USOO8722956B2

(12) United States Patent (10) Patent No.: US 8,722,956 B2 BrOWn et al. (45) Date of Patent: *May 13, 2014

(54) KIT FOR DECOMPOSING (56) References Cited ORGANOPHOSPHORUS COMPOUNDS U.S. PATENT DOCUMENTS (75) Inventors: R. Stanley Brown, Kingston (CA); 3,079.346 A 2f1963 Jackson Alexei A. Neverov, Kingston (CA); 3,725,269 A 4, 1973 Wolverton Josephine S. W. Tsang, Kingston (CA) 4,337,368 A * 6/1982 Pytlewski et al...... 588,316 4,602,994. A * 7/1986 Pytlewski et al... 208,262.1 (73) Assignee: Queen's University at Kingston, 4,874,526 A * 10/1989 Grade et al...... 210,697 Kingston, ON, CA (US) 5,859,064 A 1/1999 Cronce 6.479,723 B1 * 1 1/2002 Malhotra et al...... 588,316 (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 254 days. FOREIGN PATENT DOCUMENTS This patent is Subject to a terminal dis DE 2994.58 4f1992 claimer. EP O906773 A1 4f1999 (Continued) (21) Appl. No.: 13/012,269 OTHER PUBLICATIONS (22) Filed: Jan. 24, 2011 Harrison et al.; The Chemistry of Organophosphorous Chemical (65) Prior Publication Data Warefare Agents; PATAI's Chemistry of Functional Groups; 2009.* US 2011 FO253580-A1 Oct. 20, 2011 (Continued) Related U.S. Application Data Primary Examiner — Guinever Gregorio (63) Continuation of application No. 1 1/713,805, filed on (74) Attorney, Agent, or Firm — Angela Lyon; Carol Mar. 5, 2007, now Pat. No. 7,875,739, which is a Miernicki Steeg continuation of application No. 10/798,880, filed on Mar. 12, 2004, now Pat. No. 7,214,836. (57) ABSTRACT (60) Provisional application No. 60/453.762, filed on Mar. Methods and kits for decomposing organophosphorus com 12, 2003. pounds in non-aqueous media at ambient conditions are (51) Int. C. described. Insecticides, pesticides, and chemical warfare BOI. 23/00 (2006.01) agents can be quickly decomposed to non-toxic products. The A62D 3/38 (2007.01) method comprises combining the organophosphorus com A62D 3/00 (2006.01) pound with a non-aqueous solution, preferably an , A62D 3/30 (2007.01) comprising metalions and at least a trace amount of alkoxide (52) U.S. C. . In a first preferred embodiment, the metal is a lan USPC ...... 588/300; 588/320:588/313; 502/302 thanum ion. In a second preferred embodiment, the metalion is a transition metal. (58) Field of Classification Search None See application file for complete search history. 30 Claims, 10 Drawing Sheets g La3. QJLa 3. (EIOP-0Ar Pt 34 N La3. CAr O- o1 Yo-sp^ CH, ch, R (OEt) -phosphate C t

i).6.Yo oA -6La y af N." heriiCHO1 Y(OEtz her(EIO: OA Hc-'n?Eo-OAf US 8,722.956 B2 Page 2

(56) References Cited Khan, A., et al. “Strong Zn" and Co'Catalysis of the Methanolysis of Acetyl Imidazole and Acetyl Pyrazole'. Can. J. Chem. 77: 1005 U.S. PATENT DOCUMENTS 1008 (1999). Nagelkerke, R., et al. “Alkali-metal Ion Catalysis and Inhibition in 6,852,903 B1* 2/2005 Brown et al...... 588.299 2004/00964.15 A1 5, 2004 Franke et al. Nucleophilic Displacement Reactions at Carbon, Phosphorus and 2005/0256539 A1 * 1 1/2005 George et al...... 6O7.2 Sulfur Centres. IX. p-Nitrophenyl Diphenyl Phosphate”. Org. 2007/0184970 A1* 8, 2007 Gao ...... 502,159 Biomol. Chem. 1: 163-167 (2003). 2007/0249509 A1* 10, 2007 Tucker ...... 510/110 Neverov, A.A., et al. “Catalysis of the Methanolysis of 2012/0149963 A1* 6, 2012 A1 Nashefet al. . 588,320 Acetylimidazole by Lanthanum Triflate'. Can. J. Chem. 78: 1247 2012/0149964 A1* 6, 2012 Al Nashefet al...... 588,320 1250 (2000). Neverov, A.A., et al. “La"-Catalyzed Methanolysis of Phosphate FOREIGN PATENT DOCUMENTS Diesters. Remarkable Rate Acceleration of the Methanolysis of Diphenyl Phosphate, Methyl p-Nitrophenyl Phosphate, and Bis(p- EP O909774 A1 4f1999 nitrophenyl) Phosphate”. . 40: 3588-3595 WO WO96/05208 2, 1996 WO WOOOf 48684 8, 2000 (2001). WO WOO1/30452 A1 5, 2001 Neverov, A.A., et al. “Catalysis of Reactions by WO WO O2/O72206 A1 9, 2002 Lanthanides Unprecedented Acceleration of Methanolysis of Aryl and Alkyl Promoted by La(OTf) at Neutral pH and Ambient OTHER PUBLICATIONS Temperatures”. Can. J. Chem. 79: 1704-1710 (2001). Neverov, A.A., et al. “Catalysis of the Methanolysis of Activated Balakrishnan, V.K., et al., “Catalytic Pathways in the Ethanolysis of by Divalent and Trivalent Metal Ions. The Effect of Zn", Fenitrothion, an Organophosphorothioate Pesticide. A Dichotomy in Co", and La" on the Methanolysis of Acetylimidazole and Its the Behaviour of Crown/Cryptand Cation Complexing Agents”. Can. (NH). Co'Complex”. J. Am. Chem. Soc. 123: 210-217 (2001). J. Chem. 79: 157-173 (2001). Neverov, A.A., et al. “Europium Ion Catalyzed Methanolysis of Bosch, E., et al. “Retention of Ionizable Compounds on HPLC. pH Esters at Neutral pH and Ambient Temperature. Catalytic Involve Scale in -Water and the pK and pH Values of Buffers”. ment of Eu"(CHO-)(CH3OH)”-Inorganic Chemistry.42: 228-234 Analytical Chemistry. 68: 3651-3657 (1996). Bosch, E., et al. “Hammett-Taft and Drago Models in the Prediction (2003). of Acidity Constant Values of Neutral and Cationic Acids in Metha Okano, T., et al. “Transesterification Catalyzed by Lanthanoid Tri-2- nol”. J. Chem. Soc., Perkin Trans. 2: 1953-1958 (1999). propoxides”. Chemistry Letters. 246-258 (1995). Brown, R.S., et al. “ of Neutral Phosphate and Rived, F., et al. “Dissociation Constants of Neutral and Charged Phosphonate Esters Catalysed by Co'-chelates of Tris-imidazolyl Acids in Methyl Alcohol. The Acid Strength Resolution”. Analytica Phosphines”. Inorganica Chimica Acta: 108: 201-207 (1985). Chimica Acta. 374; 309-324 (1998). Brown, R.S., et al. "Acyl and Phosphoryl Transfer to Methanol Pro Tsang, J.S.W., et al. La"-Catalyzed Methanolysis of Hydropropyl moted by Metal Ions”. J. Chem. Soc., Perkin Trans. 2: 1039-1049 p-nitrophenyl Phosphate as a Model for the RNA Transesterification (2002). Reaction. J. Am. Chem. Soc. 125: 1559-1566 (2003). Brown, R.S., et al. “La"-Catalyzed Methanolysis of Hydroxypropyl Tsang, J.S.W., et al. "Billion-fold Acceleration of the Methanolysis p-nitrophenyl Phosphate as a Model for the RNA Transesterification of Paraoxon Promoted by La(OTf) in Methanol'. J. Am. Chem. Soc. Reaction”. 39' IUPAC Congress and 86' Conference of the Cana 125: 7602-7607 (2003). dian Society for Chemistry. Ottawa, Ontario, Aug. 10-15, 2003. Yang, Y-C., et al. “Decontamination of Chemical Warfare Agents”. (Abstract). Chem. Rev.92: 1729-1743 (1992). Buncel, E., et al. “Alkali Metal Ion Catalysis in Nucleophilic Dis Yang, Y.-C., et al. “Chemical Reactions for Neutralizing Chemical placement by Ethoxide Ion on p-nitrophenyl Phenylphosphonate: Warfare Agents”. Chemistry & Industry (London). 9: 334-337 Evidence for Multiple Metal Ion Catalysis”. Can. J. Chem. 81: 53-63 (1995). (2003). Yang, Y-C., et al. “Peroxyhydrolysis of Nerve Agent VX and Model Clewley, R.G., et al. “Mono and Dinuclear M'Chelates as Catalysts Compounds and Related Nucleophilic Reactions”. J. Chem. Soc., for the Hydrolysis of Organophosphate Triesters”. Inorganica Perkin Trans. 2:607-613 (1997). Chimica Acta. 157: 233-238 (1989). Yang, Y-C. “Chemical Detoxification of Nerve Agent VX”. Acc. Desloges, W., et al. “Zn"-Catalyzed Methanolysis of Phosphate Chem. Res. 32: 109-115 (1999). Triesters: A Process for Catalytic Degradation of the Barr, L., etal. "Metallocyclodextrin Catalysts for Hydrolysis of Phos Organophosphorus Pesticides Paraoxon and Fenitrothion”. Inor phate Triester”, Tet. Lett., 43: 7797-7800 (2002). ganic Chemistry. Submitted (2003). Bunton, C. A., et al. “Source of Catalysis of Dephosphorylation of Gans, P. etal. “Investigation of Equilibria in Solution. Determination p-nitrophenyldiphenylphosphate by Metallomicelles'. J. Chem. of Equilibrium Constants with the HYPERQUAD Suite of Pro Soc., Perkin Trans. 2, 3:419–425 (1996). grams”. Talanta. 43(10): 1739-1753 (1996). Scrimin, P. et al. "Metallomicelles as Catalysts of the Hydrolysis of Gibson, G., et al. "Potentiometric Titration of Metal Ions in Metha Carboxylic and Phosphoric Acid Esters”. J. Org. Chem. 56: 161-166 nol”. Can. J. Chem. 81: 495-504 (2003). (1991). Ketelaar, J.A.A., et al. “Metal-catalysed Hydrolysis of Thiophosphoric Esters”. Nature. 177: 392–393 (1956). * cited by examiner

U.S. Patent May 13, 2014 Sheet 2 of 10 US 8,722,956 B2

S

H CHOH H n r / S 3 p Hoo--och,OCH CN d YoCH,N -- to OCH ( e. -- NO2

Figure 1C {Cu°12laneNsfoCH.)

0.03

0.00 0.0000 0.0005 0.0010 0.0015 La(OTf), M

Figure 2 U.S. Patent May 13, 2014 Sheet 3 of 10 US 8,722,956 B2

5 6 7 8 9 10 11

Figure 3 U.S. Patent May 13, 2014 Sheet 4 of 10 US 8,722,956 B2

La2(OCH3)2 La2(OCH3)4 OOOO8

0.0006 N OOOO4 :

Figure 4 U.S. Patent May 13, 2014 Sheet 5 of 10 US 8,722,956 B2

O f 2 3 4. 5 6 Cu(OTf)2total, mM Figure 6 U.S. Patent May 13, 2014 Sheet 6 of 10 US 8,722,956 B2

100

8 n 60

40

O.O 0.5 1.0 1.5 Cu(OTf)2total, m

Figure 7

600

5OO

4 O O

3 O O

2 O O

(NaOMe), mM

Figure 8 U.S. Patent May 13, 2014 Sheet 7 of 10 US 8,722,956 B2

Zn(OTf), mM Figure 9A

750

Zn(OTf)2), mM Figure 9B U.S. Patent May 13, 2014 Sheet 8 of 10 US 8,722,956 B2

1.OC

9 0.75

s

OSO

is 0.25

O.OO O 250D 5000 7500 10000 Time, sec

Figure 10

50

40 s E 30

s 20

10

O O 0.5 10 15 2.0 Equivalents of NaOMe.

Figure 11 U.S. Patent May 13, 2014 Sheet 9 of 10 US 8,722,956 B2

1OO

75

50

25

O 2 Zn(ClO4)2total, mV. Figure 12

(OCH3)/(Znflotal

Figure 14 U.S. Patent May 13, 2014 Sheet 10 of 10 US 8,722,956 B2

1250

1000 0.0020 S. t s is 3. rs 500--1------0.000 2 D. vs 250 0.0005 s

OOOOO 0.0000 O,0005 0.001 O 0.0015 0.0020 0.0025 Zn(OTf)2]otal, M Figure 13A

100

75 re w S. E 9. i 50 g se b. 25 s

O.OOOO O.OOO5 O.OOO 0.0015 O.0020 Zn (OTf)2a, M Figure 13B US 8,722,956 B2 1. KT FOR DECOMPOSING ORGANOPHOSPHORUS COMPOUNDS O O

RELATED APPLICATIONS N(CH3)2 / Tabun (GA) (GB) This application is a continuation of U.S. patent applica tion Ser. No. 1 1/713,805, filed Mar. 5, 2007, now U.S. Pat. O No. 7,875,739, issued Jan. 25, 2011, which is a continuation | O of U.S. patent application Ser. No. 10/798,880, filed Mar. 12, 10 O-P-F 2004, now U.S. Pat. No. 7,214,836, issued May. 8, 2007, and O-P-F claims the benefit of the filing date of U.S. Provisional Patent Application No. 60/453,762, filed Mar. 12, 2003, the contents Soman (GD) GF of which are incorporated herein by reference in their entirety. 15 FIELD OF THE INVENTION Y 1so s-1- This invention relates to methods of decomposing organo phosphorus compounds. The invention more particularly N. relates to metal ion and metal species catalysis of an alco holysis reaction which converts toxic organophosphorus compounds into non-toxic compounds. The invention further ) relates to lanthanum ion catalyzed degradation of chemical 25 warfare agents, insecticides and pesticides. ----- BACKGROUND OF THE INVENTION Russian-VX

30 The Chemical Weapons Convention was adopted by the Although some chemical warfare agents are water Soluble, Conference on Disarmament in Geneva on Sep. 3, 1992, they may be applied in combination with a polymer so that, entered into force on Apr. 29, 1997, and calls for a prohibition being thickened, they adhere well to surfaces. These “thick of the development, production, Stockpiling and use of ened’ agents are only minimally soluble in water. In the case chemical weapons and for their destruction under universally 35 of decomposition using a hydrolysis reaction, products in applied international control. Eliminating the hazard of which a phosphorus-Sulfur bond is preserved are common; chemical warfare agents is desirable both in storage sites and these are toxic in their own right and are relatively resistant to on the battlefield. Decontamination of battlefields requires further reaction. Another disadvantage of an aqueous decon speed and ease of application of decontaminant. Surfaces tamination system is that hydrolysis reactions are not cata involved pose a challenge for decontamination techniques 40 lytic, and therefore require Stoichiometric amounts of since some Surfaces absorb Such agents, making decontami reagents. Furthermore, commonly used aqueous methods, nation difficult. Examples of surfaces that could be involved due to their alkaline pH, are not suitable for decontamination include those of tanks, ships, aircraft, weapons, electronic of human skin. Yet another disadvantage of aqueous decon devices, ground, protective clothing and human skin. The 45 tamination methods is the caustic wastewater produced as an decontaminants should not be corrosive, so that Surfaces are end product, which poses a challenge for disposal. not damaged during/following decontamination. An opti Historically, decontamination of chemical warfare agents mum of a decontaminating method should provide has been effected using hydrolysis or oxidation using bleach ease of application, of the chemical warfare agent, or alkali salts. Bleach is corrosive to skin, rubber, and metal non-corrosiveness, and minimal environmental contamina 50 surfaces and is ineffective in cold weather conditions. Alkali tion. Since the establishment of the Convention, considerable salts require excess hydroxide ion in order for the reaction to effort has been directed toward methods of facilitating the go to completion rapidly, thus resulting in a caustic product. controlled decomposition of organophosphorus compounds. Non-catalytic methanolysis of V-agents has been studied, Aqueous decontamination systems, such as hydrolysis sys wherein the reaction of VX with alkoxide leads primarily to a tems, have been used in the past, most notably for nerve 55 displacement of the SR group (Yang et al., 1997). agents, particularly for the G-agents tabun (GA), Sarin (GB). Transition metalions and lanthanide series ions and certain soman (GD) and GF. However, hydrolysis reactions are not mono- and dinuclear complexes thereof are known to pro Suitable for all chemical warfare nerve agents such as mote hydrolysis of neutral phosphate and/or phosphonate V-agents VX (S-2-(diisopropylamino)ethyl O-ethyl meth esters. However, the available literature on the hydrolysis of ylphosphonothiolate) and Russian-VX (S-2-(diethylamino) 60 phosphothiolate (P=S) esters and phosphothiolates is quite ethyl O-isobutyl methylphosphonothiolate), whose decon sparse with only the softer ions such as Cu, Hg" and Pd* tamination chemistries are very similar to one another (Yang, showing significant catalysis. The lack of examples may be 1999). The V-agents are about 1000-fold less reactive with due to reduced activity of Pi—S esters, their poor aqueous hydroxide than the G-agents (due to their poor solubility in solubility and the fact that anionic hydrolytic products bind to water under basic conditions), and they produce product mix 65 the metal ions thereby inhibiting further catalysis. tures containing the hydrolytically stable, but toxic, thioic There is a need for a viable catalytic decontamination acid byproduct. method which is inexpensive, has high catalyst turnover, and US 8,722,956 B2 3 4 occurs at relatively neutral pH and ambient temperature, and In further embodiments, said medium further comprises most importantly, proceeds rapidly, e.g. t <1 min. alkoxide ions in addition to said at least a trace amount of alkoxide ions. BRIEF STATEMENT OF THE INVENTION Infurther embodiments, the concentration of said alkoxide ions is about 0.1 to about 2 equivalents of the concentration of According to one aspect of the invention there is provided the metal ions. a method for decomposing an organophosphorus compound Infurther embodiments, the concentration of said alkoxide comprising Subjecting said organophosphorus compound to ions is about 1 to about 1.5 equivalents of the concentration of an alcoholysis reaction in a medium comprising non-radio the metal ions. active metal ions and at least a trace amount of alkoxide ions, 10 In further embodiments, said medium is prepared by com wherein, through said alcoholysis reaction, said organophos bining a metal salt and an alkoxide salt with at least one of phorus compound is decomposed. alcohol, alkoxyalkanol and aminoalkanol. In one embodiment of the invention, said organophospho In further embodiments, said metal ions are selected from rus compound has the following formula (10): the group consisting of lanthanide series metalions, transition 15 metal ions, and combinations thereof. In further embodiments, said metal ions are selected from the group consisting of lanthanide series metal ions, copper, (10) platinum, palladium, Zinc, nickel, yttrium, Scandium ions, and combinations thereof. In further embodiments, said metal ions are selected from the group consisting of Cut, Pt, Pd, Zn, Y, Sc", Ce", La", Pr", Nd", Sm", Eu", Gd", Tb3+, Dy", Ho", Er", Tm, Yb", and combinations thereof. where: In further embodiments, said metal ions are lanthanide J is O or S: 25 series metal ions. X, G, Z are the same or different and are selected from the In further embodiments, said lanthanide series metal ions group consisting of Q, OQ, QA, OA, F, Cl, Br, I, QS, SQ and are selected from the group consisting of Ce", La", Pr", C=N; Nd", Sm", Eu", Gd", Tb3+, Dy", Ho", Er", Tm, Yb", Q is hydrogen or a substituted or unsubstituted branched, and combinations thereof. straight-chain or cyclic alkyl group having 1-100 carbon 30 In further embodiments, said metal ions are selected from atoms; and the group consisting of Cui", Pt", Pd", Zn", and combina A is a substituted or unsubstituted aryl group selected from tions thereof. the group consisting of phenyl, biphenyl, benzyl, pyridyl, In further embodiments, said metal ions are selected from naphthyl, polynuclear aromatic, and aromatic and non-aro the group consisting of Y", Sc", and combinations thereof. matic heterocyclic; 35 In further embodiments, said metal ion is La". wherein, when X, G, Z are the same, In further embodiments, said organophosphorus com (i) X, G, Z are not Q; or pound is a pesticide. (ii) Q is not H; and In further embodiments, said organophosphorus CO wherein said Substituents are selected from the group con pound is an insecticide. sisting of Cl, Br, I, F, nitro, nitroso, Q, alkenyl, OQ, carboxy 40 In further embodiments, said organophosphorus CO alkyl, acyl, SOH, SOO, S—O(Q), S(=O)C, amino, alky pound is paraoxon. lamino (NHQ), arylamino (NHA), alkylarylamino, In further embodiments, said organophosphorus CO dialkylamino and diarylamino. pound is a chemical warfare agent. In some embodiments, said medium is a solution further In further embodiments, said organophosphorus CO comprising a solvent selected from the group consisting of 45 pound is a G-agent. methanol, Substituted and unsubstituted primary, secondary In further embodiments, said organophosphorus com and tertiary , alkoxyalkanol, aminoalkanol, and com pound is selected from the group consisting of VX and Rus binations thereof. sian-VX. In a preferred embodiment, said organophosphorus com In further embodiments, said organophosphorus com pound has at least one phosphorus atom double bonded to an 50 pound is a nerve agent. oxygen or a sulfur atom. In further embodiments, said chemical warfare agent is In another embodiment, said medium further comprises a combined with a polymer. non-inhibitory buffering agent. In further embodiments, said medium further comprises In yet another embodiment said buffering agent is selected one or more ligands. from the group consisting of anilines, N-alkylanilines, N.N- 55 In further embodiments, said ligand is selected from the dialkylanilines, N-alkylmorpholines, N-alkylimidazoles, group consisting of 2,2'-bipyridyl, 1,10-phenanthryl, 2.9- 2,6-dialkylpyridines, primary, secondary and tertiary , dimethylphenanthryl, crown ether, and 1.5.9-triazacy trialkylamines, and combinations thereof. clododecyl. In another embodiment, said medium is a solution further In further embodiments, said ligand further comprises comprising a solvent selected from the group consisting of 60 Solid Support material. methanol, , n-propanol, iso-propanol, n-butanol, In further embodiments, said solid Support material is 2-butanol, methoxyethanol, and combinations thereof. selected from a polymer, silicate, aluminate, and combina In further embodiments, said solution further comprises a tions thereof. Solvent selected from the group consisting of nitriles, esters, In further embodiments, said medium is a solid. ketones, amines, ethers, hydrocarbons, Substituted hydrocar 65 In further embodiments, said medium is a solution. bons, unsubstituted hydrocarbons, chlorinated hydrocarbons, In further embodiments, said solution is disposed on an and combinations thereof. applicator. US 8,722,956 B2 5 6 Infurther embodiments, the concentration of said alkoxide FIG. 7 shows the effect of Cu"12laneN:(OCH) (cop ions is about 0.5 to about 1.5 equivalents of the concentration per triflate in the presence of equimolar ligand and 0.5 equiva of the metal ions. lents of methoxide) on the rate of methanolysis of paraoxon In another broad aspect, the invention provides a kit for (O) and fenitrothion () as a plot of the k vs. total concen decomposing an organophosphorus compound comprising a 5 tration of Cu(OTf), conducted at T=25° C. Substantially non-aqueous medium for an alcoholysis reac FIG. 8 shows the effect of methoxide ion concentration on tion, said medium comprising non-radioactive metalions and the rate of Zn"-catalyzed methanolysis of paraoxon as plots at least a trace amount of alkoxide ions. ofk vs added NaOCH for the methanolysis of paraoxon in In a first embodiment, said medium is contained in an the presence of 1 mM Zn(CIO), where: ampule. 10 O, no added ligand; (), 1 mM phen; In a second embodiment, the kit comprises an applicator O, 1 mM diMephen; and bearing the medium, said applicator being adapted so that the 1 mM 12aneN medium is applied to the organophosphorus compound and (lines through the data drawn as visual aid only). the compound decomposes. 15 FIG. 9A shows the catalyzed methanolysis offenitrothion In some embodiments, the kit further comprises written as a plot of k vs. concentration of zinc ion (Zn(OTf).) instructions for use. alone, and in the presence of equimolar ligand at constant (OCH)/Zn", ratios, where: BRIEF DESCRIPTION OF THE DRAWINGS O, no ligand, (OCH)/Zn' O.3: O, phen, (OCH)/Zn"I-0.5; and For a better understanding of the invention and to show l, diMephen, (OCH)/Zn, 1.0. more clearly how it may be carried into effect, reference will FIG.9B shows the catalyzed methanolysis of paraoxon as now be made by way of example to the accompanying draw a plot of k vs. concentration of Zinc ion (Zn(OTf)) alone ings, which illustrate aspects and features according to pre and in the presence of equimolar ligand at constant ferred embodiments of the present invention, and in which: 25 (OCH)/Zn", ratios, where: FIG. 1A shows a proposed mechanism for catalysis by a O, no ligand, (OCH)/Zn' O.3: lanthanum methoxide dimer of the methanolysis of an aryl O, phen, (OCH)/Zn"I-0.5; and phosphate. l, diMephen, (OCH)/Zn, 1.0. FIG. 1B shows a proposed mechanism for catalysis by a FIG. 10 shows the disappearance of paraoxon (O) and Zinc methoxide complex of the methanolysis of an aryl phos 30 appearance of diethyl methyl phosphate () product over phate. time for a methanolysis reaction in the presence of Zinc ion, FIG.1C shows the reaction scheme for Cu: 12aneN, cata methoxide, and ligand in deuterated methanol in a plot of lyzing the methanolysis offenitrothion. relative signal integration of the reagent and product PNMR FIG. 2 shows a plot of k vs. concentration of La(OTf). signals for a system containing 15 mM paraoxon, 1 mM for the La"-catalyzed methanolysis of paraoxon (2.04x10 35 Zn(OTf), 1 mM NaOCH and 1 mM diMephen at T=25° C. M) at 25°C., where FIG. 11 shows the effect of increasing concentration of , pH 8.96: methoxide on the rate of Zn"-catalyzed methanolysis of O, pH 8.23; and paraoxon in a plot of the pseudo-first order rate constants O, pH 7.72. (k) for methanolysis of paraoxon in the presence of 1 mM FIG.3 shows a plot of the log k. (M's) vs. pH for 40 Zn(OTf), and absence of added ligand as a function of added La"-catalyzed methanolysis of paraoxon at 25°C. The dot NaOCH. ted line through the data was computed on the basis of a fit of FIG. 12 shows the effect of zinc ion concentration on the the k data to equation 3, the two dominant forms being rate of Zn"-catalyzed methanolysis of paraoxon as plots of La(OCH) and La(OCH). the k for the methanolysis offenitrothion (O), paraoxon FIG. 4 shows a speciation diagram for the distribution of 45 (O) and p-nitrophenyl acetate () vs. Zn(CIO), at a con La(OCH), forms in methanol, n=1-5, as a function of pH, stant Zn"(OCH)/Zn" ratio of 0.3, T=25° C. Lines calculated for La(OTf)=2x10 M. Data represented as through the data are calculated on the total basis of fits to (O) correspond to second order rate constants (k”) for equation (6). La"-catalyzed methanolysis of paraoxon presented in Table FIG. 13A shows the effect of Zn":12laneN, on the rate of 13. 50 Zn"-catalyzed methanolysis of paraoxon as a plot ofk, for FIG. 5 shows a plot of the predicted k” vs. pH rate methanolysis of paraoxon as a function of Zn(OTf), profile for La"-catalyzed methanolysis of paraoxon (- - - ) containing equimolar 12aneN and NaOCH, T-25° C. based on the kinetic contributions of La(OCH) ( . . . ) Right axis gives Zn":12laneN:(OCH) determined by La(OCH) (solid line) and La(OCH), (---) computed HyperquadTM fitting of titration data. The arrows are pre from the k", k, and k, rate constants (Table 14), and 55 sented as a visual aid to connect the various species concen their speciation (FIG. 4); data points () are experimental trations with the kinetic rate constant. k.” rate constants from Table 13. FIG. 13B shows the effect of Zn":phen on the rate of FIG. 6 shows the effect of copper triflate (in the presence of Zn"-catalyzed methanolysis of paraoxon as a plot ofk, for equimolar ligand and 0.5 equivalents of methoxide) on the methanolysis of paraoxon as a function of Zn(OTf), rate of methanolysis offenitrothion as a plot of the k Vs. 60 containing equimolar phen and NaOCH, T-25° C. Right total concentration of Cu(OTf), for the methanolysis offeni axis gives Zn":phen:(OCH) determined by Hyper trothion catalyzed by various species at T=25° C. and quadTM fitting of titration data. The arrows are presented as a OCH/Cut 0.5, when ligand is used, Cul visual aid to connect the various species concentrations with Ligand, where the kinetic rate constant. O, Cu":no ligand:(OCH)}: 65 FIG. 14 shows the titration profiles obtained by potentio 0, Cut:phen:(OCH); and metric titration of 2 mM Zn(OTf) with no added ligand (O), with 2 mM phen (0), with 2 mM diMephen (), with 2 mM US 8,722,956 B2 7 8 12|aneN. (D) and with 1.2 mMadded HClO. Lines through As used herein, the term “pH is used to indicate pH in a the titration curves with phen and 12laneN, were derived non-aqueous solution (Bosch et al., 1999, Rived et al., 1998, from HyperquadTM fitting of the data. Bosch et al., 1996). One skilled in the art will recognize that if a measuring electrode is calibrated with aqueous buffers DETAILED DESCRIPTION OF THE INVENTION 5 and used to measure pH of an aqueous Solution, the term "pH is used. If the electrode is calibrated in water and According to a broad aspect of the invention there is pro the pH of a neat methanol solution is then measured, the vided a method of decomposing an organophosphorus com term "pH is used, and if the latter reading is made, and a pound by combining the organophosphorus compound with a correction factor of 2.24 (in the case of methanol) is added, Substantially non-aqueous medium comprising alcohol, 10 alkoxyalkanol oraminoalkanol, metalions and at least a trace then the term pH is used. amount of alkoxide ions. When so combined the organophos As used herein, the term “non-inhibitory agent or com phorus compound undergoes an alcoholysis reaction and pound” means that the agent or compound does not substan forms a less toxic or non-toxic compound. tially diminish the rate of a catalyzed reaction when com More particularly, the invention provides a method of 15 pared to the rate of the reaction in the absence thereof. increasing the rate of decomposition of an organophosphorus As used herein, the term “inhibitory agent or compound compound by combining the compound with a catalytic spe means that the agent or compound does Substantially dimin cies formed in a Substantially non-aqueous medium compris ish the rate of a catalyzed reaction when compared to the rate ing metal ions; alcohol, alkoxyalkanol or aminoalkanol; and of the reaction in the absence thereof. alkoxide ions. In some embodiments, the medium is a solu tion. As used herein, the term “metal species' means a metal in As used herein, the term “alcohol means a compound an oxidation state of Zero to 9. which comprises an R-OH group, for example, methanol, As used herein, the term "mononuclear” or "monomeric' primary alcohols, and Substituted or unsubstituted secondary means a species comprising one metal atom. alcohols, tertiary alcohols, alkoxyalkanol, aminoalkanol, or a 25 mixture thereof. In an embodiment of the invention, the catalytic species is As used herein, “substantially non-aqueous medium’ a metal alkoxide species of the Stoichiometry means an organic solvent, solution, mixture or polymer. As it {M"(OR),L} where M is a metal selected from lan is very difficult to obtain anhydrous alcohol, a person of thanide series metals or transition metals; n is the charge on ordinary skill in the art would recognize that trace amounts of 30 the metal which may be 1 to 9, most preferably 2 to 4: OR is water may be present. For example, absolute ethanol is much alkoxide; m is the number of associated alkoxide ions and less common than 95% ethanol. However, the amount of alcohol present in a medium or solution according to the may be 1, 2, ..., n-1, n, n+1, n+2, ... n+6, most preferably invention should not have so much water present as to inhibit 1 to n-1, S is 1 to 100; L is ligand; g is the number of ligands the alcoholysis reaction, nor should a Substantial amount of 35 complexed to the metal ion, and may be 0 to 9; where g is hydrolysis occur. greater than 1, the ligands may be the same or different. As used herein, the term “organophosphorus compound' Examples of this embodiment include the lanthanum dimer includes compounds which comprise a phosphorus atom dou {La"(OMe), and copper monomer Cu(OMe)L}. bly bonded to an oxygen or a sulfur atom. In preferred embodiments such organophosphorus compounds are delete 40 The inventors contemplate an embodiment wherein the rious to biological systems, for example, a compound may be oxidation state of the metal atom is Zero. For example, it is an acetylcholine esterase inhibitor, a pesticide or a chemical well known in the art that transition metals having an oxida warfare agent. tion state of Zero may be reactive and may form complexes. As used herein, the term “decomposing an organophospho Copper is an example of Such a metal, and it is expected that rus compound” refers to rendering a deleterious organophos 45 Cu" may catalyze alcoholysis of organophosphorus com phorus compound into a less toxic or non-toxic form. pounds according to the invention. Decomposition of an organophosphorus compound As used herein, the term “ligand’ means a species contain according to the invention may be carried out in Solution ing a donor atom or atoms that has a non-bonding lone pair or form, or in Solid form. Examples of Such decomposition pairs of electrons which are donated to a metal centre to form include, applying catalyst as a solution directly to a solid 50 one or more metal-ligand coordination bonds. In this way, chemical warfare agent or pesticide. Sucha Solution would be ligands bond to coordination sites on a metal and thereby limit for example, an appropriately buffered alcoholic, alkoxyal dimerization and prevent further oligomerization of the metal kanolic or aminoalkanolic solution comprising metal ions species, thus allowing a greater number of active mono and alkoxide ions, in which one or more catalytic species nuclear species to be present than is the case in the absence of forms spontaneously, which may be applied to a Surface 55 ligand or ligands. which has been contacted with an organophosphorus agent. As used herein, the term “catalytic species' means a mol As used herein, the term “{M":L:OR}” (which differs ecule or molecules, comprising metal ions and alkoxide ions, from the above described system, {M"(OR),L} by the whose presence in an alcoholic, alkoxyalkanolic or aminoal use of the symbol":” between constituents of the brace"{ }) kanolic solvent containing an organophosphorus compound 60 is used when no stoichiometry is defined for a system com increases the rate of alcoholysis of the organophosphorus prising metal ions (M'), ligand (L), and alkoxide (TOR). compound relative to its rate of alcoholysis in the solvent This technique is meant to encompass any and all catalyti without the catalytic species. cally active stoichiometries thereof including but not limited As used herein, the term “appropriately buffered” means to dimers, trimers and longer oligomers, monoalkoxides, that the pH of a solution is controlled by adding non-inhibi 65 dialkoxides, polyalkoxides, etc. tory buffering agents, or by adding about 0.1 to about 2.0 In another embodiment of the invention, the catalytic spe equivalents of alkoxide ion per equivalent of metal ion. cies has the general formula 20: US 8,722,956 B2 10 In another embodiment of the invention, the catalytic spe (20) cies has the general formula 30: where Z is a non-radioactive lanthanide series metalion or a transition metal ion; R° and R are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocarbon con taining 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 10 net positive charge. where Z" and Z are the same or different non-radioactive Another embodiment of the invention, the catalytic species lanthanide, copper, platinum or palladium ions; has the general formula 30: R", R, R and R are each independently alkyl groups where Z is a non-radioactive lanthanide series metalion or a transition metal ion; selected from a branched, cyclic or straight-chain hydrocar 15 R° and R are each independently alkyl groups selected bon containing 1-12 carbon atoms, preferably 1-4 carbon from a branched, cyclic or straight-chain hydrocarbon con atoms; taining 1-12 carbon atoms, preferably 1-4 carbon atoms; p is a number from 1-6; and a is a number from 1-3; and m and q are each independently Zero or 1 or more, prefer b is Zero or 1 or more, Such that the catalytic species has a ably 1-5, such that the dimer has a net charge of Zero. net positive charge; In another embodiment of the invention, the catalytic spe wherein unoccupied coordination sites on the metal may be cies has the general formula 20: occupied by one or more ligands. where Z" and Z are the same or different non-radioactive In another embodiment of the invention, the catalytic spe lanthanide series metal ions, copper, platinum or palladium cies has the general formula 40: ions; 25 R", R, R and R are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocar (40) bon containing 1-12 carbon atoms, preferably 1-4 carbon m R5d * atoms; p is a number from 1-6; and 30 f O O m and q are each independently Zero or 1 or more, prefer Z3 OR3 ably 1-5, such that the dimer has a net charge of Zero. In another embodiment of the invention, the catalytic spe (RO)- 7S -f / (OR), cies has the general formula 20: 35 where Z and Z are the same or different non-radioactive R4 R6 lanthanide series metal ions, and/or transition metal ions; R R. R. R. and R are each independently alkyl groups selected from a branched, cyclic or straight-chain hydrocar where Z, Z and Z are the same or different non-radioac bon containing 1-12 carbon atoms, preferably 1-4 carbon 40 tive lanthanide, copper, platinum or palladium ions; atoms; R", R. R. R. R. Rand Rare each independently alkyl p is a number from 0-6; and groups selected from a branched, cyclic or straight-chain m and q are each independently Zero or 1 or more, prefer hydrocarbon containing 1-12 carbon atoms, preferably 1-4 ably 1-5. Such that the dimer has a net positive charge. carbon atoms; In another embodiment of the invention, the catalytic spe 45 p is a number from 1-4; cies has the general formula 20: m, d, q and t are each independently Zero or 1 or more, where Z" and Z are the same or different non-radioactive preferably 1-5. Such that the oligomer has a net charge of Zero; lanthanide series metal ions, and/or transition metal ions; and R", R, R and R are each independently alkyl groups r is a number from 0 to 100, or in the case of polymeric selected from a branched, cyclic or straight-chain hydrocar 50 material may be greater than 100. bon containing 1-12 carbon atoms, preferably 1-4 carbon In yet another embodiment of the invention, the catalytic atoms; species has the general formula 40: p is a number from 1-6; and where Z, Z and Z are the same or different non-radioac m and q are each independently Zero or 1 or more, prefer tive lanthanide series metal ions, or transition metal ions or ably 1-5. Such that the dimer has a net positive charge. 55 combinations thereof; In another embodiment of the invention, the catalytic spe R", R. R. R. R. Rand Rare each independently alkyl cies has the general formula 30: groups selected from a branched, cyclic or straight-chain hydrocarbon containing 1-12 carbon atoms, preferably 1-4 carbon atoms; where Z is a non-radioactive lanthanide, copper, platinum 60 p is a number from 1-4; or palladium ion; m, d, q and t are each independently Zero or 1 or more, R and R are each independently alkyl groups selected preferably 1-5, such that the oligomer has a net positive from a branched, cyclic or straight-chain hydrocarbon con charge; and taining 1-12 carbon atoms, preferably 1-4 carbon atoms; r is a number from 0-100, or in the case of polymeric a is a number from 1-3; and 65 material may be greater than 100. b is Zero or 1 or more, such that the catalytic species has a The alcoholic solution comprises a primary, secondary or net charge of Zero. tertiary alcohol, analkoxyalkanol, an aminoalkanol, or a mix US 8,722,956 B2 11 12 ture thereof. In one embodiment, a non-inhibitory buffering ligand. Although not meant to be limiting, examples of Such agent is added to the solution to maintain the pH at the ligands are 2,2'-bipyridyl (“bpy), 1,10-phenanthryl optimum range of pH, for example in the case of La" in (“phen'), 2,9-dimethylphenanthryl (“diMephen') and 1.5.9- methanol, pH 7 to 11 (see FIG. 3). Examples of non-inhibi triazacyclododecyl (“12aneN), crown ether, and their tory buffering agents include: anilines: N-alkylanilines; N.N- Substituted forms. Such ligands may be attached via linkages dialkylanilines: N-alkylmorpholines; N-alkylimidazoles: to solid Support structures such as polymers, silicates or alu 2,6-dialkylpyridines; primary, secondary and tertiary amines minates to provide Solid catalysts for the alcoholysis of orga Such as trialkylamines; and their various derivatives. nophosphorus compounds which are decomposed according In another embodiment, non-inhibitory buffering agents to the invention. The point of attachment of the metal:ligand: are not added, but additional alkoxide ion is added in the form 10 of an alkoxide salt to obtain metalions and alkoxide ions in a alkoxide complex to the solid support is preferably at the 3 or metal:alkoxide ratio of about 1:0.01 to about 1:2, for some 4 position in the case of bipyridyl or the 3, 4 or 5 position in embodiments preferably about 1:1 to about 1:1.5, for other the case of phenanthrolines using linking procedures and embodiments preferably about 1:0.5 to about 1:1.5. A person connecting spacers which are known in the art. In the case of skilled in the art will recognize that an alcoholic solution 15 aza ligands, such as, for example, 12laneN, the point of contains trace amounts of alkoxide ions. This concept is attachment of the complex to the solid support would prefer analogous to water containing a trace amount of hydrogen ably be on one of the nitrogens of the macrocycle, using ions and hydroxide ions, thus water of pH 7 contains, by methods and connecting spacers known in the art. Such definition, H=1x107M and OH=1x107 M. For this attachment to Solid Supports offers advantages in that the reason, when alkoxide Salts are added according to this Solid catalysts may be conveniently recovered from the reac embodiment of the invention, they are referred to as “addi tion media by filtration or decantation. In an embodiment of tional alkoxide ions. Suitable non-inhibitory cations for the the invention wherein ligands are attached to Solid Support alkoxide salts include monovalentions such as, for example, structures, organophosphorus compounds may be decom Na', K", Cs", Rb", NR." and NR'R"R"R" (where R', R", posed by running a solution through a column Such as a R", and R" may be the same or different and may be hydro 25 chromatography column. In another embodiment of the gen or Substituted or unsubstituted alkyl or aryl groups) and invention wherein ligands are attached to Solid Support struc divalentions such as the alkali earth metals, and combinations tures, organophosphorus compounds may be decomposed by thereof. In some instances such ions may prolong the life of a contact with a polymer comprising metal species and alkox catalyst by bonding to and, for example, precipitating, an ide ions. inhibitory product of organophosophorus decomposition, an 30 Suitable anions of the metal salts are non-inhibitory or example of which is Ca" bonding to fluoride. substantially non-inhibitory and include, for example, CIO, To obtain the metal ions, metal salts are added to the solu BF, BRI, Br, CFSO, (also referred to herein as "tri tion. Preferably, the metalion is a non-radioactive lanthanide flate' or “OTf) and combinations thereof. Preferred anions series metal ion. Suitable lanthanide series metal ions are CIO, and CFSO. In the case of BF, a solvent other include, for example, Ce", La", Pr, Nd, Sm", Eu", 35 than methanol is preferred. Gd, Tb, Dy, Ho, Er, Tm and Yb and combina The solution comprises , wherein preferred sol tions thereof or complexes thereof. Suitable non-lanthanide vents are alcohols, including primary and secondary alcohols series metal ions include, for example, divalent transition Such as methanol, ethanol, n-propanol, iso-propanol, n-bu metal ions such as, for example, Cu, Pd, Pt", Zn", and tanol, 2-butanol and methoxyethanol, and combinations trivalent transition metal ions such as, for example, Sc" and 40 thereof. Most preferably the solution is all alcohol or all Y", as well as combinations thereof or complexes thereof, alkoxyalkanol or all aminoalkanol; however, combinations including combinations/complexes of those with non-radio with non-aqueous non-inhibitory solvents can also be used, active lanthanide series metal ions. While La" (pKa=7.8) including, for example, nitriles, ketones, amines, ethers, has good catalytic efficacy from pH 7.3 to 10.3, other metal hydrocarbons including chlorinated hydrocarbons and esters. ions which have lower pKa values (for example Ho" and 45 In the case of esters, it is preferable that the alkoxy group is Eu" have pKa values of 6.6, while Yb" has a pKa value the same as the conjugate base of the solventalcohol. In some of 5.3, Gibson et al. 2003) may be efficacious at lower pH. embodiments, esters may cause side reactions which may be An embodiment of the invention is a catalytic system com inhibitory. prising mixtures of metal ions, for example, mixtures of lan Initial studies have been undertaken in methanol since thanide series metal ions which would be active between the 50 methanol is closest to waterinterms of structure and chemical wide pH range of 5 to 11. Lanthanide series metal ions and properties and is readily available. However, methanol is less alkoxide may form several species in Solution, an example of desirable than other solvents due to its toxicity and its rela which, species forming from La" and methoxide is shown in tively low boiling point of 64.7°C. which makes it volatile the figures. In the case of La", a dimer containing 1 to 3 and prone to evaporation from open vessels. For these rea alkoxides is a particularly active catalyst for the degradation 55 Sons, use of higher alcohols such as ethanol, n-propanol and of organophosphorus compounds. In the case of non-lan iso-propanol has been explored (see Examples 1 and 2). Etha thanide series metalions, such as, for example Zn" and Cui", nol, n-propanol and iso-propanol are Substantially less Vola a mononuclear complex containing alkoxides is an active tile (boiling points 78.97.2 and 82.5°C. respectively), are less catalyst for the degradation of organophosphorus com toxic, and have better solubilizing characteristics for hydro pounds. 60 philic Substrates. The higher boiling points mean that these In some embodiments, the invention provides limiting of solvents are more amenable to field conditions since there dimerization and prevention of further oligomerization by would conveniently be less evaporation and thus less Solvent addition of ligand Such as, for example, bidentate and triden would be lost to the atmosphere. tate ligands. By coordination at one or more sites on a metal, Other preferred solvents include n-butanol and 2-butanol a ligand limits dimerization and prevents further oligomer 65 since they have higher boiling points than the lower alcohols. ization of a metal species, thus allowing a greater number of In accordance with the invention, the metal ion species active mononuclear species than is the case in the absence of catalyzes an alcoholysis reaction of an organophosphorus US 8,722,956 B2 13 14 compound or a mixture of organophosphorus compounds temperature range between the freezing and boiling points of represented by the following general formula (10): the solvents or mixture of solvents used.

(10) 5 J EtO- o o–K)- NO OEt Paraoxon 10 where P is phosphorus; J is O (oxygen) or S (sulfur); EtO- -S -()-so X, G, Z are the same or different and are selected from the OEt group consisting of Q, OQ, QA, OA, F (fluoride), Cl (chlo 15 O,O'-diethyl-S-p-nitrophenylphosphothioate ride), Br (bromide), I (iodide), QS, SQ and C=N; S where Q is hydrogen or a substituted or unsubstituted branched, straight-chain or cyclic alkyl group consisting of H3CO- - O NO 1-100 carbon atoms; wherein when X, G, Z are the same, X, OCH G, Zare not Q, and when X, G, Z are the same Q is not H: CH3 A is a mono-, di-, or poly-substituted or unsubstituted aryl group selected from phenyl, biphenyl, benzyl, pyridine, Fenitrothion naphthyl, polynuclear aromatics, and 5- and 6-membered aromatic and non-aromatic heterocycles; The G-type and V-type classes of chemical warfare agents wherein each said substituent is selected from Cl, Br, I, F, 25 nitro, nitroso, Q, alkenyl, OQ, carboxyalkyl, acyl, SOH, are too toxic to be handled without specialized facilities and SOQ, S=O(Q), S(=O)C, amino, alkylamino (NHO), ary are often modeled by simulants such as, for the G-agents: lamino (NHA), alkylarylamino, dialkylamino and diary paraoxon and p-nitrophenyl diphenyl phosphate, and for the lamino. V-agents: O.S.-dialkyl- or O.S.-arylalkyl-phosphonothioates Most preferably, the phosphorus atom of FIG. 10 has at 30 or S-alkyl-phosphinothioates or S-aryl-phosphinothioates least one good leaving group attached. For this reason, orga (Yang, 1999). We have used three such simulants and report nophosphorus compounds which are decomposed according herein, degradation of paraoxon as a model of G-agents, to the invention do not have three alkyl groups, nor three degradation of O,O'-diethyl-S-p-nitrophenylphosphorothio hydrogens, northree hydroxyl groups attached. One skilled in ate as a model of V-agents, and degradation offenitrothion as the art will recognize that a 'good leaving group' is a Sub 35 a model of (P=S)-containing pesticides. Structures for these stituent with an unshared electron pair that readily departs model compounds are shown below. These three compounds from the substrate in a nucleophilic substitution reaction. The were chosen because each possess a chromophore which best leaving groups are those that become either a relatively makes the UV-vis kinetics simpler to study with low concen stable anion or a neutral molecule when they depart, because trations of materials. It is expected that this invention has they cause a stabilization of the transition state. Also, leaving 40 wide applicability for other organophosphorus compounds groups that become weak bases when they depart are good including chemical warfare agents and other pesticides Such leaving groups. Good leaving groups include halogens, as, for example, parathion and malathion. alkanesulfonates, alkyl Sulfates, and p-toluenesulfonates. In our studies, which are detailed in the following As used herein, the term "heterocycle” means a substituted examples, we have: confirmed the degradation of paraoxon, or unsubstituted 5- or 6-membered aromatic or non-aromatic 45 O.O'-diethyl-S-p-nitrophenylphosphorothioate and femi hydrocarbon ring containing one or more O.S or Natoms, or trothion when placed in an alcoholic Solution of metal ions polynuclear aromatic heterocycle containing one or more N. and at least a trace amount of alkoxide ions; determined the O, or Satoms. rate of the decomposition of paraoxon in a methanol Solution An advantage of the decomposition method of the inven containing La" and additional methoxide ions; characterized tion is that the solvent, being hydrophobic, relative to water, 50 Stoichiometry and proposed a structure of active permits good solubility of organophosphorus agents such as {La"(OCH)} dimers; studied catalyzed alcoholysis in the VX, Russian-VX, tabun (GA), soman (GD), sarin (GB), GF, presence of ligand and determined that faster rates are pos hydrophobic polymers, insecticides and pesticides. sible in Some Such systems relative to catalysis in the absence Another advantage of the invention is that it provides a of ligand; and confirmed the complete destruction of non-aqueous Solution and reaction products that can be easily 55 paraoxon and O,O'-diethyl-S-p-nitrophenylphosphorothio and safely disposed of by incineration. It will thus be appre ate relative to catalyst in La":OMe}, {Cu:OMe, and ciated that the decontamination method of the invention can {Zn":OMe) systems thus confirming the true catalytic be used for a broad range of chemical warfare agents, or nature of this method. mixtures of Such agents, or blends of Such agents with poly The data presented in the following examples Support the mers, as well as other toxic compounds Such as insecticides, 60 following conclusions: pesticides and related organophosphorus agents in general. Destruction of Paraoxon (Model G Agent): A preferred A further advantage of the invention is that destruction of embodiment for methanolysis of paraoxon is a organophosphorus agents occurs with or without the addition {La":OCH system according to the invention. The pro of heat. An ambient temperature reaction is cost-efficient for cedure involves preparation of a 2 mM La(OTf) methanolic large scale destruction of stockpiled organophosphous mate 65 solution, containing equimolar NaOCH, which affords a 10 rial Such as chemical weapons, insecticides or pesticides. The fold acceleration of the methanolysis of paraoxon relative to catalyst species can catalyze the alcoholysis over the full the background reaction at the same pH in the absence of US 8,722,956 B2 15 16 catalyst (t-20 sec). A second preferred embodiment for the All scientific and patent publications cited herein are hereby methanolysis of paraoxon is a {Zn":diMephen:OMe sys incorporated by reference in their entirety. tem. This system affords accelerations of up to 1.8x10-fold for the methanolysis of paraoxon and has broader applicabil EXAMPLES ity than La" as Zn" also catalyzes the decomposition of 5 fenitrothion. Destruction of O,O'-diethyl-S-p-nitrophenylphospho Examples 5 to 8 provide a summary of the La" ion cata rothioate (Model V Agent): lyzed alcoholysis of paraoxon. Example 10 is a prophetic A preferred embodiment for methanolysis of O,O'-diethyl example of an La" ion catalyzed alcoholysis of VX. Due to S-p-nitrophenylphosphorothioate is a {Cu":OCH:12 the fact that the dimeric lanthanum methoxide catalyst is andN} system. A second preferred embodiment for the 10 stable in Solution, and the reaction takes place at room tem methanolysis of O,O'-diethyl-S-p-nitrophenylphospho perature and at neutral pH (neutral pH in methanol is ~8.4), rothioate is methanolic solution of {Zn":diMephen: we expect that this reaction is amenable to scale-up and to use OCH}. A third preferred embodiment for the methanolysis in the field. of O,O'-diethyl-S-p-nitrophenylphosphorothioate is a metha In the examples, methanol (99.8% anhydrous), sodium nolic solution of La":OCH}. 15 methoxide (0.5 M solution in methanol), La(CFSO) and Destruction of Fenitrothion (Model Pesticide): A preferred paraoxon were purchased from Sigma-Aldrich (St. Louis, embodiment for methanolysis offenitrothion is a {Cut:12 Mo.) and used without any further purification. HClO (70% aneN:OCH system according to the invention. The pro aqueous solution) was purchased from BDH (Dorset, cedure involves preparation of a 2 mMCu(OTf), methanolic England). H NMR and 'PNMR spectra were determined at solution containing 0.5 equivalents of N(Bu)OCH and 1 400 MHz and 161.97 MHz. 'P NMR spectra were refer equivalent of 12laneN, which catalyzes the methanolysis of enced to an external standard of 70% phosphoric acid in fenitrothion with a ta of ~58 sec accounting for a water, and up-field chemical shifts are negative. 1.7x10-fold acceleration of the reaction at near neutral pH In the examples, the CH-OH" concentration was deter (8.75). A second preferred embodiment for the methanolysis mined using a Radiometer Vit 90 Autotitrator, equipped with of fenitrothion is a {Zn":diMephen:OCH} system. This 25 a Radiometer GK2322 combination (glass/calomel) elec system affords accelerations of 13x10-fold for the metha trode calibrated with Fisher Certified Standard aqueous buff nolysis of fenitrothion at 2 mM each of Zn(OTf), ligand ers (pH=4.00 and 10.00) as described in recent papers (Nev diMephen and NaOCH and exhibits broad applicability as it erov et al 2000: Neverov et al., 2001(a); Neverov et al., also catalyzes the decomposition of paraoxon. Fenitrothion 2001(b); Neverov et al., 2001(c); Brown et al., 2002: Tsanget decomposition is not appreciably accelerated in the presence 30 al., 2003). Values of pH were calculated by adding a correc of a La" system according to the invention. This points out tion constant of 2.24 to the experimental meter reading as the importance of matching the relative hard/soft character reported by Bosch et al., 1999. istics of catalyst and Substrate, and suggests that softer metal The pK values of buffers used in the examples were ions such as Cu" and Pd" could show enhanced catalytic obtained from the literature or measured at half neutralization activity toward the methanolysis of Sulfur-containing phos 35 phorus species. of the bases with 70% HCIO in MeOH. Destruction of a Suspected Organophosphorus Compound Example 1 of Unknown Structure: A preferred embodiment of the inven tion for catalyzed alcoholysis of an unknown agent which is M'-Catalyzed Ethanolysis of Paraoxon and Suspected to be an organophosphorus compound, is a mixture 40 of M":OCH} and M*:L:OCH in an alcohol solu Fenitrothion: Reaction Conditions and Rates tion. Examples of such a mixture include La":OCH} and The ethanolysis offenitrothion and paraoxon was studied {Cu":12laneN:OCH}; and La":OCH} and {Zn": in ethanol using various metal ions with varying amounts of diMephen:OCH}. Although such a M" system is less reac added base. These reactions were followed by UV-vis spec tive toward paraoxon than the M" system; unlike M", the 45 troscopy by observing the rate of disappearance of a starting M" system does catalyze alcoholysis offenitrothion. This material signal or the rate of appearance of a product signal mixture produces an effective method for destruction of both Such as 4-nitrophenol in the case of paraoxon or 3-methyl-4- P—S pesticides and P=O chemical warfare agents. nitrophenol in the case offenitrothion. Reaction conditions The invention also provides a kit for decomposing an orga and the catalyzed reaction’s rate constants are summarized in nophosphorus compound comprising a Substantially non 50 Table 1. 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, TABLE 1 e.g., an ampule, which is opened so that the medium can be Maximum pseudo-first order kinetic rate constants for the ethanolysis applied to the organophosphorus compound. Alternatively, 55 offenitrothion and paraoxon catalyzed by metal ions (0.001M) the kit may include an applicator bearing the medium, in the presence of optimum amount of base (maxk) wherein the applicator is adapted so that the medium is and at equimolar amount (k... 1:1 OCH/M ratio), T = 25 C. applied to the organophosphorus compound and the com Paraoxon Fenitrothion pound consequently decomposes. The applicator may com prise a moist cloth, i.e., a cloth bearing a solution according to 60 Metals 10 Max kobs, s 104 kobs, s–15 104 kobs, s-lib the invention. The applicator may be a sprayer which sprays Lanthanides medium according to the invention on the organophosphous compound. In some embodiments, the kit comprises written La3+ 544.15 (1:1) S44.15 No catalysis Pr3+ 253.24 (1:1) 253.24 No catalysis instructions for use to decompose an organophosphorus com Ndl3+ 247.59 (1:1) 247.59 No catalysis pound. 65 Gd3+ 220.14 (1:1) 220.14 No catalysis The following examples further illustrate the present Smit 185.88 (1:1) 185.88 No catalysis invention and are not intended to be limiting in any respect. US 8,722,956 B2 17 18 TABLE 1-continued paraoxon so that the latter's total concentration was 15.4 mM. The alcoholic Solution was then incubated at room tempera Maximum pseudo-first order kinetic rate constants for the ethanolysis offenitrothion and paraoxon catalyzed by metal ions (0.001M) ture for 72 hours after which the 'P NMR spectrum was in the presence of optimum amount of base (maxk) recorded. This spectrum showed complete disappearance of and at equimolar amount (k 1:1 OCH M ratio), T = 25°C. 5 the paraoxon starting material and complete formation of diethyl methyl phosphate (product of reaction with methanol) Paraoxon Fenitrothion (Ö=-0.3 ppm) and diethyl 2-propyl phosphate (product of reaction with 2-propanol) (Ö -2.4 ppm) was observed and Metals 10 Max kobs, s 104 kobs, s-lib 104 kobs, s-lib formation of the products 4-nitrophenol, diethyl methylphos Eut 160.0 (1:1) 160 No catalysis 10 phate and diethyl 2-propyl phosphate were confirmed by 'H Tb3+ 146.34 (1:1) 146.34 No catalysis Ho3+ 99.72 (1:1) 99.72 No catalysis NMR. Dy" 63.65 (1:1) 63.65 No catalysis The ratio of the two phosphate products from each of the Ert 62.61 (1:1) 62.61 No catalysis propanol solvents was determined from their 'PNMR spec Tn3+ 49.34 (1:1) 49.34 No catalysis tra and were found to be: Transition 15 Metals Zn2+ 48.22 (1:0:5) 37.28 S.42 y3+ 32.56 (1:1) 32.56 No catalysis MeOH reaction product:Propanol reaction product Co2+ 25.70 (1:0:5) Catalysis, Catalysis, rate unknown rate unknown 1-propanol reaction 1:2.8 Yb3+ 25.73 (1:1) 25.73 No catalysis 20 2-propanol reaction 2.2:1. Ni2+ 23.63 (1:0:5) 12.18 No catalysis Cu2+ No catalysis No catalysis Catalysis, rate unknown These ratios show that if the medium for catalysis accord Sc3+ No catalysis No catalysis No catalysis ing to the invention is a mixture of alcohol, alkoxyalkanol and Introduced as commercially available triflate salts and used as received 25 aminoalkanol, the reaction will select for the least hindered 0.001M in each of M" salt and added NaOCH one. This factor may determine what an “effective amount of Product formation was observed by final UV-vis spectra, but determination of exact value methanol will be for a given system. of the rate constant was not possible due to high absorbance of the solutions, Example 3 Example 2 30 La"-Catalyzed Methanolysis of Paraoxon: La" and Zn"-Catalyzed of Paraoxon in Experimental Details Propanols: Kinetics and NMR Studies Paraoxon, when placed in an appropriately buffered methanol solution containing La" ions held in a pH region The Solvolysis of paraoxon was studied in two alcohols that 35 between 7 and 11, underwent rapid methanolysis at ambient are less polar than methanol, namely 1-propanol and 2-pro temperature to produce diethyl methyl phosphate and p-ni panol. In the case of 1-propanol, kinetics were monitored by UV-vis spectroscopic techniques following the appearance of trophenol. A detailed reaction scheme is given in Scheme 1. the product of the solvolysis, 4-nitrophenol, at 335 nanom eters. For example, at a concentration of La(OTf)=0.5 40 Scheme 1 mM-concentration of NaOCH, in the absence of any ligand, catalyzed solvolysis of paraoxon proceeded with a pseudo O first order rate constant of 2.1x10's". At a concentration of La(OSCF3)3, NaOCH3 EtO-P-O NO2 -> Zn(OTf)=0.5 mM-concentration of NaOCH, in the pres CHOH, pH 8-10 ence of equimolar diMephen, the catalyzed solvolysis of 45 OEt paraoxon proceeded with a pseudo-first rate constant of 1.93x Paraoxon 104 sl. The true catalytic nature of the system was demonstrated in the following Nuclear Magnetic Resonance (NMR) studies. to--och, + HO NO To 2.5 mL of a solution of 1-propanol containing 5% metha 50 OEt nol, and 0.5 mM each of Zn(OTf), diMephen and NaOMe was added 8.3 uL of paraoxon so that the latters total con Diethyl Methyl Phosphate p-Nitrophenol centration was 15.4 mM. The alcoholic solution was then incubated at room temperature for 72 hours after which the To two mL of dry methanol at ambient temperature was 'P NMR spectrum was recorded. This spectrum showed 55 added N-ethylmorpholine (25.5uL or 23 mg) half neutralized complete disappearance of the paraoxon starting material and with 11.4 M HClO4 (8.6 uL) so that the final total buffer complete formation of diethyl methyl phosphate (product of concentration was 0.1 M. To this was added 16.0 mg of reaction with methanol) (Ö=-0.3 ppm) and diethyl 1-propyl paraoxon. The 'PNMR spectrum showed a single signal at phosphate (product of reaction with 1-propanol) (Ö=-1.23 8-6.35 ppm. To the resulting mixture was added 12.9 mg of ppm). This indicates true catalysis with more than 30 turn 60 La(OSCF) and 40 uL of 0.5 MNaOCH in methanol solu overs in 72 hr. The solvents were removed, and the residues tion. At this point the concentration of paraoxon was 0.057M dissolved in deuterated methanol-da and the "H NMR spectra and that of La(OSCF) was 0.011 Mand the measured pH were recorded showing the presence of the products: 4-nitro of the methanol solution was 8.75, essentially neutrality. This phenol, diethyl methyl phosphate and diethyl 1-propyl phos solution was allowed to stand for 10 minutes, after which time phates. Similarly, an NMR study was done such that 2.5 mL 65 the 'PNMR spectrum indicated complete disappearance of of 2-propanol containing 5% methanol, 0.5 mM each of the paraoxon signal and the appearance of a new signal at Ö Zn(OTf), diMephen and NaOMe was added 8.3 uL of 0.733 ppm corresponding to diethyl methyl phosphate. The US 8,722,956 B2 19 20 "H NMR spectrum indicated complete disappearance of the at pH>7.0, the metalion was partially neutralized by adding starting material and full release of free p-nitrophenol. an appropriate amount of NaOMe to help control the pH at the desired value. pH measurements were performed before Example 4 and after each experiment and in all cases the values were consistent to within 0.1 units. La"-Catalyzed Methanolysis of G-agent: A Shown in FIG. 2 are three representative plots of the Prophetic Example pseudo-first order rate constants (k) for methanolysis of To 200 mL of methanol is added 2.55 mL of N-ethylmor paraoxon as a function of added concentration of pholine (2.3 g) and 0.86 mL of 11.4 MHCIO to bring the 10 La(OSCF) at pH 7.72, 8.23 and 8.96. (For original k total buffer concentration to 0.1 M. To this solution is added vs. concentration of La" kinetic data see Tables 2-12). 1.29 g of La(OSCF) and 4 mL of a 0.5 M solution of NaOCH in methanol. TABLE 2 To the above solution is added 2 g of the G-agent Sarin (0.016 moles, 0.08M) and the solution is allowed to stand at 15 Observed pseudo-first order rate constants for La catalyzed ambient temperature for 15 minutes. It is expected that analy methanolysis of paraoxon (2.04 x 10M) at 25° C.; pH 5.15 sis of the resulting Solution would indicate Substantially com plete disappearance of Sarin. This reaction may be inhibited dimethylaniline buffer = 1.00 x 10 M, W = 328 nm. by F in which case Ca" may be added to the reaction solution to precipitate this inhibitory product. La(OSCF), M kas, s'

Example 5 4.OOE-05 3.11E-07 La"-Catalyzed Methanolysis of Paraoxon: Kinetics 6.OOE-OS S.46E-07 25 8.OOE-OS 4.90E-07 The kinetics of the alcoholysis degradation reaction have 2.OOE-04 1.17E-OS been thoroughly investigated using the pesticide paraoxon. 4.OOE-04 2.46E-OS For methanolysis with dimeric lanthanum catalysts at 25°C., 6.OOE-04 3.78E-OS as little as 10 M of the catalytic specie?s) promotes the 8.OOE-04 S.34E-OS methanolysis reaction by ~10-fold relative to the back 30 ground reaction at a neutral pH of -8.5. The uncatalyzed 1.OOE-03 6.13E-OS methoxide-promoted reaction of paraoxon proceeds with the 1.2OE-03 7.72E-05 second order rate constant, k,'' of 0.011 M's deter mined from concentrations of NaOCH between 1x10 M and 4x10° M. Methanolysis of paraoxon is markedly accel 35 erated in the presence of La" with an observed second order TABLE 3 rate constant, k,” of -17.5M's at the near neutral pH of Observed pseudo-first order rate constants for La catalyzed 8.23. Assuming that the methoxide reaction persists at pH methanolysis of paraoxon (2.04 x 10M) at 25° C.; pH 5.58 8.23, the acceleration afforded to the methanolysis of dimethylaniline bufferl = 2.00 x 10 M. J. = 328 nm. paraoxon at that pH by a 2x10M solution of La(OSCF). 40 is 1.1x10-fold giving a half-life time of 20 seconds. The La(OSCF), M kais, S' acceleration is 2.3x10-fold at pH 7.72 and 2.7x10-fold 4.OOE-05 S.37E-06 at pH 8.96. 6.OOE-OS 6.23E-06 UV kinetics of the methanolysis of paraoxon were moni 8.OOE-OS 5.63E-06 45 2.OOE-04 8.33E-06 tored at 25°C. by observing the rate of loss of paraoxon at 268 4.OOE-04 4.28E-OS nm or by the rate of appearance of p-nitrophenol at 313 nm or 6.OOE-04 6.93E-OS 328 nm at a concentration of paraoxon=2.04x10M using an 8.OOE-04 9.48E-OS OLIS(R)-modified Cary 17 UV-vis spectrophotometer. The 1.OOE-03 105E-04 concentration of La(OSCF) was varied from 8x10 M to 1.2OE-03 1.26E-04 4.8x10 M. All reactions were followed to at least three 50 half-times and found to exhibit good pseudo-first order rate behavior. The pseudo-first order rate constants (k) were evaluated by fitting the Absorbance vs. time traces to a stan TABLE 4 dard exponential model. Observed pseudo-first order rate constants for La catalyzed The kinetics were determined under buffered conditions. 55 methanolysis of paraoxon (2.04 x 10M) at 25°C.; pH 5.82 Buffers were prepared from N,N-dimethylaniline dimethylaniline bufferl = 2.93 x 10 M. J. = 328 nm. (pKa=5.00), 2.6-lutidine (PK-6.70), N-methylimidazole (pKa=7.60), N-ethylmorpholine (pKa=8.60) and triethy La(OSCF), M kai s' 4.OOE-05 1.15E-06 lamine (pKa=10.78). Due to the fact that added counterions 6.OOE-OS 1.71E-O6 can ion-pair with La" ions and affect its speciation in solu 60 8.OOE-OS 2.52E-O6 tion, ionic strength was controlled through neutralization of 2.OOE-04 3.13E-OS the buffer and not by added salts. The total concentration of 4.OOE-04 7.11E-OS 6.OOE-04 1.15E-04 buffer varied between 7x10M and 3x10M, and the buff 8.OOE-04 192E-04 ers were partially neutralized with 70% HCIO to keep the 1.OOE-03 217E-04 concentration of CIO, at a low but constant value of 5x10 65 1.2OE-03 3.07E-04 M which leads to a reasonably constant ionic strength in solution. With the concentration of La">5x10 M

US 8,722,956 B2 23 24 plots exhibit two domains, a nonlinear one at low concentra the concentration range where the kinetic plots of k Vs. tion of La" suggestive of a second order behavior in La", concentration of La" in this study are linear. The potentio followed by a linear domain at higher concentration of La". metric titration data were successfully analyzed with the Following the approach we have used before, (Neverov et al., computer program HyperquadTM (Gans et al., 1996) through 2001, Neverov et al., 2000& Neverov et al., 2001) we use the fits to the dimer model presented in equation (1) where n linear portion of these plots to calculate the observed second assumes values of 1-5, to give the various stability constants order rate constants (k”) for La"-catalyzed methanolysis (K) that are defined in equation (2). On the basis of the five of paraoxon at the various pH values. These are tabulated in computed stability constants, log K is 11.66:0.04. Table 13 and graphically presented in FIG. 3 as a log 20.86+0.07, 27.520.09, 34.56-0.20 and 39.32+0.26, we k” vs. pH plot which is seen to have a skewed bell-shape, 10 constructed the speciation diagram shown in FIG. 4 which maximizing at pH ~9. presents the distribution of the various La(OCH), forms as a function of pH at La(OSCF), 2x10 M. TABLE 13 Observed second order rate constants for La catalyzed methanolysis 15 of paraOXOn at various pH values, T = 25 C. (1) K pH kobs, M-1s-1a La(OMe), 2La" + noMe (2) 5.15 O.065 O.OO2 5.58 O.11 - O.O1 K = [La(OCH3)/La'IOCHI’ S.82 O.28 O.O2 6.69 1.07 - O.04 7.10 2.4 + 0.1 Also included on FIG.4 as data points (O) are thek,” data 7.30 5.6 0.1 for La"-catalyzed methanolysis of paraoxon which predomi 7.72 113 O.S nantly coincide with the pH distribution of La" (OCH) 8.23 17.5 - O.S 25 8.96 23.20.9 but with an indication that higher order species such as 10.34 114 - 0.8 La" (OCH) and/or La" (OCH) have some activity. To 10.97 5.404 determine the activities for the various La",(OCH), we analyzed the k, data as a linear combination of individual k2 determined from slope of the ki vs. (La"local plots at higher La at each pH. rate constants (equation (3). 30 Example 6 La"Catalyst Species: Stoichiometries where k", k, . . . . k" are the second order rate As shown in FIG. 3, the reactivity of the catalytic species 35 constants for the methanolysis of paraoxon promoted by the increases with increasing pH up to -9.0. This fact seems to various dimeric forms. Given in Table 14 are the best-fit rate indicate the involvement of at least one methoxide, although constants produced by fitting under various assumptions. TABLE 1.4 Computed second order rate constants for various dimeric forms La(OCH3), catalyzing the methanolysis of paraoxon, as determined from fits of k,” data in Table 13 to equation(3), ILa(OSCF)all, 2x 10 M., T = 25 C. Fitti K2:1 (M's) k2:2 (M's) k2:3 (M's) k2:4 (M's) R2 1G 15.93.2 49.8 2.2 67.236.0 8.8 11.2 O.9976 2b 1845.4 47.2 24 110.4 11.8 O.9861 3e 514 2.8 1034 - 17 O9664 Including all dimeric forms except La2(OCH3)0 and La(OCH3)6. Computed value of k2: = (-3.4 + 10.8) Computed without the involvement ofk' andk'. Computed without the involvement ofk', k24 and k,25. the general shape of the plot Suggests the catalytic involve We have analyzed the titration data to determine speciation ment of more than one species. Since the second order k.” for a total La" concentration of 2x10 M which is in the values for the La"-catalyzed reactions in the neutral pH 55 general concentration range where the kinetic behavior of the region are some 1000- to 2300-fold larger than the methoxide methanolysis of paraoxon is linearly dependent on concen k', the role of the metal ion is not to simply decrease tration of La", and thus largely controlled by dimeric spe the pKa of any bound CH-OH molecules that act as nucleo cies. In FIG. 5 are presented kinetic plots for all three species philes. This points to a dual role for the metal. Such as acting (La" (OCH), La" (OCH) and La" (OCH)) based on as a Lewis acid and as a source of the . 60 their second order rate constants for catalyzed methanolysis Detailed mechanistic evaluation of kinetic data requires of paraoxon, and their concentrations as a function of pH. additional information Such as the Stoichiometries and con Their combined reactivities as a function of pH give the centrations of various La"-containing species that are predicted log k vs. pH profile shown as the dashed line formed as a function of both pH and concentration of La". on FIG. 5. The computed line is also presented in the plot in A study of the potentiometric titration of La" was performed 65 FIG. 2 of log k.” vs. pH. Included on FIG.5 as data points under various conditions, with the concentration of () are the actual experimentally-determined values which La(OSCF) from 1x10 M to 3x10M, which is within fit on the computed profile with remarkable fidelity, strongly US 8,722,956 B2 25 26 indicating that these three species are responsible for the thanide series metalions and actinide series metalions, a first observed activity. At pH values below 9, the La" (OCH) step probably involves transient formation of a paraoxon: complex accounts for essentially all the activity, while at pH La":(OCH)} complex. Since it is unlikely that the 10 and above, the dominantly active form is La" (OCH). bridged methoxy is sufficiently nucleophilic to attack the Throughjoint consideration of the ki VS. concentration of coordinated phosphate, in the proposed mechanism, one of La" kinetics and a detailed analysis of the potentiometric the La" OCH La" bridges opens to reveal a singly titration data for La" in methanol, we have determined that coordinated {La":OCH} adjacent to a Lewis acid coordi the dominant species in solution are dimers of the general nated phosphate which then undergoes intramolecular formula La(OCH), where n=1-5, and three of these dimers, nucleophilic addition followed by ejection of the p-nitrophe La"(OCH), La" (OCH), and La" (OCH), account 10 for all the catalytic activity with La".(OCH) being the noxy leaving group. La" (OCH), is regenerated from the most important form at pH-9. final product by a simple deprotonation of one of the metha The pH dependence of the metal ion is such that several nols of Solvation and dissociation of the phosphate product, complexes are present with their individual concentrations (EtO),P(O)OCH, maximized at different pH values. It is only through comple 15 Example 8 mentary analyses of the kinetic and potentiometric titration data that one can satisfactorily explain the kinetic behavior of M'-Catalyzed Methanolysis of O,O'-diethyl-S-p- complex mixtures having several pH dependent forms. nitrophenylphosphorothioate: Experimental Details, Through a series of detailed potentiometric titrations of the {La":OMe) system in methanol, and through studies of the Kinetics and NMR Studies kinetics of methanolysis of paraoxon as a function of La" O.O-diethyl-S-p-nitrophenyl phosphorothiolate, when concentration and pH, it has been determined that in this placed in an appropriately buffered methanol Solution con {La":OMe-paraoxon system there are two dominant sto taining La" and OCH, ions held in the pH region between ichiometries of catalysts, La(OCH) with a proposed struc 7 and 11, underwent rapid methanolysis at ambient tempera ture of a bis-methoxybridged dimer between pH 8 and 10 25 ture to produce diethyl methyl phosphate and 5-mercapto-2- (maximum concentration of ~80% at pH 8.9), and La nitrobenzene. A detailed reaction scheme is given in Scheme (OCH) with a proposed structure of tris-methoxy bridged 2 and reaction conditions are detailed below. dimer) between pH 9 and 11 (maximum concentration of ~25% at pH 10). Above a total La" of about 2x10 M, these species form spontaneously in Solution without any 30 Scheme 2. requirement for added ligands, so that in the millimolar con centration range, dimer formation is essentially complete. O Mi" (OCH) Given that we know the dominantly active forms are EtO-P-S NO - -- La"(OCH), and La",(OCH), we can derive a kinetic CHOH, 259 C. expression (equation 4) which gives values ofk’’=51.4+2.8 35 OEt and k=103+17 M's for the second order rate constants O,O'-diethyl-S-p-nitrophenylphosphothioate for methanolysis of paraoxon catalyzed by the bis-methoxy dimer and the tris-methoxy dimer respectively (Table 14). EtO- - OCH + HS -()– NO 40 OEt The net effect of this is that a solution containing 2x10 M Methyldiethylphosphate 5-Mercapto-2-nitrobenzene of La(OTf), generating 1x10M of total dimer, will cata lyze the methanolysis of paraoxon with t values of 30 s. 20 s, 15s and 30s at respective pH values of 7.7, 8.2, 9.0 and To 4.9 mL of anhydrous methanol at ambient temperature 10.3. By way of reference, at pH 7.7 the methoxide back 45 was added N-ethylmorpholine (63.8 L or 57.7 mg) half ground rate constant is (0.011 M's 'x10' MOCHI)= neutralized with 11.4 M HClO (21.5 LL), so that the final 1.1x10's", corresponding to at of 1994 years, so that total buffer concentration was 0.1M in 4.95 mL solution. The the acceleration afforded by the La" catalyst is some two measured pH of the buffer solution was 8.89. To 0.8 mL of billion-fold at that pH. this buffer and 0.2 mL deuterated methanol was added 8.8 mg 50 of O,O-diethyl-S-p-nitrophenyl phosphorothiolate. The 'P Example 7 NMR spectrum of this solution showed a single signal at 8 22.39 ppm. Following NMR analysis, a 10 uL aliquot of a La"Catalysis: Proposed Mechanism lanthanum ion/sodium methoxide/methanol solution was added which had been prepared by dissolving 16.4 mg We have shown above that La" in methanol is a remark 55 La(OSCF) in 56.9 uL of 0.5M sodium methoxide metha ably effective catalyst for the decomposition of paraoxon and nol solution. At this point, the concentrations in the NMR tube that there are three forms of dimeric species which have were: 0.030 Mphosphorothiolate, 0.1 MN-ethylmorpholine, maximal activities at different pH values. Of these, the 0.01M sodium methoxide and 0.0098 MLa(OSCF). The highest activity is attributed to La" (OCH) operating 'P NMR spectrum, obtained 103 sec after addition of the most effectively in the neutral pH region between 7.7 and 60 aliquot indicated complete disappearance of the phospho 9.2 (neutral pH in methanol is 8.4). Given in FIG. 1A is a rothiolate signal and the appearance of a new signal at Ö 3.57 proposed mechanism by which La" (OCH3)2, as a bis ppm, attributable to diethyl methyl phosphate in the presence methoxy bridged dimer, promotes the methanolysis of of 0.0098 MLat. paraoxon. Although none of our k vs. La" kinetics pro The absorbance of a 0.5 mL solution of methanol contain files shows saturation behavior indicative of formation of a 65 ing 1 mM of Cu(OTf), 1 mM of 12laneN, 0.5 mM of strong complex between paraoxon and La", given the well NaOCH and 0.5 mM of O,O'-diethyl-S-p-nitrophenylphos known coordinating ability of trialkyl phosphates to lan phorothioate was monitored at 280 nm as a function of time. US 8,722,956 B2 27 28 The reaction exhibited first order kinetics with k, 4.3x10 s' (t=16 sec) corresponding to a 8.3x107-fold acceleration Scheme 3 over the background reaction at pH-8.41. S The absorbance of a 2.5 mL solution of methanol contain | L:M?" (OCH) 5 H3CO-P-O NO - - ing 1 mM of Zn(OTf), 1 mM of 12aneN, 0.5 mM of CHOH, 259 C. NaOCH and 0.5 mM of O,O'-diethyl-S-p-nitrophenylphos OCH phorothioate was monitored at 280 nm as a function of time. CH The reaction exhibited first order kinetics with k=4.1x10' s' (to 28 min) corresponding to a 4.1x10-fold accelera Fenitrothion tion over the background reaction at pH-8.70. S HS NO H3CO-P-OCH + Example 9 OCH CH 15 Phosphorothioic acid, O.O.O-trimethyl p-Nitrophenol

La"-Catalyzed Methanolysis of VX: A Prophetic As seen in FIGS. 6 and 7, Cut:(OCH) at 25° C. either Example alone or in the presence of equimolar 12aneN, bpy or phen shows both great catalytic efficacy and specificity toward the P—S derivatives. To 200 mL of methanol is added 2.55 mL of N-ethylmor pholine (2.3 g) and 0.86 mL of 11.4 MHCIO to bring the Apparently matching the hard/soft characteristics of the total buffer concentration to 0.1 M. To this solution is added metalion and the Substrate is important in designing an effec 25 tive catalytic system for P=S substrates. With due consider 1.29 g of La(OSCF) and 4 mL of a 0.5 M solution of ation for matching the hard/soft characteristics of the sub NaOCH in methanol. strate and the metal ion, dramatic rate and selectivity can be To the above solution is added 2 g of VX (8.33x10 moles, achieved in the methanolysis of P=O vs. Pi—S phosphates. 0.041 M) and the solution is allowed to stand at ambient temperature for 15 minutes. It is expected that analysis of the 30 resulting Solution would indicate Substantially complete dis Example 11 appearance of VX. Zn"-Catalyzed Methanolysis of Paraoxon and Example 10 35 Fenitrothion The methanolyses of paraoxon and fenitrothion were M*-Catalyzed Methanolysis of Fenitrothion investigated as a function of added Zn(OTf) or Zn(CIO) in methanol at 25°C. either alone, or in the presence of equimo The activity of this system may be increased by adding 40 lar concentration of ligands:phen, diMephen and 12laneN. equimolar amounts of bi- or tri-dentate ligands to complex The catalysis requires the presence of methoxide, and when Zn"(OCH) and limit oligomerization of Zn"(OCH) in studied as a function of added NaOCHI, the rate constants solution. The systems studied herein used methoxide and the (k) for methanolysis with Zn" alone or in the presence of ligands phen, diMephen and 12aneN. The active forms of equimolar phen or diMephen, maximize at different the metalions at neutral pH are Zn"(OCH) with no added 45 OCH/Zn" ratios of 0.3, 0.5 and 1.0 respectively. ligand and {Zn":L:(OCH)} when ligand (L) is present. In Plots of k vs. Zn, either alone or in the presence of the case of phen ligand, decreasing the oligomerization does equimolar ligands phen and diMephen at the IOCH/ not prevent the formation Zn (OCH) dimers since the bulk (Zn), ratios corresponding to the rate maxima are curved of the material is now present as LZn (OCH)Zn"L} and show a square root dependence on Zn". In the cases of which is not catalytically active, but is in equilibrium with an 50 phen and diMephen, this is explained as resulting from for active mononuclear form. The propensity to form the latter mation of a non-active dimer, formulated as a bis-L-methox inactive dimers can be reduced either by increasing the Steric ide bridged form (L:Zn"(OCH)Zn":L) in equilibrium interaction (ligand diMephen) or by changing the coordina with an active mononuclear form, L:Zn"(OCH). In the tion number (ligand 12laneN) in which cases the overall 55 case of the Zn":12laneN system, no dimeric forms are activity of the catalytic system increases. In the case of ligand present as can be judged by the strict linearity of the plots of diMephen, the dimerization is definitely reduced but the bind k vs. Zn", in the presence of equimolar 12laneNs and ing to the metal ion is not as strong as in the case of phen or OCH. Analysis of the potentiometric titration curves for 12|aneN, which means that there is some free Zn" in solu Zn" alone and in the presence of the ligands allows calcula tion under the concentrations and pH region where the cata 60 tion of the speciation of the various Zn" forms and shows that lyst is active. the binding to ligands phen and 12laneN is very strong, A reaction scheme is given below (Scheme 3) for the while the binding to ligand diMephen is weaker. This {Zn": methanolysis offenitrothion where M" is a transition metal 12|aneN:OMe) system exhibits excellent turnover of the ion, most preferably Zn" or Cu". In a preferred embodiment methanolysis of paraoxon when the Substrate is in excess. A a ligand is present, preferably abidentate ortridentate ligand, 65 mechanism for the catalyzed reactions is proposed (see FIG. most preferably 12laneN for Cu" and diMephen or 12 1B) which involves a dual role for the metal ion as a Lewis aneN for Zn". acid and source of nucleophilic Zn"-bound OCHs. US 8,722,956 B2 29 30 Example 12 methoxide occurring in one rather steep step. In the presence of ligands phen, diMephen and 12laneN, the titration curve Zn"-Catalyzed Methanolysis of Paraoxon and changes due to the formation of complexes. To analyze these Fenitrothion and p-nitrophenyl acetate titration data, a number of different dissociation schemes were attempted and the final adopted ones were selected A second set of methanolysis experiments was performed based on goodness offit to the titration profiles along with due with three Substrates, namely paraoxon, fenitrothion and consideration of the various species suggested by the kinetic p-nitrophenyl acetate, as a function of total added studies. Zn(CIO), maintaining the (OCH)/Zn, ratio at The case of the ligand triazacrown ether 12aneN is the 0.3 with added NaOCH. The three plots shown in FIG. 12 all 10 simplest to analyze since we have no evidence Supporting the exhibit a similar curvature independent of the nature of the presence of any species containing more than one Zn" ion. substrate. The curvature thus cannot be due to substrate bind This fact, coupled with the high pKa of 12aneN. H. ing and is modeled according to the overall process given in allows one to define the relevant species in solution as 12 equation (5) where an active mononuclear form (assumed to aneN, H., Zn":12laneN, Zn":12laneN:(OCH) and be Zn(OCH) is in equilibrium with a non-active dimer. 15 Zn":12laneN:(OCH), which, when fit via the Hyper Given in equation (6) is the appropriate kinetic expression quadTM 2000 program, produces a theoretical titration curve based on equation (5) which includes a possible methoxide (FIG. 14) which is in excellent agreement with the observed dependent term (kr) which is present for the most curve. The best fit formation constants for 12aneN. H. reactive Substrate (p-nitrophenyl acetate) but not important Zn: 12aneN, Zn":12laneN:(OCH) and Zn":12 for the phosphate triesters. This expression shows a square aneN:2(OCH) are given in Table 15. The Zn" speciation root dependence on the IM". Shown in FIGS.9A and 9B diagram constructed from these constants (not shown) indi are the concentration dependencies for the methanolysis of cates that in the pH region used in our kinetic studies, greater fenitrothion (FIG. 9A) and paraoxon (FIG. 9B) catalyzed by than 95% of the total Zn" is present as Zn":12laneN: Zn" alone and in the presence of ligands phen and diMephen (OCH). Shown in FIG. 13A is a plot of the pseudo-first where the ratio of (OCH)/Zn", is kept at a constant 25 order rate constants for the methanolysis of paraoxon in the value (i.e. 0.3 for Zn" alone, 0.5 for phen, and 1.0 for diMe presence of Zn(OTf)2 with a right hand axis depicting the phen). Zn":12laneN:(OCH) as function of total Zn(OTf).). These plots are also curved, not due to a saturation binding The very good correlations between the kinetic data and the of the phosphorus triesters to the metal, but due to the mono speciation data strongly supports Zn":12laneN:(OCH) mer:dimer equilibrium given in equation (5). The lines 30 as the catalytically active component, with a derived second through the FIG. 9A, 9B data are derived on the basis of order rate constant of 50.4M'min' for the methanolysis of NLLSQ fits to equation (6) and yield the kinetic constants paraoXon. given in Table 16. As shown in FIG. 13A, the kinetic depen Potentiometric titration of an equimolar mixture of dence in the presence of ligand 12laneN is Substantially Zn(OTf) and phen in the presence of 0.6 equivalents of linear and shows no evidence of monomer:dimer equilibrium. 35 perchloric acid showed that all the added Hwas released in the strong acid region below pH 3 with one additional step consuming a single equivalent of methoxide around pH 10. (5) The former indicates strong binding between Zn" and phen even at pH-3, but does not allow us to determine an exact 'R Kais kn 40 value of the Zn":phen binding constant other than to set a M2+ M2+ S- 2 MP'(OCH3) - T - Products lower limit for its formation constant of 10'M' which was N/ Substrate used as a fixed value in all Subsequent fittings. In the higher pH region where the kinetic experiments were per formed, we employed a model where the Zn" exists pre (6) 45 dominantly as {Zn":phen:(OCH) and Zn":phen: kobs {km KaiseW1 -- 8M loy. - 1)/4+ kbackground) (OCH), both of these being inferred by the kinetic data. HyperquadTM 2000 fitting of the full titration profile using the previously determined stability constants for phen-H and Zn":phen, produces a good fit and provides respective sta Example 13 50 bility constants for {Zn":phen:(OCH)} and Zn":phen: (OCH) given in Table 15. Zn"-Catalyst Stoichiometry In the catalysis of methanolysis of paraoxon and femi trothion by {Zn":OMe), either alone or in the presence of Potentiometric titration of Zn(OTf), solutions of varying complexing ligands, two things are clear: first, Zn" species concentrations (0.5-2 mM) in anhydrous methanol were per 55 are appreciably soluble in solution at all pH values and all formed in the absence and presence of equimolar amounts of concentrations employed; and second, equilibria consisting ligands phen, diMephen and 12laneN in order to determine of dimeric species in equilibrium with a kinetically active the speciation of the Zn" ions under conditions similar to mononuclear species are formed in the case of Zn", {Zn": those of the kinetic experiments. phen and {Zn":diMephen, but not in the case of {Zn": Independent titrations of 1 mM solutions of each ligand 60 12|aneN} where only the kinetically active mononuclear were performed and the resulting data were analyzed using form is present. High solubility of Zn" has been found with HyperquadTM 2000 fitting routine providing the pK values triflate and perchlorate counterions. These anions are pre for the last acid dissociation step, of 5.63+0.01 for phen-H". ferred for their relative kinetic inertness since they give the 6.43+0.01 for diMephen-Hand >13 for 12laneN. H" highest rates for catalyzed reactions relative to other anions respectively. 65 such as bromide, chloride or acetate. Methanolysis of The potentiometric titration curve of Zn(OTf) presented paraoxon, catalyzed by 1 mM Zn(OTf) with 0.3 equation of in FIG. 14 shows the consumption of two equivalents of added NaOCH is relatively unaffected by the addition of up US 8,722,956 B2 31 32 to 5 mM NaOTf or NaClO, but is significantly inhibited by 12|aneN modify the kinetic behaviour in important ways the addition of 1 mM NaCl, NaBr or Na(OCCH). depending on whether the methoxide/Zn" ratio is less than or The ability of the Zn" species to methanolyze both the greater than 1. P—O and P=S species with second-order rate constants 50 to 1000-fold larger than the corresponding second-order rate Example 15 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 Zn"-Catalyzed Methanolysis of Paraoxon: NMR solvation of metal ions relative to water. Studies of Catalytic Turnover Preparatively useful forms of catalysts can be generated by 10 the addition of known amounts of ligand, Zn(OTf) and meth A 'P NMR experiment was performed to determine a oxide. In the case of a solution comprising 2 mM Zn(OTf)2 turnover rate for the methanolysis of paraoxon using Zn": mM diMephen ligand and 2 mM NaOCH which generates diMephen:OCH. a pH of ~9.5, methanolysis of paraoxon is accelerated 1.8x 10-fold and methanolysis of fenitrothion is accelerated 15 To 0.6 mL of dry methanol (with 20% of CDOD as an 13x10-fold. Likewise, a solution comprising 1 mM of NMR lock signal) containing 1 mM each of Zn(OTf), diMe Zn(OTf), 1 mM 12laneN ligand and 0.5 mM NaOCH phen and NaOCH at ambient temperature was added 2.54 generates a pH of 9.3 and methanolysis of paraoxon is mg of paraoxon. At this point the concentration of paraoxon accelerated 1.7x10-fold. was 15 mM and that of Zn":diMephen:OCH was taken as Unlike the dimeric form of La", which are effective for 1.0 mM with the measured pH of the methanol solution methanolyzing paraoxon, dimeric forms of Zn" are not as being 8.75, close to neutrality (8.34). The 'PNMR spectrum of the solution was monitored periodically over ~160 minutes effective as its monomers. at which time it indicated complete disappearance of the Example 14 25 paraoxon signal which had been at 6-6.35 ppm and complete appearance of a new signal at Ö 0.733 ppm corresponding to Zn"-Catalyzed Methanolysis of Paraoxon and the product diethyl methyl phosphate. The HNMR spectrum Fenitrothion: Kinetic and Potentiometric Studies was obtained after 150 min and it confirmed the complete disappearance of the starting material and full release of the The kinetics for Zn"-catalyzed methanolysis of paraoxon 30 product p-nitrophenol. and fenitrothion fall into two distinct classes depending on The 'P NMR spectrum of a solution containing 15 mM what ligand is coordinated to the metal ion and how much paraoxon and 1 mM in each of Zn(OTf), NaOCH and ligand methoxide is added. Without any ligand, as shown in FIG. 11, diMephen was continuously monitored at ambient tempera the k for methanolysis of paraoxon in the presence of 1 mM ture over a period of ~160 minutes. The spectra were summed Zn(OTf) is maximized between 0.1 and 0.4 mM added 35 each 15 minutes to produce the time profile given in FIG. 10 NaOCH. There is an initially very strong dependence on the which displays the disappearance of paraoxon and the appear concentration of methoxide, the slope of which for the first ance of a new signal at 8 0.733 ppm attributed to diethyl 0.05 equation added yields a second order rate constant of 34 methyl phosphate. Fitting of these two time profiles to a first M' min' for methanolysis of paraoxon. Undoubtedly this 40 order expression gave an average pseudo-first order rate con methoxide is coordinated to Zn" to establish the Zn stant of (4.5+0.1)x10's over 15 turnovers (t 25 min), (OCH)' s 2 {Zn(OCH)}" equilibrium but as thus showing the true catalytic nature of the system. additional methoxide is added, the overall rate drops signifi cantly suggesting formation of inactive species having a (OCH)/Zn"greater than 1. This agrees with a potentio 45 metric titration of Zn" in methanol which displayed a Example 16 steeper-than-normal consumption of 2 methoxides in an apparent single event having a midpoint of ~pK, 9.8 which, Zn"-Catalyzed Methanolysis of Paraoxon and when analyzed via HyperquadTM fitting to a model containing Fenitrothion: Kinetics only the mononuclear species Zn"(OCH) and Zn" 50 (OCH) gives apparent pK and pK values of 10.66 and 8.94. While our original fitting (Gibson, et al., 2003) did As shown by the various formation constants given in Table not include dimer and oligomer formation, the fact that the 15, phen binds very tightly to Zn" at all values in methanol. second apparent pK, is lower than the first indicates some According to potentiometric titration data, the major species cooperative effect facilitating addition of a second methoxide 55 in the pH domain surrounding 01 probably exist in solution as oligo 60 paraoxon vs. Zn" (see FIG. 14B) follows the square mers of {Zn (OCH), sa), held together with methoxide root dependence of equation (6) that corresponds to the pro bridges. Added bi- or tridentate ligands could, in principle, cess presented in equation (5) with the derived kinetic param disrupt this arrangement by capping one face of the Zn eters being given in Table 16. The same general phenomenon favouring the formation of dimers and monomers of Stoichi is seen with ligand diMephen although its binding to Zn" is ometry {Zn":L(OCH), Zn":L(OCH)(HOCH) or 65 weaker than phen (as is known to be the case in water) Such Zn":L(OCH) depending on the methoxide/Zn" ratio. that at any given pH, only about 85% of the Zn" is bound to Indeed, as shown in FIG. 8, ligands phen, diMephen and diMephen. US 8,722,956 B2 33 34 TABLE 1.5 tions. In methanol, the M*-L binding constant is large (log K=10.11), ensuring that there is essentially no free Formation constants for various species determined by potentiometric titration. ligand in solution, and the pK for ionization of the complex Zn":12laneN: HOCH is 9.1. The k vs. Zn" plot Log K Log K Log K L = L = L = shown in FIG. 13A is a straight line consistent with (Zn": Equilibrium phen diMephen 12aneN 12|aneN:(OCH)) being the active catalyst and predomi L - H/LH) S.63 6.43 14.92 nant form. ZnLLZn) 10 4.25 10.11 (Zn-L2(OMe)2]/[Li'Zn (Ome 36.33 28.05 10 ZnL(OMe)/LZnOme? 20.58 21.67 Example 17 ZnL(OMe)/LZnOMe) 17.79 Cu"-Catalyzed Methanolysis of Paraoxon and Fenitrothion: Kinetic Studies 15 TABLE 16 In the absence of metal ions, uncatalyzed attack of meth Kinetic constants for the methanolysis offenitrothion oxide on paraoXon is some 15 times faster than on feni and paraOxon catalyzed by Zn" in the absence and presence trothion, but in the presence of all Cut:(OCH)} species of ligands phen, diMephen, 12laneN, at T = 25 C. are more effective forfenitrothion than paraoxon. This can be Paraoxon Fenitrothion quantified by the relative selectivity parameter given in Table Catalyst K. (mM), k, (M'min') k. (M'min') 18 which compares the relative reactivity of the metal-coor OCH, O.66 O.O43 O.OO1 dinated methoxide reaction relative to free methoxide attack Zn2+

The kinetics of methanolysis were monitored at 25°C. in A turnover experiment with Substrate in excess of catalyst anhydrous methanol by observing the rate of appearance of 25 was conducted using 0.4 mM Cu(OTf) along with equimolar p-nitrophenol or 3-methyl-4-nitrophenol between 312 and 12|aneN and 0.5 equation of NBuOCH. The methanolysis 335 nm at paraoxon or fenitrothion=4 to 12x10M under of 2 mM fenitrothion was monitored by UV/vis at T=25.0°C. pseudo-first order conditions of excess Cu(OTf) (0.2 to 5.0x and showed 10 turnovers relative to the active catalyst (0.2 10 M). All reactions were followed to at least three half mM Cut: 12aneN:(OCH)) within 100 min. times and found to exhibit good pseudo-first order rate behav 30 Although this invention is described in detail with refer ior and the first order rate constants (k) were evaluated by ence to preferred embodiments thereof, these embodiments fitting the Abs. vs. time traces to a standard exponential are offered to illustrate but not to limit the invention. It is model. The kinetics were all determined under self-buffered possible to make other embodiments that employ the prin conditions where the pH was controlled by a constant Cu"/ ciples of the invention and that fall within its spirit and scope Cu"(OCH) ratio and in the cases with ligands 12laneNs, 35 as defined by the claims appended hereto. bpy and phen, these were added in amounts equivalent to the Cult. Under these conditions the observed pH values REFERENCES correspond to the apparent pK value for ionization of the {Cu?":L:(HOCH)} {Cut:L:(OCH)}+"HOCH, Bosch, E.; Rived, F.; Roses, M.; Sales, J., “Hammett-Taft and system. 40 Drago Models in the Prediction of Acidity Constant Values As shown in FIGS. 6 and 7 the overall behaviour portrayed of Neutral and Cationic Acids in Methanol J. Chem. Soc., in thek.Vs. Cu"plots falls into two categories depending Perkin Trans. 2, 1999, 1953. on the nature of the ligand employed. In the absence of any Bosch, E.; Bou, P.; Allemann, H.; Roses, M. "Retention of ligand, or in the presence of equimolar bpy or phen, the FIG. Ionizable Compounds on HPLC. pH Scale in Methanol 45 Water and the pK and pH Values of Buffers’ Anal. Chem. 6 plots are non-linear and indicative of a square-root depen 1996, 3651 dence which can be fit via a standard Non-Linear Least Brown, R. S.; Neverov, A. A., “Acyl and Phosphoryl Transfer Squares (NLLSQ) treatment to equation (6) derived on the to Methanol Promoted by Metal Ions”.J. Chem. Soc. Perkin following assumptions: all the ligand is bound to Cu"; an 2 2002, 1039. active (rate constant k.) mononuclear species {Cu":L: 50 Brown, R. S.; Zamkanei, M., “Hydrolysis of Neutral Phos (OCH)} is in rapid equilibrium (dissociation constant K.) phate and Phosphonate Esters Catalysed by Co-Chelates with an inactive dimer (equation 4) and k is negli of Tris-Imidazolyl Phosphines’ Inorg. Chim. Acta. 1985, gible since it is undetectable. How good the fit of the lines is 108, 201. may be seen by examining the computed lines through the Desloges, W.; Neverov, A. A.; Brown, R. S., "Zinc "-Cata FIG. 6 data and the best fit constants are given in Table 18. 55 lyzed Methanolysis of Phosphate Triesters: a Process for Also in Table 18 are the measured pH values over the entire Catalytic Degradation of the Organophosphorus Pesticides Cu" range under the self-buffering conditions which devi Paraoxon and Fenitrothion” Inorg. Chem. 2004, submitted. ate by an acceptable 0.2 or less units. In the case of paraoxon, Gans, P.; Sabatini, A.; Vacca, A., “Investigation of Equilibria the catalyzed reactions were sufficiently slow that we have in Solution. Determination of Equilibrium Constants with placed upper limits on the rate and equilibrium constants. 60 the HYPERQUAD Suite of Programs' Talanta. 199643, A system comprising 2 mM Cu(OTf), along with 0.5 1739. equation of N(Bu)OCH and 1 equivalent of 12aneN cata Gibson, G.; Neverov, A. A.; Brown, R. S., "Potentiometric lyzes the methanolysis offenitrothion with at of ~58 sec Titration of Metal Ions in Methanol Can. J. Chem. 2003, accounting for a 1.7x10-fold acceleration of the reaction 81,495. relative to the background reaction at a near neutral pH of 65 Neverov, A. A.; Brown, R. S., “Catalysis of the Methanolysis 8.75. In this system the concentration of catalyst is in excess of Acetylimidazole by Lanthanum Triflate Can. J. Chem. over the concentration offentrothion. 2000, 78, 1247. US 8,722,956 B2 37 38 Neverov, A. A.; Brown, R.S., “La"-Catalyzed Methanolysis 8. The kit of claim 1 or 2, wherein said medium is prepared of Phosphate Diesters. Remarkable Rate Acceleration of by combining a metal salt and an alkoxide salt with at least the Methanolysis of Diphenyl Phosphate, Methyl p-Nitro one of alcohol, alkoxyalkanol and aminoalkanol. phenyl Phosphate, and Bis(p-nitrophenyl) Phosphate' 9. The kit of claim 1 or 2, wherein said medium further Inorg. Chem. 2001(a), 40,3588. 5 comprises a non-inhibitory buffering agent. Neverov, A. A.; McDonald, T., Gibson, G.; Brown, R. S., 10. The kit of claim 9, wherein said buffering agent com “Catalysis of Transesterification Reactions by Lan prises an aniline, N-alkylaniline, N,N-dialkylaniline, N-alky thanides Unprecedented Acceleration of Methanolysis lmorpholine, N-alkylimidazole, 2.6- dialkylpyridine, pri of Aryl and Alkyl Esters Promoted by La(OTf) at mary , secondary amine, tertiary amine, trialkylamine, or a combination thereof. Neutral pH and Ambient Temperatures' Can. J. Chem. 10 2001(b), 79, 1704. 11. The kit of claim 1 or 2, wherein the concentration of Neverov, A. A.; Montoya-Pelaez, P.J.; Brown, R. S., "Cataly said alkoxide ions is about 0.01 to about 2 equivalents of the sis of the Methanolysis of Activated Amides by Divalent concentration of the metal ions. and Trivalent Metal Ions. The Effect of Zn", Co", and 12. The kit of claim 1 or 2, wherein the concentration of La"on the Methanolysis of Acetylmidazole and Its said alkoxide ions is about 0.1 to about 2 equivalents of the (NH). Co'Complex” J. Am. Chem. Soc. 2001(c), 123, 15 concentration of the metal ions. 210. 13. The kit of claim 1 or 2, wherein the concentration of Rived, F.; Rosés, M.; Bosch, E., “Dissociation Constants of said alkoxide ions is about 0.5 to about 1.5 equivalents of the Neutral and Charged Acids in Methyl Alcohol. The Acid concentration of the metal ions. Strength Resolution’ Anal. Chim. Acta 1998, 374, 309. 14. The kit of claim 1 or 2, wherein the concentration of Tsang, J.; Neverov, A. A.; Brown, R. S., “Billion-Fold Accel said alkoxide ions is about 1 to about 1.5 equivalents of the eration of the Methanolysis of Paraoxon Promoted by concentration of the metal ions. 15. The kit of claim 1 or 2, wherein said metal ions are La(OTf) in Methanol J. Am. Chem. Soc. 2003, 125,7602. selected from the group consisting of lanthanide series metal Yang, Y.-C.; Berg, F. J.; Szafrainiec, L. L.; Beaudry, W. T.; ions, copper, cobalt, platinum, palladium, zinc, nickel, Bunton, C. A.; Kumar, A., “Peroxyhydrolysis of Nerve 25 Agent VX and Model Compounds and Related Nucleo yttrium, Scandium ions, and combinations thereof. philic Reactions”.J. Chem. Soc. Perkin Trans. 2 1997, 607. 16. The kit of claim 1 or 2, wherein said metal ions are Yang, Y.-C. “Chemical Detoxification of Nerve Agent VX selected from the group consisting of Cut, Co, Pt", Pd", Acc. Chem. Res. 1999, 32, 109-115. Zn?", Y3+. Sc", Ce", La", Pr", Nd", Sm", Eu", Gd", We claim: Tb, Dy, Ho, Er, Tm, Yb", and combinations 1. A kit for decomposing an organophosphorus compound 30 thereof. comprising a Substantially non-aqueous medium for an alco 17. The kit of claim 1 or 2, wherein said metal ions are holysis reaction, said medium comprising non-radioactive lanthanide series metal ions. 18. The kit of claim 17, wherein said lanthanide series metal ions selected from the group consisting of lanthanide metal ions are selected from thegroup consisting of Ce", series metal ions, transition metal ions, and combinations 35 thereof, and at least a trace amount of alkoxide ions; and a La", Pr", Nd", Sm", Eu", Gd", Tb3+, Dy". Ho 3+. Er", container, Tm, Yb", and combinations thereof. wherein the container is opened so that the medium can 19. The kit of claim 1 or 2, wherein said metal ions are contact the organophosphorus compound. selected from the group consisting of Cut", Pt", Pd, Zn", 2. A kit for decomposing an organophosphorus compound and combinations thereof. comprising a substantially non-aqueous medium for an alco 40 20. The kit of claim 1 or 2, wherein said metal ions are holysis reaction, said medium comprising non-radioactive selected from the group consisting of Y", Sc", and combi metal ions selected from the group consisting of lanthanide nations thereof. series metal ions, transition metal ions, and combinations 21. The kit of claim 1 or 2, wherein said metal ions com thereof, and at least a trace amount of alkoxide ions; and an prise La". applicator bearing the medium, said applicator being adapted 45 22. The kit of claim 1 or 2, wherein said medium further so that the medium is applied to the organophosphorus com comprises one or more ligands. 23. The kit of claim 22, wherein said one or more ligands pound and the compound decomposes. comprise 2,2'-bipyridyl, 1,10-phenanthryl, 2,9-dimeth 3. The kit of claim 1 or 2, further comprising written ylphenanthryl, crown ether, 1.5.9-triazacyclododecyl substi instructions for use. 50 4. The kit of claim 1 or 2, wherein said medium further tuted forms thereof, or combinations thereof. comprises a solvent selected from the group consisting of 24. The kit of claim 22, wherein said one or more ligands methanol, Substituted and unsubstituted primary, secondary are attached via linkages to Solid Support material. 25. The kit of claim 24, wherein said solid support material and tertiary alcohols, alkoxyalkanol, aminoalkanol, and com comprises polymer, silicate, aluminate, or combinations binations thereof. 55 5. The kit of claim 4, wherein said medium comprises thereof. aminoalkanol. 26. The kit of claim 1 or 2, wherein said medium is a solid. 6. The kit of claim 1 or 2, wherein said medium further 27. The kit of claim 1 or 2, wherein said medium is a comprises a solvent selected from the group consisting of Solution. 28. The kit of claim 1, wherein said medium is contained in methanol, ethanol, n-propanol, iso-propanol, n-butanol, 60 2-butanol, methoxyethanol, and combinations thereof. an ampule. 7. The kit of claim 1 or 2, wherein said medium further 29. The kit of claim 2, wherein the applicator comprises a comprises a solvent selected from the group consisting of moist cloth bearing the medium. nitriles, esters, ketones, amines, ethers, hydrocarbons, Substi 30. The kit of claim 2, wherein the applicator is a sprayer tuted hydrocarbons, unsubstituted hydrocarbons, chlorinated which is adapted to spray the medium. hydrocarbons, and combinations thereof. k k k k k