Mechanism of Aqueous Hydroperoxidolysis of O,S-Dimethyl Methylphosphonothiolate

Brittany M. Curtis and Eric V. Patterson*Department of Chemistry, Truman State University, Kirksville, Missouri

Introduction Objectives

Acknowledgments

Results and Discussion

Methods

O-ethyl S-(diisopropylamino)ethyl methylphosphonothioate (VX) is a V-series nerve agent used in chemical warefare. VX can cause convulsions and death within fif-teen minutes by inhibiting acetylcholinesterase.

The Chemical Weapons Convention of 1993 mandated the destruction of all stock-piles of chemical warfare agents. To date, the United States Army has destroyed 88 percent of stockpiled agents. While simpler nerve agents such as sarin are easily destroyed by aqueous sodium hydroxide, VX is resistant to alkaline hydrolysis at ambient temperature.

Therefore, the process the army uses to discard VX involves alkaline hydrolysis at elevated temperatures, followed by an oxidation step.

In contrast to alkaline hydrolysis, hydroperoxidolysis (use of hydroperoxide anion as the nucleophile) of VX leads to complete detoxification. The mechanism of hydrox-iperodolysis of O,S-dimethyl methylphosphonothiolate (O,S-DMMP), a VX simulant, has been thoroughly studied in the gas phase both theoretically1 and via mass spectrometry.2 A consistent feature of the presumed mechanism is nucleophilic attack opposite methoxide, followed by an unusual intramolecular oxidation step.

Results and Discussion

While the gas-phase mechanism for the hydroperoxidolysis of O,S-DMMP is well understood, the precise solution phase mechanism remains unknown.

The purpose of this experiment is to study the effects of aqueous solvent during the hydroperoxidolysis of VX. Specifically, an explicit solvent model will be employed to ascertain how water might be directly involved in the mechanism. The primary ob-jectives are:

1) Determine how the presence of water alters the initial nucleophilic attack.

2) Determine whether the intramolecular oxidation step is unique to the gas-phase mechanism.

Explicit solvent is represented by 200 effective fragment potential (EFP) water mol-ecules surrounding the solute, and the entire system is embedded in an aqueous polarizable continuum model (PCM). In order to reduce computational time O,S-dimethyl methylphosphonothiolate is used as a simulant for VX. The M06-2X/6-31+G(d,p) level of theory has been used to model the solute.

Water molecules were randomly placed in a sphere around each solute to give an initial density of 1.0 g/mL.

Packmol was used to generate the initial cluster geometries.All calculations were performed using the October 2010 release of GAMESS-US. All results were visualized using MacMolPlt.

Funding provided by:

National Science FoundationCHE-0746096MRI-0821581

Research Corporation for Science AdvancementCCSA7789

‡

P

O

OCH2CH3

SRCH3

P

O

OH

OCH2CH3

CH3

P SRCH3

OH

O

R=CH2CH2[CH(CH3)2]2

A-

- RS-

- EtO-

VX

EMPAA = HO- (87%), HOO- (100%)

EA 2192 (toxic)A = HO- (13%), HOO- (0%)

VX acetylcholine

1. Šečkutė et al. J. Org. Chem. 2005, 70, 8649-8660.2. McAnoy et al. J. Org. Chem. 2009, 74, 9319-9327.

(oxygen atoms colored green for future clarification)

Inital calculations were performed on isolated hydroperoxide and O,S-DMMP, each surrounded by a sphere of 100 EFP water molecules. The systems were then merged at a distance of 20 Angstroms, and moved incrementally closer. The geometries of the solutes and the positions of the waters were optimized at each step.

System at 17.4 Angstrom separation between nucleophilic atom and phosphorus.

This is the point of initial contact between the two spheres.

System at 5.8 Angstrom separation between nucleophilic atom and phosphorus.

Note the sphere of water around the hydroperoxide is no longer merging with the other waters.

Relative Energy (kcal/mol)

-50.0

-40.0

-30.0

-20.0

-10.0

0.0

10.0

0 5 10 15 20 25

Rela

tive

Ener

gy (k

cal/m

ol)

Separation (Angstroms)

Relative Energy (kcal/mol)

Relative energy as a function of distance between nucleophilic atom and phosphorus is inconclusive and suggests potential problems with our ap-proach.

Future plans:

Analyze current data to identify structural waters and trim system to remove non-structural solvent molecules.

Attempt to locate intramolecular oxidation pathway in the presence of explicit solvent.