Instantaneous Hydrolysis of Methyl Paraoxon Nerve Agent Simulant Is Catalyzed by Nontoxic Aminoguanidine Imines

Abstract

Exposure to organophosphate-based nerve agents and pesticides poses health and security threats to civilians, soldiers, and first responders. Thus, there is a need to develop effective decontamination agents that are nonhazardous to human health. To address this, we demonstrate that instantaneous hydrolysis of methyl paraoxon (Me-POX), a nerve agent simulant, can be achieved in the presence of aminoguanidine imines at pH 10: ● the pyridine-4-aldehyde aminoguanidine-imine (1) and ● the 2,3-butanedione aminoguanidine-imine (2). The hydrolysis of Me-POX under these conditions is substantially faster than that of the state-of-the-art decontaminating agent, Dekon-139 (2,3-butanedione oxime, potassium salt). Furthermore, Dekon-139 shows adverse effects when applied on skin surfaces, making it of great interest to develop safer but effective decontaminating agents for neutralizing nerve agents and pesticides exposed to skin-surface areas. Our pharmaceutically relevant aminoguanidine derivatives serve as rather nontoxic and safe decontaminating agents for organophosphate-based nerve agents and pesticides. The hydrolytic degradation products of Me-POX by our aminoguanidine-based imines and Dekon-139 are pH dependent. At pH > 10, Me-POX is hydrolyzed to give dimethyl phosphate as the exclusive product, whereas at pH < 9, the major product of hydrolysis is methyl 4-nitrophenyl phosphate (M4NP). We applied Quantum Mechanics calculations to investigate the mechanism of this dramatically accelerated decontamination process. We predict that in the rate-determining transition state, both 1 and 2 stabilize the reaction center through hydrogen bonding. Compared to Dekon-139, the rate constants of the rate-determine steps (RDS) are predicted to be over 9,000 times larger for 1 and over 600 times larger for 2, explaining the improvement. Quantum Mechanics calculations rationalize the pH-dependent hydrolysis products of the Me-POX in the gas phase, and gauge-including atomic orbital (GIAO)-³¹P NMR chemical shift calculations confirm the experimental values.

Figure 1

Structures of some organophosphate-based nerve agents (GB, GF, GV, and GD) and nerve agent simulants (Me-POX, DCP, DMMP).

Figure 2

Proton-decoupled ³¹P NMR spectra (161.9 MHz) for the reaction of Me-POX with small-molecule decontaminating agents.

Figure 3

Proton-decoupled ³¹P NMR spectra (161.9 MHz) for the reaction of Me-POX with small-molecule decontaminating agents in 0.5 M borate buffer (in DMSO); pH 8.5 at 25 °C.

Scheme 1. pH-Dependent Hydrolytic Products of Methyl Paraoxon (Me-POX)

Figure 4

Proton-decoupled ³¹P NMR (161.9 MHz) for the reaction of Me-POX with pyridine-4-aldehyde aminoguanidine imine (1); 2,3-butanedione aminoguanidine imine (2); and Dekon-139 (3) in 0.5 M borate buffer (in DMSO) at pH 8–10.

Figure 5

Time-course conversion of Me-POX (10 mM) to the nontoxic products in the presence of the aminoguanidine analogs -(1, 4-PAAGI, and 2, 2,3-BDAGI), Dekon 139 (50 mM), and alkaline water in 1.0 M glycine-DMSO buffer at (a) pH 10, (b) pH 9, and (c) pH 8 at 25 °C.

Figure 6

Proposed mechanism for the aminoguanidine aldimines-catalyzed hydrolysis of methyl paraoxon (Me-POX) at pH > 9 (A), and at pH < 9 (B).

Figure 7

Prototypical first-order kinetic model for Me-POX (10 mM) conversion catalyzed by the aminoguanidine analogs (1, 4-PAAGI, and 2, 2,3-BDAGI), Dekon 139 (50 mM), and alkaline Water in 1.0 M glycine-DMSO buffer at (a) pH 10, (b) pH 9, and (c) pH 8 at 25 °C.

Scheme 2. DFT-Calculated Proton Affinities (PA) for the Methyl Paraoxon (Me-POX)

Figure 8

Product distribution of Me-POX (10 mM) degradation in 1.0 M glycine-DMSO buffer, (pH 9.1) catalyzed by the (a) 4-PAAGI (1) (50 mM), (b) 2,3-BDAGI (2) (50 mM), and (c) Dekon-139 (3) (50 mM) in 1.0 M glycine-DMSO buffer at 25 °C.

Figure 9

DFT (M06-2X-D3/6-31G+**) computed free energy profile of the Me-POX hydrolysis mechanism with (blue) and without 1 and 2 and Dekon-139 decontamination (red).