International Journal of Molecular Sciences Article Quantum Calculations of VX Ammonolysis and Hydrolysis Pathways via Hydrated Lithium Nitride Calen J. Leverant 1,2 , Chad W. Priest 1, Jeffery A. Greathouse 1, Mark K. Kinnan 1 and Susan B. Rempe 1,* 1 Sandia National Laboratories, Albuquerque, NM 87185, USA; [email protected] (C.J.L.); [email protected] (C.W.P.); [email protected] (J.A.G.); [email protected] (M.K.K.) 2 Department of Chemical Engineering, University of Florida, Gainesville, FL 32611, USA * Correspondence: [email protected] Abstract: Recently, lithium nitride (Li3N) has been proposed as a chemical warfare agent (CWA) neutralization reagent for its ability to produce nucleophilic ammonia molecules and hydroxide ions in aqueous solution. Quantum chemical calculations can provide insight into the Li3N neutralization process that has been studied experimentally. Here, we calculate reaction-free energies associated with the Li3N-based neutralization of the CWA VX using quantum chemical density functional theory and ab initio methods. We find that alkaline hydrolysis is more favorable to either ammonolysis or neutral hydrolysis for initial P-S and P-O bond cleavages. Reaction-free energies of subsequent reactions are calculated to determine the full reaction pathway. Notably, products predicted from favorable reactions have been identified in previous experiments. Keywords: VX; aminolysis; base hydrolysis; decontamination; Hartree–Fock; density functional Citation: Leverant, C.J.; Priest, C.W.; theory; chemical warfare agent Greathouse, J.A.; Kinnan, M.K.; Rempe, S.B. Quantum Calculations of VX Ammonolysis and Hydrolysis Pathways via Hydrated Lithium 1. Introduction Nitride. Int. J. Mol. Sci. 2021, 22, 8653. Organophosphates (OPs), a class of nerve agents and pesticides, are among the most https://doi.org/10.3390/ toxic of chemical warfare agents (CWAs) [1]. Upon exposure, OPs attack the central ijms22168653 nervous system, causing involuntary bodily functions such as seizures. OPs have binding affinities similar to that of the neurotransmitter acetylcholine, allowing OPs to inhibit Academic Editor: Luísa the action of acetylcholinesterase in neuromuscular junctions, disrupting the breakdown Margarida Martins of the neurotransmitter [2–4]. The neutralization of OP compounds can be achieved Received: 15 June 2021 through oxidation [5,6], enzyme degradation [7–9], hydrolysis [10–12], and incineration [13]. Accepted: 2 August 2021 Nevertheless, each method is not without its limitations. Oxidation requires large excesses Published: 11 August 2021 of oxidizing agents and is not very selective [6,14]. Enzymes used in CWA degradation are not stable and cannot be stored for long periods of time [15]. Hydrolysis often uses a large Publisher’s Note: MDPI stays neutral quantity of water [14]. Finally, incineration requires that the CWAs are moved to facilities with regard to jurisdictional claims in with the appropriate equipment [16], and thus cannot be used in many locations. published maps and institutional affil- Of the OP CWAs, ethyl({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphin- iations. ate, or VX, is among the most toxic. Like most OPs, it contains a pentavalent central phosphorous atom, P(V). It has a four-coordinate chiral center at the P(V)-atom, with two enantiomer forms (S)-VX and (R)-VX. The structure contains a phosphoester (P-OR), a 0 methyl (P-CH3), a terminal oxide (P=O), and a phosphothiol (P-SR ) bond. Here, R is an 0 Copyright: © 2021 by the authors. ethyl group and R is a complex constituent containing a (diisopropylamino)ethyl chain. Licensee MDPI, Basel, Switzerland. Molecular modeling is a useful tool to study CWA properties such as liquid struc- This article is an open access article ture [17,18], adsorption [19–21], and reactivity [22]. Quantum methods, specifically density distributed under the terms and functional theory (DFT) and ab initio techniques, are ideally suited to investigate fun- conditions of the Creative Commons damental reaction pathways of these compounds. Understanding the mechanistic steps Attribution (CC BY) license (https:// involved in the decomposition of toxic chemicals such as CWAs continues to be an active creativecommons.org/licenses/by/ area of research [23]. Many computational efforts have studied decontamination of VX, 4.0/). Int. J. Mol. Sci. 2021, 22, 8653. https://doi.org/10.3390/ijms22168653 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 8653 2 of 11 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 12 or its analogues (e.g., O,S-dimethyl methylphosphonothiolate) by different chemical pro- cesses. Theseor include its analogues neutral (e.g hydrolysis,., O,S-dimethyl alkaline methylphosphonothiol hydrolysis, oxidation,ate) by anddifferent aminolysis chemical pro- reactions [10,12cesses.,22,24 These,25]. include Most of neutral these hydrolysis, chemical decontaminationalkaline hydrolysis, processes oxidation, relyand onaminolysis a nucleophile. Forreactions these [10,12,22,24,25]. compounds, nucleophilicMost of these chem reactionsical decontamination can undergo twoprocesses competing rely on a nu- solvolysis reactioncleophile. pathways: For these P-S compounds, or P-O bond nucleophilic cleavage reactions [6,26,27 ],can shown undergo in Schemetwo competing1 for sol- alkaline hydrolysis.volysis P-Oreaction cleavage pathways: produces P-S or toxicP-O bond EA-2192 cleavage (S-[2-(diisopropylamino)ethyl] [6,26,27], shown in Scheme 1 for al- hydrogen methylphosphonothioate),kaline hydrolysis. P-O cleavage while P-Sproduces cleavage toxic yields EA-2192 the non-toxic(S-[2-(diisopropylamino)ethyl] EMPA (ethyl methylphosphonichydrogen acid). methylphosphonothioate Alkaline hydrolysis of), VXwhile yields P-S cleavage 13% EA-2192 yields the and non-toxic 87% EMPA EMPA [6]. (ethyl methylphosphonic acid). Alkaline hydrolysis of VX yields 13% EA-2192 and 87% EMPA In earlier computational work, Patterson and coworkers used a combination of DFT [6]. and Hartree–FockIn (HF) earlier methods computational to study work, the Patterson alkaline and hydrolysis coworkers of used sarin a andcombination OP com- of DFT pounds [10–12and]. ForHartree–Fock VX, their (HF) results methods showed to study that thethe alkaline reaction hydrolysis pathway of involving sarin and P-SOP com- bond cleavagepounds is thermodynamically [10–12]. For VX, their favorable results comparedshowed that with the reaction P-O cleavage pathway [12 involving]. The P-S decompositionbond of VX cleavage catalyzed is thermodyna by the hydroxidemically favorable or hydroperoxide compared with anions P-O cleavage also showed [12]. The de- that the P-S cleavagecomposition is the of most VX catalyzed favorable by thermodynamic the hydroxide or hydroperoxide pathway [11]. anions As validation also showed of that their methods,the the P-S calculated cleavage is enthalpy the most favorable of activation thermodynamic for sarin agrees pathway well [11]. with As validation the experi- of their ment [12]. Mandalmethods, et al. the used calculated DFT methodsenthalpy of to activation examine for the sarin P-O agrees and P-S well bond with cleavagethe experiment reaction pathways[12]. Mandal in the VX et al. analogue, used DFT O,S-dimethyl methods to examine methylphosphonothiolate, the P-O and P-S bond cleavage in the gas reaction phase and in thepathways presence in ofthe various VX analogue, implicit O,S-dimethyl solvents [24 methylphosphonothiolate,]. Although previous calculations in the gas phase suggested thatand P-S in bondthe presence cleavage of various is approximately implicit solvents 5–10 [24]. kcal/mol Although more previous favorable calculations than sug- gested that P-S bond cleavage is approximately 5–10 kcal/mol more favorable than P-O P-O bond cleavage in similar compounds [11,12], results from Mandal et al. indicate that bond cleavage in similar compounds [11,12], results from Mandal et al. indicate that breaking either bond is equally favorable [24]. They also showed that within the COSMO breaking either bond is equally favorable [24]. They also showed that within the COSMO implicit solventimplicit model, solvent the typemodel, of the solvent type of had solvent little had effect little on effect the barrier on the barrier heights heights or net or net reaction energiesreaction [24]. energies [24]. SchemeScheme 1. Alkaline 1. Alkaline hydrolysis hydrolysis of VX resulting of VX in resulting EA-2192 from in EA-2192 P-O cleavage from or P-O EMPA cleavage from P-S or cleavage. EMPA from P-S cleavage. Recently, Li3N has been proposed as a multifunctional reagent for broadband CWA neutralization, with the objective to use a minimal amount of the reagent to disable bulk CWAs through neutralization or solidification [28,29]. When Li3N is hydrated, hydroxide ions and ammonia are generated, both of which can serve as nucleophiles in the decon- tamination of CWAs (Schemes1 and2). Here, hypothesized NH 3 ammonolysis products include DIEMPAT (S-(2-(diisopropylamino) ethyl) P-methyl phosphonamidothioate) from P-O cleavage, and EMPAM (ethyl P-methyl phosphonamidite) from P-S cleavage. This work aims to explore the complete decontamination of VX from base hydrolysis and am- monolysis processes in the Li3N aqueous environment. These reactions can contribute toward the development of new decontamination methods and to further understand the Li3N CWA decontamination process. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 12 Recently, Li3N has been proposed as a multifunctional reagent