²⁺:diMephen:^-OCH₃.

0149To 0.6 mL of dry methanol (with 20% of CD₃OD as an NMR lock signal) containing 1 mM each of Zn(OTf)₂, diMephen and NaOCH₃ at ambient temperature was added 2.54 mg of paraoxon. At this point the concentration of paraoxon was 15 mM and that of Zn²⁺: diMephen: ^-OCH₃ was taken as 1.0 mM with the measured <maths id="math0112"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0127.tif" /></maths> of the methanol solution being 8.75, close to neutrality (8.34). The ³¹P NMR spectrum of the solution was monitored periodically over ~160 minutes at which time it indicated complete disappearance of the paraoxon signal which had been at <img file="EP1613402B1_D0128.tif" />-6.35 ppm and complete appearance of a new signal at δ 0.733 ppm corresponding to the product diethyl methyl phosphate. The ¹H NMR spectrum was obtained after 150 min and it confirmed the complete disappearance of the starting material and full release of the product p-nitrophenol.

0150The ³¹ P NMR spectrum of a solution containing 15 mM paraoxon and 1 mM in each of Zn(OTf)₂, NaOCH₃ and ligand diMephen was continuously monitored at ambient temperature over a period of -160 minutes. The spectra were summed each 15 minutes to produce the time profile given in <figref idref="f0008">Figure 10</figref> which displays the disappearance of paraoxon and the appearance of a new signal at δ 0.733 ppm attributed to diethyl methyl phosphate. Fitting of these two time profiles to a first order expression gave an average pseudo-first order rate constant of (4.5 ± 0.1) x 10^-4 s^-1 over 15 turnovers (t_1/2= 25 min), thus showing the true catalytic nature of the system.

Example 16. Zn²⁺-Catalyzed Methanolysis of Paraoxon and Fenitrothion: Kinetics

0151As shown by the various formation constants given in Table 15, phen binds very tightly to Zn²⁺ at all values in methanol. According to potentiometric titration data, the major species in the <maths id="math0113"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0129.tif" /></maths> domain surrounding 0 &lt; [methoxide]/[Zn²⁺]_t &lt; 1 is the dimer {Zn²⁺:phen:(^-OCH₃)}₂ which is in equilibrium with a small amount of kinetically active monomer, {Zn²⁺phen(-OCH₃)}. Under conditions where the [methoxide]/[Zn²⁺]_t = 0.5, a plot of k_obs for catalyzed methanolysis of paraoxon vs. [Zn²⁺]_total (see <figref idref="f0009">Figure 14B</figref>) follows the square root dependence of equation (6) that corresponds to the process presented in equation (5) with the derived kinetic parameters being given in Table 16. The same general phenomenon is seen with ligand diMephen although its binding to Zn²⁺ is weaker than phen (as is known to be the case in water) such that at any given <maths id="math0114"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts><mo>,</mo></math><img file="EP1613402B1_D0130.tif" /></maths> only about 85% of the Zn²⁺ is bound to diMephen. <tables id="tabl0016" num="0016"><table frame="all"><title>Table 15 -- Formation constants for various species determined by potentiometric titration.</title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="49mm" /><colspec colnum="2" colname="col2" colwidth="31mm" /><colspec colnum="3" colname="col3" colwidth="38mm" /><colspec colnum="4" colname="col4" colwidth="38mm" /><thead><row><entry valign="middle"><b>Equilibrium</b></entry><entry valign="middle"><b>Log</b><maths id="math0115"><math display="block"><mmultiscripts><mi mathvariant="normal">K</mi><mprescripts /><mi mathvariant="italic">s</mi><mi mathvariant="italic">s</mi></mmultiscripts></math><img file="EP1613402B1_D0131.tif" /></maths><b>L = phen</b></entry><entry valign="middle"><b>Log</b><maths id="math0116"><math display="block"><mmultiscripts><mi mathvariant="normal">K</mi><mprescripts /><mi mathvariant="italic">s</mi><mi mathvariant="italic">s</mi></mmultiscripts></math><img file="EP1613402B1_D0132.tif" /></maths><b>L = diMephen</b></entry><entry valign="middle"><b>Log</b><maths id="math0117"><math display="block"><mmultiscripts><mi mathvariant="normal">K</mi><mprescripts /><mi mathvariant="italic">s</mi><mi mathvariant="italic">s</mi></mmultiscripts></math><img file="EP1613402B1_D0133.tif" /></maths><b>L = [12]aneN₃</b></entry></row></thead><tbody><row><entry>[L-H⁺]/[L][H⁴⁺]</entry><entry>5.63</entry><entry>6.43</entry><entry>14.92</entry></row><row><entry>[ZnL]/[L][Zn]</entry><entry>10</entry><entry>4.25</entry><entry>10.11</entry></row><row><entry>[Zn₂L₂(OMe)_2]/[L]²[Zn]²[OMe]²</entry><entry>36.33</entry><entry>28.05</entry><entry /></row><row><entry>[ZnL(OMe)₂]/[L][Zn²⁺][OMe]²</entry><entry>20.58</entry><entry /><entry>21.67</entry></row><row><entry>[ZnL(OMe)]/[L][Zn][OMe]</entry><entry /><entry /><entry>17.79</entry></row></tbody></tgroup></table></tables><tables id="tabl0017" num="0017"><table frame="all"><title>Table 16 -- Kinetic constants for the methanolysis of fenitrothion and paraoxon catalyzed by Zn²⁺ in the absence and presence of ligands phen, diMephen, [12]aneN₃, at T = 25°C.</title><tgroup cols="4"><colspec colnum="1" colname="col1" colwidth="41mm" /><colspec colnum="2" colname="col2" colwidth="41mm" /><colspec colnum="3" colname="col3" colwidth="43mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><thead><row><entry valign="top" /><entry valign="top" /><entry colsep="0" valign="top"><b>Paraoxon</b></entry><entry valign="top"><b>Fenitrothion</b></entry></row><row><entry valign="top"><b>Catalyst</b></entry><entry valign="top"><b>K_dis (mM)^a</b></entry><entry colsep="0" valign="top"><b>K_m (M^-1 min^-1)^a</b></entry><entry valign="top"><b>k_m(M^-1 min^-1)^a</b></entry></row></thead><tbody><row><entry>^-OCH₃</entry><entry>-</entry><entry>0.66</entry><entry>0.043 ± 0.001</entry></row><row><entry>Zn^2+b</entry><entry>&lt; 0.005</entry><entry>72.5 ±1.5</entry><entry>11.2 ±0.4</entry></row><row><entry>{Zn²⁺:phen}^c</entry><entry>&lt; 0.005</entry><entry>124 ± 2.5</entry><entry>19.0 ± 0.6</entry></row><row><entry>{Zn²⁺:phen:2(^-OCH₃)}^d</entry><entry>-</entry><entry>29.5 ± 0.7</entry><entry>2.7 ± 0.1</entry></row><row><entry>Zn²⁺:diMephen^e</entry><entry>0.6 ± 0.2</entry><entry>101 ± 1</entry><entry>48.0 ± 0.7</entry></row><row><entry>Zn²⁺:[12]aneN₃:(^-OCH₃)^f</entry><entry>-</entry><entry>50.8 ± 0.8</entry><entry>2.9 ± 0.1</entry></row><row><entry>{2La³⁺:2(^-OCH₃)}^g</entry><entry>-</entry><entry>2830 ± 140</entry><entry>No catalysis</entry></row></tbody></tgroup><tgroup cols="4" rowsep="0"><colspec colnum="1" colname="col1" colwidth="41mm" /><colspec colnum="2" colname="col2" colwidth="41mm" /><colspec colnum="3" colname="col3" colwidth="43mm" /><colspec colnum="4" colname="col4" colwidth="43mm" /><tbody><row><entry namest="col1" nameend="col4" align="justify">^a Dimer dissociation constant (K_dis) and conditional second order rate constant (k_m) for monomer defined as in equation(5); "-" means non-applicable since there is no observable dimerization under the specific conditions. ^b Based on NLLSQ fits of k_obs vs. [Zn²⁺]total data to equation(6) at [methoxide]/[Zn²⁺]_total ratio of 0.3 ^c Based on NLLSQ fits of K_obs vs. [Zn²⁺:phen] _total data to equation(6) at [methoxide]/[Zn²⁺]_t ratio of 0.5 ^d Based on linear fits of K_obs vs. [Zn²⁺:phen] _total data to equation(6) at [methoxide]/[ Zn²⁺]_t ratio of 2.0 ^e Based on NLLSQ fits of K_obs vs. [Zn²⁺:diMephen] _total data to equation(6) at [methoxide]/[ Zn²⁺] _total ratio of 1.0 ^f Based on linear fits of K_obs vs. [Zn²⁺:[12]aneN₃:(^-OCH₃)]_t data at [methoxide] = [Zn²⁺]_total = [[12]ane₃]. ^g From reference Tsang <i>et al.,</i> 2003</entry></row></tbody></tgroup></table></tables>

0152As shown in <figref idref="f0006">Figure 8</figref> for the methanolysis of paraoxon, the Zn²⁺:phen and Zn²⁺:diMephen systems behave differently in the 1 &lt; [methoxide]/[Zn²]_tolal &lt; 2 domains with the overall activity increasing and decreasing respecively. Because of the weak binding inherent in the Zn²⁺:diMephen system, the additional methoxide probably displaces the ligand from the {Zn²⁺:diMephen:(^-OCH₃)}_1,2 forms to generate uncomplexed diMephen and {Zn(OCH₃)₂}_n oligomers which are not active. However, because of the far stronger binding of phen to Zn²⁺, the additional methoxide breaks apart the {Zn²⁺:phen:(^-OCH₃)}₂ dimer as shown in <figref idref="f0001">Figure 1B</figref> to form Zn²⁺:phen:(^-OCH₃)₂. The presence of Zn²⁺:phen:(^-OCH₃)₂ and its catalytic viability is respectively confirmed by the potentiometric titration data and by the fact that a plot of k_obs for methanolysis of both substrates vs. [Zn²⁺]_t under conditions where the [Zn²⁺]:phen:methoxide ratio is 1:1:2 gives a straight line with a slope of k_m = 29.5 M^-1 min^-1 for the methanolysis of paraoxon and k_m = 2.7 M^-1s^-1 for the methanolysis of fenitrothion.

0153The Zn²⁺:[12]aneN₃:OCH₃^- system is a simple one because of very strong binding and the lack of formation dimers {Zn²⁺:[12]aneN₃:(^-OCH₃)}₂ under employed conditions. In methanol, the M²⁺-L binding constant is large <maths id="math0118"><math display="inline"><mfenced><mi>log</mi><mspace width="1em" /><mmultiscripts><mi mathvariant="normal">K</mi><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts><mo>=</mo><mn>10.11</mn></mfenced><mo>,</mo></math><img file="EP1613402B1_D0134.tif" /></maths> ensuring that there is essentially no free ligand in solution, and the <maths id="math0119"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi>s</mi><mi>s</mi></mmultiscripts></math><img file="EP1613402B1_D0135.tif" /></maths> for ionization of the complex Zn²⁺:[12]aneN₃:HOCH₃ is 9.1. The k_obs vs. [Zn²⁺]_total plot shown in <figref idref="f0010">Figure 13A</figref> is a straight line consistent with (Zn²⁺:[12]aneN₃:(^-OCH₃)) being the active catalyst and predominant form.

Example 17. Cu

2+

-Catalyzed Methanolysis or Paraoxon and Fenitrothion: Kinetic Studies

0154In the absence of metal ions, uncatalyzed attack of methoxide on paraoxon is some 15 times faster than on fenitrothion, but in the presence of all {Cu²⁺:(^-OCH₃)} species are more effective for fenitrothion than paraoxon. This can be quantified by the relative selectivity parameter given in Table 18 which compares the relative reactivity of the metal-coordinated methoxide reaction relative to free methoxide attack for P=S and P=O substrates. Relative Selectivity parameters clearly correlate with the hard/soft properties of the metal ion. The "hard" ion La³⁺ exhibits exclusive selectivity for the P=O substrate (relative selectivity parameter ~0), while the softer Zn²⁺ ion shows almost equal affinity for P=O and P=S substrates (relative selectivity parameter ~1). Of the three ions, Cu²⁺ is softest, and exhibits very high selectivities for the P=S substrates with relative selectivity parameter values from -55-340 with the highest values exhibited in the case of the aromatic ligands. The best combination of selectivity and overall high catalytic activity is achieved with {[12]aneN₃:Cu²⁺:(^-OCH₃)} perhaps due to reduced dimerization. All the Cu²⁺-catalyzed reactions proceed with computed second order rate constants larger than those for the uncatalyzed attack of methoxide on paraoxon or fenitrothion which indicates that there is a dual role for the metal ion. As in other Mⁿ⁺-promoted hydrolytic and methanolytic reactions, the metal ion is reasonably proposed to deliver a Mⁿ⁺-coordinated OH^- or CH₃O^- and act as a Lewis acid to polarize a P=S or P=O unit, which provides both rate and selectivity enhancement. There is a 17,000-fold enhancement of attack of [12]aneN₃:Cu²⁺:(^-OCH₃) on fenitrothion vs. attack of free ^-OCH₃ even though the latter is ~10⁸-fold more basic. This represents the largest acceleration reported for metal-catalyzed phosphoryl transfer reactions to solvent. Through turnover experiments, it has been demonstrated that this is a truly catalytic system which, at millimolar concentration can provide 1.7 x 10⁹-fold acceleration of the methanolysis of fenitrothion at neutral <maths id="math0120"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0136.tif" /></maths> and ambient temperature.

0155In the presence of ligand [12]aneN_3, the kinetic plots, k_obs vs. [Cu(OTf)₂]_total (see <figref idref="f0006">Figure 7</figref>), for methanolysis of paraoxon and methanolysis of fenitrothion are strictly linear which is indicative of complete formation of a mononuclear catalyst of the structure: [12]aneN₃:Cu²⁺:(^-OCH₃). The second order rate constants, k_m, for paraoxon and for fenitrothion were evaluated as the gradients of the linear plots, these values being given in Table 18. <tables id="tabl0018" num="0018"><table frame="all"><title>Table 18 -- Kinetic constants for thte methanolysis of paraoxon and fenitrothion catalyzed by Cu²⁺ in the absence and presence of ligands [12]aneN_3, bpy and phen at T = 25 °C.</title><tgroup cols="6"><colspec colnum="1" colname="col1" colwidth="30mm" /><colspec colnum="2" colname="col2" colwidth="26mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><colspec colnum="4" colname="col4" colwidth="29mm" /><colspec colnum="5" colname="col5" colwidth="28mm" /><colspec colnum="6" colname="col6" colwidth="28mm" /><thead><row><entry valign="top" /><entry align="center" valign="top" /><entry align="center" valign="top" /><entry align="center" valign="top"><b>Paraoxon</b></entry><entry align="center" valign="top"><b>Fenitrothion</b></entry><entry align="center" valign="top" /></row><row><entry valign="middle"><b>Catalyst</b></entry><entry align="center" valign="middle"><maths id="math0121"><math display="block"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0137.tif" /></maths><b>at 0.5 eq of base</b></entry><entry align="center" valign="middle"><b>K_dis (mM)^a</b></entry><entry align="center" valign="middle"><b>k_m (M^-1s^-1)^a</b></entry><entry align="center" valign="middle"><b>k_m (M^-1</b> s^-1))^a<b>k_m (M^-1s^-1))^a</b> (M^-1s^-1))^a</entry><entry align="center" valign="middle"><b>Relative selectivity^b</b></entry></row></thead><tbody><row><entry>^-OCH₃</entry><entry align="center" /><entry align="center">N.A</entry><entry align="center">1.1 x 10^-2</entry><entry align="center">(7.2 ± 0.2) x 10^-4</entry><entry align="center">1</entry></row><row><entry>Cu²⁺ :(^-OCH₃)^c</entry><entry align="center">6.86 ± 0.2</entry><entry align="center">&lt; 0.005</entry><entry align="center">0.22 ± 0.02</entry><entry align="center">0.79 ± 0.03</entry><entry align="center">55</entry></row><row><entry>Cu²⁺: bpy:(^-OCH₃)^d</entry><entry align="center">7.8 + 0.2</entry><entry align="center">&lt; 0.005</entry><entry align="center">&lt;0.2</entry><entry align="center">4.48 ± 0.12</entry><entry align="center">342</entry></row><row><entry>Cu²⁺:phen: (^-OCH₃)^e</entry><entry align="center">7.45 ± 0.2</entry><entry align="center">&lt;0.005</entry><entry align="center">&lt;0.2</entry><entry align="center">2.44 ± 0.06</entry><entry align="center">186</entry></row><row><entry>Cu²⁺:[12]aneN₃:(^-OCH₃)^f</entry><entry align="center">8.75 ± 0.1</entry><entry align="center">-</entry><entry align="center">2.76 ± 0.17</entry><entry align="center">12.2 ± 0.4</entry><entry align="center">67</entry></row><row><entry>Zn²⁺:[12]aneN₃:(^-OCH₃)^g</entry><entry align="center">9.3</entry><entry align="center">-</entry><entry align="center">0.85 ± 0.01</entry><entry align="center">(4.8 ± 0.2) x 10^-2</entry><entry align="center">0.86</entry></row><row><entry>La³⁺₂(^-OCH₃)₂^h</entry><entry align="center" /><entry align="center">-</entry><entry align="center">47.2 ± 2.3</entry><entry align="center">No catalysis</entry><entry align="center">~0</entry></row></tbody></tgroup><tgroup cols="6" rowsep="0"><colspec colnum="1" colname="col1" colwidth="30mm" /><colspec colnum="2" colname="col2" colwidth="26mm" /><colspec colnum="3" colname="col3" colwidth="28mm" /><colspec colnum="4" colname="col4" colwidth="29mm" /><colspec colnum="5" colname="col5" colwidth="28mm" /><colspec colnum="6" colname="col6" colwidth="28mm" /><tbody><row><entry namest="col1" nameend="col6" align="justify">^a Dimer dissociation constant (K_dis) and conditional second order rate constant (k_m) for reaction with monomer defined as in text. "-" means non-applicable since there is no observable dimerization under the specific conditions. The K_dis of &lt;0.005 indicates very strong dimerization and is quoted as an upper limit based on an iterative fitting procedure which provided the lowest standard deviations. ^b Defined as (k_m/ k_OCH3)^fenitrothion / (k_m/k_OCH3) ^paraoxon^c Based on NLLSQ fits of k_obs vs. [Cu²⁺]_total data to equation(6) at [methoxide]/[Cu²⁺]_total ratio of 0.5 ^d Based on NLLSQ fits of k_obs vs. [bpy:Cu²⁺]_total data to equation(6) at [methoxide]/[Cu²⁺]_total ratio of 0.5 ^e Based on NLLSQ fits of k_obs vs. [phen:Cu²⁺]_total data to equation(6) at [methoxide]/[Cu²⁺]_t ratio of 0.5 ^f Based on linear fits of k_obs vs. [Cu²⁺:[12]aneN₃:(^-OCH₃)]_total data at methoxide]/[Cu²⁺]_t ratio of 0.5. ^g From reference Desloges, <i>et al.</i> 2004. ^h From ref erence Tsang <i>et al.,</i> 2003.</entry></row></tbody></tgroup></table></tables>

0156The kinetics of methanolysis were monitored at 25°C in anhydrous methanol by observing the rate of appearance of p-nitrophenol or 3-methyl-4-nitrophenol between 312 and 335 nm at [paraoxon] or [fenitrothion] = 4 to 12 x 10^-5 M under pseudo-first order conditions of excess Cu(OTf)₂ (0.2 to 5.0 x 10^-3 M). All reactions were followed to at least three half times and found to exhibit good pseudo-first order rate behavior and the first order rate constants (k_obs) were evaluated by fitting the Abs. vs. time traces to a standard exponential model. The kinetics were all determined under self-buffered conditions where the <maths id="math0122"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0138.tif" /></maths> was controlled by a constant Cu²⁺/Cu²⁺COCH₃) ratio and in the cases with ligands [12]aneN_3, bpy and phen, these were added in amounts equivalent to the [Cu²+]_total. Under these conditions the observed <maths id="math0123"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0139.tif" /></maths> values correspond to the apparent <maths id="math0124"><math display="inline"><mmultiscripts><msub><mi>pK</mi><mi mathvariant="normal">a</mi></msub><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0140.tif" /></maths> value for ionization of the {Cu²⁺:L:(HOCH₃)} ⇄ {Cu²⁺:L:(^-OCH₃)} + ⁺H₂OCH₃ system.

0157As shown in <figref idref="f0005">Figures 6</figref> and <figref idref="f0006">7</figref> the overall behaviour portrayed in the k_obs vs. [Cu²⁺] plots falls into two categories depending on the nature of the ligand employed. In the absence of any ligand, or in the presence of equimolar bpy or phen, the <figref idref="f0005">Figure 6</figref> plots are non-linear and indicative of a square-root dependence which can be fit via a standard Non-Linear Least Squares (NLLSQ) treatment to equation (6) derived on the following assumptions: all the ligand is bound to Cu²⁺; an active (rate constant k_m) mononuclear species {Cu²⁺:L:(^-OCH₃)} is in rapid equilibrium (dissociation constant K_dis) with an inactive dimer (equation4) and k_background is negligible since it is undetectable. How good the fit of the lines is may be seen by examining the computed lines through the <figref idref="f0005">Figure 6</figref> data and the best fit constants are given in Table 18. Also in Table 18 are the measured <maths id="math0125"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0141.tif" /></maths> values over the entire [Cu²⁺] range under the self-buffering conditions which deviate by an acceptable 0.2 or less units. In the case of paraoxon, the catalyzed reactions were sufficiently slow that we have placed upper limits on the rate and equilibrium constants.

0158A system comprising 2 mM Cu(OTf)₂, along with 0.5 equationof N(Bu)₄OCH₃ and 1 equivalent of [12]aneN₃ catalyzes the methanolysis of fenitrothion with a t_1/2 of ~58 sec accounting for a 1.7 x 10⁹-fold acceleration of the reaction relative to the background reaction at a near neutral <maths id="math0126"><math display="inline"><mmultiscripts><mi>pH</mi><mprescripts /><mi mathvariant="normal">s</mi><mi mathvariant="normal">s</mi></mmultiscripts></math><img file="EP1613402B1_D0142.tif" /></maths> of 8.75. In this system the concentration of catalyst is in excess over the concentration of fentrothion.

0159A turnover experiment with substrate in excess of catalyst was conducted using 0.4 mM Cu(OTf)₂ along with equimolar [12]aneN₃ and 0.5 equationof NBu₄OCH₃. The methanolysis of 2mM fenitrothion was monitored by UV/vis at T = 25.0 °C and showed 10 turnovers relative to the active catalyst (0.2 mM Cu²⁺:[12]aneN₃:(^-OCH₃)) within 100 min.

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