Theoretical Proton Affinity and Fluoride Affinity of Nerve Agent VX

Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States, and Air Forc...
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J. Phys. Chem. A 2010, 114, 13189–13197

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Theoretical Proton Affinity and Fluoride Affinity of Nerve Agent VX Narayan C. Bera,† Satoshi Maeda,† Keiji Morokuma,*,† and Al A. Viggiano‡ Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322, United States, and Air Force Research Laboratory, Space Vehicles Directorate, 29 Randolph Road, Hanscom AFB, Massachusetts 01731-3010, United States ReceiVed: August 15, 2010; ReVised Manuscript ReceiVed: NoVember 5, 2010

Proton affinity and fluoride affinity of nerve agent VX at all of its possible sites were calculated at the RIMP2/cc-pVTZ//B3LYP/6-31G* and RI-MP2/aug-cc-pVTZ//B3LYP/6-31+G* levels, respectively. The protonation leads to various unique structures, with H+ attached to oxygen, nitrogen, and sulfur atoms; among which the nitrogen site possesses the highest proton affinity of -∆E ∼ 251 kcal/mol, suggesting that this is likely to be the major product. In addition some H2, CH4 dissociation as well as destruction channels have been found, among which the CH4 + [Et-O-P(dO)(Me)-S-(CH2)2-N+(iPr)dCHMe] product and the destruction product forming Et-O-P(dO)(Me)-SMe + CH2dN+(iPr)2 are only 9 kcal/mol less stable than the most stable N-protonated product. For fluoridization, the S-P destruction channel to give Et-O-P(dO)(Me)(F) + [S-(CH2)2-N-(iPr)2]- is energetically the most favorable, with a fluoride affinity of -∆E ∼ 44 kcal. Various F- ion-molecule complexes are also found, with the one having F- interacting with two hydrogen atoms in different alkyl groups to be only 9 kcal/mol higher than the above destruction product. These results suggest VX behaves quite differently from surrogate systems. 1. Introduction VX, S-2-(diisopropylamino)ethyl O-ethyl methylphosphonothioate, [Et-O-P(dO)(Me)-S-(CH2)2-N(iPr)2], is one of the most harmful nerve agents, classified as weapons of mass destruction in UN resolution 687, of which a very small amount causes flaccid paralysis of all the muscles of the body. There are thousand tons of stockpiles of VX molecules in United States. The very strong toxicity of this VX molecule can be destroyed by breaking its S-P bond, which can be achieved by solvolysis in base solution.1–3 During solvolysis the S-P bond breaking occurs through the nucleophilic attack of hydroxide, hydroperoxide, or alkoxide anionic to the P atom. An O-P bond cleavage can also take place also as a minor process compared to S-P bond cleavage, but the ratio of the two cleavages depends on the pH of the solution. The product formed by O-P bond breaking is still highly toxic. Although the hydrolysis of VX proceeds at room temperature, at 90 °C the hydrolysis of both VX and the product of O-P bond cleavage takes place. Hence, the detoxification of VX is carried out utilizing alkaline hydrolysis at 90 °C.4 Some theoretical calculations5–8 have been performed to establish the detailed reaction mechanisms of the S-P bond cleavage by the HO-, HOO-, and C2H5O- anions. Real time detection of chemical warfare agents including VX is critical in homeland security, battlefield operations, chemical weapon stockpile handling, and chemical weapon disposal facilities. Chemical ionization mass spectrometry (CIMS) is a powerful technique to detect the atmospheric neutrals selectively and sensitively.9–17 Its use in detection of chemical warfare agents has been attempted by Viggiano et al. recently.18–20 The CIMS technique requires data measured in laboratories, primary ions that react rapidly with the agents and yield product ions * Corresponding author, [email protected] (K.M.). † Emory University. ‡ Air Force Research Laboratory.

with unique mass signatures. Since the real chemical weapons cannot be used readily in most laboratories, they collected the required data by employing surrogate molecules without toxicity; diethyl methylthiomethylphosphonate (DEMTMP) and triethylamine were considered as surrogates of VX.20 To confirm and to complement the data, theoretical calculations of related ion-molecule reactions for real chemical warfare agents are required. Among many ion-molecule reactions measured for the surrogates of VX, proton and fluoride adduct reactions are the most important. However, the theoretical data so far available for VX itself is not sufficient. Recently Bandyopadhayay et al.21 studied theoretically metal ion coordination isomers on serin and VX. The calculation involved geometry optimizations at the B3LYP/6-31+G* level for complexes between serin/VX and H+, Li+, Na+, K+, Be2+, Mg2+, and Ca2+, where they considered proton attachment only on three sites of VX (only three optimized structures are presented for [VX · H]+). No other attempt has been made so far to study the proton affinity and fluoride affinity of VX. In this paper we have studied theoretically the reaction of proton and fluoride ion with VX nerve agent targeting from different directions to different sites of VX, and the results were compared with data for the surrogates of VX.20 2. Computational Details At first, structures of the protonation and fluorination products, [VX · H]+ and [VX · F]-, were optimized at the B3LYP level with the 3-21G* and 3-21+G* basis sets, respectively, where initial structures were generated as explained in the next paragraph. Obtained [VX · H]+ and [VX · F]- structures were reoptimized at the B3LYP/6-31G* and B3LYP/6-31+G* levels, respectively. Single point energies were evaluated at those B3LYP/6-31G* and B3LYP/6-31+G* geometries at RI-MP2/ cc-pVTZ and RI-MP2/aug-cc-pVTZ levels of calculation,22,23 respectively, for more reliable energetics, where corresponding auxiliary basis sets were employed in the RI-MP2 calculations.24

10.1021/jp107718w  2010 American Chemical Society Published on Web 11/30/2010

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Bera et al. SCHEME 1: Approaches Considered for (a) 8O, (b) 15S, (c) 10O, (d) 22N, and (e) 9P Sites, in Addition to mX-nY r H+/F- (nYm) Directions

Figure 1. Optimized VX structure at the B3LYP/6-31G* level and atomic numbering system.

We did not perform vibrational analyses on any structures, and therefore the reported energy values do not include the zero point energy corrections. Geometry optimizations were carried out with the Gaussian0325 package, and the single point calculations were performed using Turbomol 5.9.26 As shown in Figure 1, there are 11 carbon atoms, 2 oxygen atoms, and 1 phosphorus, sulfur, and nitrogen atom each in VX. In order to obtain all possible protonation and fluorination structures, we considered the attachment of H+/F- to all these 16 heavy atom sites from the following various directions. For sp3 carbon atoms, we considered four X-C r H+/F- directions, where X is an atom connected to the target C atom and a path is designated for example as 1C2 when H+/F- is coming to the 1C site along the 2C-1C bond (2C-1C r H+/F-). Similarly for all heavy atom sites (nY), an approach mX-nY r H+/Fis designated as nYm. We considered additional approach directions for oxygen, phosphorus, sulfur, and nitrogen sites. For 8O, four additional directions were considered: positive and negative directions along the bisector line of the A-O-B angle and along the perpendicular line to the A-O-B plane, designated as 8Os1, 8Os2, 8Os3, and 8Os4 (see Scheme 1a). A similar set of directions was considered also for the 15S site designated as 15Ss1, 15Ss2, 15Ss3, and 15Ss4 (see Scheme 1b). For 10O, four additional directions perpendicular to the PdO bond were considered: positive and negative directions of in and out of the S-PdO plane, designated as 10Os1, 10Os2, 10Os3, and 10Os4 (see Scheme 1c). For 22N, two more directions, from the top and the bottom of pyramidal structure were considered, which are designated as 22Ns1, 22Ns2 (see Scheme 1d). For the 9P site, six additional directions are considered, which are along bisector lines of the X-P-Y plane for all six pairs of X and Y and are designated as 9Ps1, 9Ps2, 9Ps3, 9Ps4, 9Ps5, and 9Ps6 (see Scheme 1e). Although H atoms are not reactive in general, we found that H atoms on C connected to N can react with H+. Thus, such C-H bond directions, i.e., 17C-20H r H+, 17C-21H r H+, 23C-26H r H+, and 33C-36H r H+, were also considered, which are designated as 20H17, 21H17, 26H23, and 36H33, respectively. Thus, 80 H+ paths and 76 F- paths were considered in total. The initial optimizations (with 3-21G* or 3-21+G* basis) were performed taking H+ and F- ions at 1.3 and 2.3 Å, respectively, away from the corresponding target atom in VX.

3. Results and Discussion All optimized protonated structures are shown in Figures 2-8 and their proton affinity value calculated at three computation levels are listed in Table 1 (with the total energies and optimized Cartesian coordinates in the Supporting Information). For dissociation products the optimized structures of the product complexes, rather than those of isolated fragments, are used. In Table 1, protonation sites and paths (initial structures explained above) corresponding to each protonated structure are also listed. Among the 33 structures, fragmentations took place during optimizations of P17-P33, which are labeled as “H2”, “CH4”, and “Destruction” in the site column. The products of these channels correspond to the following chemical formulas

H2 + Et-O-P(dO)(Me)-S-(CH2)2-N+(iPr)dC(Me)2 (P17-P22) CH4 + Et-O-P(dO)-S-(CH2)2 - N+(iPr)2

(P23)

CH4 + Et-O-P(dO)(Me)-S-(CH2)2-N+(iPr)dCHMe (P24-P28) CH4 + CH2O + Me-P(dO)-S-(CH2)2 - N+(iPr)2 (P29) CH3CH3 + MeP(dO)2 + CH2S + CH2dN+(iPr)2

(P30)

Et-O-P(dO)(Me)-SH + c-(CH2)2N+(iPr)2

(P31)

Et-O-P(dO)(Me)-SMe + CH2dN+(iPr)2 (P32-P33) Similarly, all optimized fluorinated structures are shown in Figure 9-12 and their energies at three computation levels are listed in Table 2 (with the total energies and optimized Cartesian coordinates in the Supporting Information). For dissociation products the optimized structures of the product complexes,

Proton and Fluoride Affinity of Nerve Agent VX

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TABLE 1: Proton Affinity (∆E ) E(product) - E(VX)) for Various Protonation Products of the VX Molecule (in kcal/mol) site

product structure

8O

P1

10O

P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13

15S

22N

P14 P15 P16

H2

P17 P18 P19 P20 P21 P22 CH4 P23: [Et-O-P()O)-S -(CH2)2-N(iPr)2]+ P24: [Et-O-P()O)(Me)-S -(CH2)2-N+(iPr)dCHMe] P25: same to P24 P26: same to P24 P27: same to P24 P28: same to P24 destruction P29: CH4, CH2O + [Me-P(dO)-S-(CH2)2-N(iPr)2]+ P30: CH3CH3, MeP(dO)2, CH2S + H2CdN+(iPr)2 P31: Et-O-P(dO)(Me)-SH + [c-(CH2)2]CdN+(iPr)2 P32: Et-O-P(dO)(Me)-SMe + CH2dN+(iPr)2 P33: same to P32 a

B3LYP/3-21G* B3LYP/6-31G* RI-MP2/cc-pVTZa

path 1C3, 2C6, 2C7, 8O9, 8Os1, 8Os2, 8Os3, 11C12 2C1 9Ps1 9P8, 10O9, 10Os1, 10Os2, 11C13, 9P15 8Os4, 9Ps3, 9Ps4, 16C19, 34C37, 34C39 10Os4 9P11 10Os3 15Ss1 9Ps5, 15Ss4 15Ss2 11C14,16C17 8O2, 9Ps6, 10P9, 15Ss3, 16C9, 17C22 17C16, 22Ns1, 24C28, 33C25, 33C34 23C26 16C15, 17C20, 22N17, 22N23, 22N33, 22Ns2, 23C24, 25C32, 33C36, 34C38, 35C42 1C4 33C22, 35C41, 36H33 1C5 20H17 21H17 26H23 9Ps2, 11C9

-208.23

-202.64

-199.31

-205.66 -226.29 -226.43

-202.31 -224.58 -224.74

-199.98 -224.44 -225.34

-226.56

-224.69

-225.17

-226.61 -227.25 -227.48 -209.48 -209.67 -210.20 -210.33 -211.10

-224.57 -225.33 -225.29 -209.57 -209.11 -208.65 -208.45 -210.11

-224.59 -225.60 -226.18 -204.66 -205.11 -204.66 -204.74 -205.77

-255.09

-247.43

-245.83

-257.92 -261.88

-251.91 -252.10

-250.95 -250.04

-237.89 -238.52 -239.85 -232.09 -230.39 -230.82 -193.62

-237.96 -236.07 -236.57 -231.26 -228.40 -228.49 -193.24

-228.16 -228.93 -226.15 -223.27 -222.73 -186.60

b

23C22, 24C23, 24C27, 24C29, 25C31 25C30 25C23 33C35, 34C33 35C33, 35C40 1C2

-247.16

-249.20

-238.60

-253.60 -248.32 -254.67 -256.14 -180.02

-250.05 -246.07 -250.54 -253.01 -187.74

-239.71 -235.18 -239.40 -241.78 -178.09

2C8

-216.50

-214.34

-201.93

15S16

-233.10

-231.74

-227.78

16C18

-260.26

-253.23

-241.95

-260.29

-253.29

-241.90

17C21 b

Single point calculations at the B3LYP/6-31G* optimized geometries. Could not get a converged energy value.

rather than those of isolated fragments, are used. In F1-F6 (designated as “A type” in Table 2) F- coordinates to H atom(s) in the upper part of VX (a moiety including atoms labeled 1-15 in Figure 9). In F7-F12 (B type) F- attaches to H atom(s) in the lower part of VX (a moiety including atoms labeled 16-42 in Figure 10), and in F13-F18 (AB type in Figure 11) F- is bound to these two moieties. In F19-F25 the S-P bond is broken and an F-P bond is formed (in Figure 12). The chemical formula for the S-P destruction channel is

Et-O-P(dO)(Me)(F) + [S-(CH2)2-N-(iPr)2](F19-F25) 3.1. Proton Affinity. Out of the 80 paths, 9 converged to the 8O position (P1 and P2 in Figure 2), 16 to 10O position (P3-P8 in Figure 3), 12 to 15S position (P9-P13 in Figure 4), 17 to 22N position (P14-P16 in Figure 5), and the others to dissociated structures (P17-P22 in Figure 6, P23-P28 in Figure 7 and P29-P33 in Figure 8). The detailed calculated proton affinities for all the sites are summarized in Table 1 along with all the unique structures in Figures 2-8. Nine paths converged to two unique 8O-protonated structures P1 and P2 (Figure 2), [Et-O+H-P(dO)(Me)-S(CH2)2-N(iPr)2]; these two structures have different conforma-

tion in the -O-Et group. In these two structures, the 8O-H+ distance is 0.98 Å. Sixteen paths related to proton attachment at 10O position gave six unique structures P3-P8 (Figure 3), [Et-O-P+(OH)(Me)-S-(CH2)2-N(iPr)2], with different conformations. In these six structures, the 10O-H+ distance is 0.97 Å. Five unique structures P9-P13 (Figure 4), [Et-OP(dO)(Me)-S+H-(CH2)2-N(iPr)2], with different conformations were found by the proton attachment at the 15S position. The S-P bond length was elongated by 0.20-0.23 Å compared to the one for isolated VX, and the S-H+ bond distance is 1.35 Å. Seventeen paths out of the 80 gave three unique structures P14-P16 (Figure 5), [Et-O-P(dO)(Me)-S-(CH2)2N+H(iPr)2] with H+ on the 22N position and are stabilized by forming an ammonium-like ion. Out of all proton attachment sites, the 22N position is the most important because the maximum number of paths converged to this site and it gives highest proton affinity value of -∆E ) 250.95 kcal/mol at the RI-MP2 level. The N-H+ bond distance is 1.02 Å. The three conformers P14-P16 arise from rotation of the -N-(iPr) group and the position of H attachment with respect to other atoms in the -N-(iPr) group of the VX molecule. Structure with highest proton affinity (P15) at the

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Bera et al.

TABLE 2: Fluoride Affinity (∆E ) E(product) - E(VX) - E(F-)) for Fluoride Complexes of the VX Molecule (in kcal/mol) site

product structure

A type

F1 F2 F3 F4 F5 F6

B type

F7 F8

F19

1C3 10Os4 8Os1 8Os4, 9Ps4 2C7 1C4, 2C6, 8Os3, 9P10, 11C14, 15S16 33C22 15S9, 15Ss3, 16C19, 22Ns1 17C20 22N17, 23C26, 24C23, 24C27, 25C30, 33C36, 34C33, 34C37, 34C38, 35C40 17C16, 22Ns2, 23C25, 35C33, 35C42 24C28 25C32 10Os2 10O9, 16C17 10Os1, 17C22 8O9, 11C9, 11C12, 11C13, 15Ss1, 16C18, 22N23, 33C25, 33C34, 34C39, 35C41 1C2, 1C5, 2C1, 2C8, 10Os3, 15Ss2, 16C15, 17C21, 22N33, 23C22, 23C24, 24C29, 25C23, 25C31, 8O2

F20 F21 F22 F23 F24 F25

8Os2, 9P11, 15Ss4 9Ps2 9P8, 9Ps1 9Ps5 9Ps6 9Ps3, 9P15

F9 F10

AB type

F11 F12 F13 F14 F15 F16 F17 F18

destruction: Et-O -P(dO)(Me)(F) + [S-(CH2)2-N-(iPr)2]-

a

B3LYP/3-21+G* B3LYP/6-31+G* RI-MP2/aug-cc-pVTZa

path

-18.14 -18.84 -28.24 -26.76 -29.43 -29.40

-16.41 -20.27 -20.47 -25.22 -27.14 -27.37

-16.91 -20.87 -21.71 -27.36 -29.13 -30.55

-16.66 -22.15

-16.33 -20.42

-18.37 -24.39

-22.35 -22.25

-20.69 -21.23

-24.99 -24.44

-24.42 -27.82 -23.10 -28.53 -29.10 -28.86 -30.63

-22.73 -26.03 -21.55 -25.85 -26.66 -28.70 -30.28

-25.95 -29.51 -27.01 -28.32 -28.72 -30.66 -32.86

-33.28

-30.61

-34.60

-22.08

-22.36

-29.01

-24.34 -28.51 -31.41 -20.42 -25.06 -35.92

-24.01 -26.70 -31.50 -37.33 -37.11 -42.17

-29.91 -35.44 -37.32 -37.31 -36.64 -44.24

Single point calculation at the B3LYP/6-31+G* optimized geometries.

Figure 2. Unique optimized structures of protonated product of VX with H+ attached at 8O position.

RI-MP2 level possesses only one path with a very small PA change ∼0.91 kcal/mol with P16 structure having the largest number of paths. Among these simple proton-attached structures, a single structure each for 8O site, 10O site, and 22N site was calculated at the B3LYP/6-31+G* level by Bandyopadhyay et al.21 In their study, proton affinities for these sites were computed to be 197.4, 220.1, and 246.4 kcal/mol, respectively, and these are qualitatively (the order of stability is) consistent with our results in Table 1. They showed that corrections to these proton affinity values due to BSSE as well as differences between MP2 and B3LYP are less than 1.0 kcal/mol. Although, in our results, the largest difference between B3LYP/6-31G* and RI-MP2/ccpVTZ, 3.33 kcal/mol in P1, was slightly larger than theirs and this does not affect the conclusion that the 22N site possesses the highest proton affinity -∆E of about 250 kcal/mol. 3.2. Destruction of VX by Protonation. We found many destructed structures P17-P33 (Figures 6-8) starting from 26 protonation paths. Although a variety of products were found, there is a common theme in the initial stage of those fragmentations: charge transfer from H+ to the [Et-O-P(dO)(Me)-S]

Figure 3. Unique optimized structures of protonated product of VX with H+ attached at 10O position.

part or the [-(CH2)2-N(isopropyl)2] part of VX giving a tetracoordinated P or N, respectively, in the final products. Different subsequent bond reorganization patterns from these protonated adducts generate a variety of destruction products. H2 Dissociation Channels. We obtained six unique structures resulting from H2 dissociation P17-P22 (Figure 6); these are all complexes of H2 with conformational isomers of an N+dC cation, [Et-O-P(dO)(Me)-S-(CH2)2-N+(iPr)dC(Me)2], which is the product of dehydration from the secondary 23C/33C. These structures have relative energies of as low as ∆E ) -229 kcal/mol, about 21 kcal/mol higher than the most stable protonation product P15, and may be accessible as a minor channel depending on experimental conditions. In all these H2 dissociation channels except for the one to P19, the other H

Proton and Fluoride Affinity of Nerve Agent VX

Figure 4. Unique optimized structures of protonated product of VX with H+ attached at 15S position.

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Figure 7. Unique optimized structures of protonated product of VX with CH4 dissociated.

Figure 5. Unique optimized structures of protonated product of VX with H+ attached at 22N position.

Figure 8. Unique optimized structures of destructed protonated product of VX.

Figure 6. Unique optimized structures of protonated product of VX with H2 dissociated.

atom in the dissociating H2 comes from an isopropyl group connected to 22N, i.e., secondary 26H or 36H. Optimization paths indicate that a charge transfer from H+ to the [-(CH2)2-N(iPr)2] moiety takes place before an abstraction of 26H/36H atom by the coming H atom. In the product, the bond between 22N and 23C/33C becomes a double bond, where the 22N-23C/33C bond distance changed from 1.49 to 1.30 Å during the optimization process. The dissociation process leading to P19 is little different; initially the proton was targeted to 1C along the 1C-5H bond (H+ f 1C-5H), 5H was replaced by H+ in the initial stage of optimization, and after a long distance

migration of 5H, 36H was abstracted by 5H to generate H2 (5H-36H) and the same product of the other H2 dissociation channels. This is considered to be a very minor channel and happened by an accident due to the initial structure; a small change in the initial position of H+ gave the same mechanism as the other H2 dissociation channels. CH4 Dissociation Channels. CH4 dissociation is another important event in the protonation of VX. Thirteen different paths led to CH4 dissociation and finally six unique structures P23, P24, P25, P26, P27, and P28 (Figure 7) were reached. Excluding P23, other five structures are complexes of CH4 with conformational isomers of an N+dC cation, [Et-O-P(dO)(Me)-S-(CH2)2-N+(iPr)dCHMe]; the methyl group in CH4 comes from an isopropyl group connected to 22N. In these reactions, a charge transfer from H+ to [-(CH2)2-N(iPr)2] and a new C-H bond generation in CH4 happened, and then a C-C bond dissociation takes place automatically due to a bond reorganization including NdC double bond generation, similarly to the above H2 dissociation reactions where the bond distance between N and C decreased from 1.49 to 1.30 Å during the optimization. These structures have relative energies of as low as ∆E ) -242 kcal/mol, only

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9 kcal/mol higher than the most stable protonation product P15, and may be accessible depending on experimental conditions. It should be noted that the generation of a very stable N+)C cationic species is the driving force for all the favorable dissociation channels of VX, as will be seen below. P23 is a complex of CH4 with [Et-O-P(dO)-S(CH2)2-N(iPr)2]+, the product of demethylation from 9P. The positive charge is delocalized in the [Et-O-P(dO)(CH3)-S] region, and bond distances between 9P and three connected atoms (8O, 10O, 15S) are shorter than those in VX; the 9P-8O distance changed from 1.63 to 1.55 Å, the 9P-10O distance changed from 1.50 to 1.47 Å, the 9P-15S distance changed from 2.11 to 2.00 Å. This structure is very high in energy and is not likely to be important. Fragmentation Channels. Protonation of the VX molecule can cause extensive fragmentations of VX. Five optimized structures of complexes of fragmentation products, P29-P33 (Figure 8), have been found. Excluding P29, all the channels involve formation of stable CdN+(iPr)2 (P30, P32, and P33) or tetracoordinated N+ P31 containing species. The reaction to P30 is a chain reaction including (1) an attachment of H+ atom to 2C in ethyl group and the charge transfer, (2) 17Cd22N double bond generation, (3) a 2C-8O bond dissociation producing ethane, and (4) two bond (9P-15S and 16C-17C) breakings, generating three neutral closed-shell species, i.e., CH3CH3, MeP(dO)2, and CH2S, as well as H2CdN+(iPr)2, another version of stable N+dC species. The reaction to P31 is a sequence of reactions involving (1) an attachment of H+ atom to 15S and the charge transfer, (2) a 16C-22N bond generation producing a three-membered NCC ring, and (3) a 15S-16C bond dissociation, producing Et-O-P(dO)(Me)-SH and c-(CH2)2N+(iPr)2. The reactions to P32 and P33, conformational isomers, are also chain reactions composed of (1) an attachment of H+ atom to 16C and the charge transfer, (2) 17Cd22N double bonds generation, and (3) a 16C-17C bond dissociation, producing Et-O-P()O)(Me)-SMe and CH2dN+(iPr)2. Among P30 to P32, the structures P32 and P33 have relative energies as low as ∆E ) -242 kcal/mol, comparable to the lowest CH4 dissociation channel and only 9 kcal/mol higher than the most stable protonation product P15, and may be accessible energetically. A justification of an unanticipated low energy of the destruction channel of VX leading to P32 (and P33), Et-OP(dO)(Me)-SMe + CH2dN+(iPr)2, can be given as follows. The relative energy of the most stable VX protonation product P15 at the RI-MP2/cc-pVTZ//B3LYP/6-31G* level is ∆E ) -250.95 kcal/mol (Table 1). To reach P32 from VX, on the other hand, the C-C bond dissociation energy for VX of BE(C-C) ) +72.49 kcal/mol is required which is compensated by a proton affinity of Et-O-P(dO)(Me)-S(CH2) of ∆E ) -219.03 kcal/mol and the difference of ionization potential between CH2dN(iPr)2 and Et-O-P(dO)(Me)-SMe, ∆IP ) IP[CH2dN(iPr)2](+111.84kcal/mol)-IP[Et-O-P(dO)(Me)-SMe] (+198.91 kcal/mol) ) -87.07 kcal/mol, and the interaction energy between the two fragments of -8.34 kcal/mol, to obtain the relative energy of P32 to be ∆E ) -241.95 kcal/mol. One can clearly see that the energy rise by C-C bond dissociation is nearly fully compensated by ∆IP, i.e., the IP of CH2dN(iPr)2 is much smaller than that of Et-O-P(dO)(Me)-SMe, namely, after protonation of Et-O-P(dO)(Me)-S(CH2) it is advantageous to move an electron from CH2dN(iPr)2 to [EtO-P(dO)(Me)-SMe]+. The reaction to P29 is also a sequence of reactions composed of (1) an attachment of H+ to 1C and the charge transfer, (2) a

Bera et al. 1C-2C bond dissociation to produce CH4, (3) a 8O-9P dissociation generating CH4, CH2O, and [Me-P(dO)S-(CH2)2-N(iPr)2]+ including a tetracoordinated P. Similarly to P23, bond distances between 9P and three connected atoms (10O, 11C, 15S) are shorter than those in VX; the 9P-10O distance changed from 1.50 to 1.48 Å, the 9P-11C distance changed from 1.82 to 1.81 Å, the 9P-15S distance changed from 2.11 to 2.04 Å. This is a very high energy channel and is not likely to take place. Implications for CIMS Detection of VX Using Protonation Reactions. Among these dissociation reactions, the H2 and CH4 dissociations do not have a barrier, which were confirmed by optimizations starting from initial geometries in which H+ is located at longer distances (4.0 Å) away from the target atoms. Recently protonation reactions of VX surrogates, i.e., DEMTMP and triethylamine, were studied experimentally,20 where these two molecules mimic an upper part of VX (above the S atom in Figure 1) and the lower part, respectively. In the experimental study, branching ratios of protonation products in reactions with various proton donors, H3O+, (HCOOH)H+, (HCOOH)2H+, (HCOOH)3H+, (H3C(O)OCH3)H3CCNH+, (CH3OH)3H+, (C2H5OH)H+, (C2H5OH)2H+, (C2H5OH)3H+, (C2H5OH)(H3CCN)2H+, (H3CCN)2H+, (H3COCH3)2H+, and (H3CC(O)CH3)2H+, were measured. The major products were protonated species (proton transfer products from the donors to VX surrogates) and associated complexes such as a cluster between protonated DEMTMP and CH3NH2. Dissociation of H2 was observed only in a reaction of triethylamine with H3O+ as a minor channel. This is because there is a barrier for a proton jump from these donor molecules to VX, and the rates of proton jumps are governed by proton affinities of donor molecules. Since we treated only bare H+ in this study, the H2 and CH4 dissociations were computed to be barrierless. The existences of these pathways may be suggesting possibility of H2 and CH4 dissociations in reactions between those proton donors and VX at higher temperature, in particular the CH4 producing channels, P24 to P28. On the other hand, we found some destruction pathways (P32-P33) in which the upper and lower parts of VX are separated into fragments, within 9 kcal/mol from the most stable P15. Although these pathways cannot be compared with the experiment using surrogate molecules mimicking the upper and lower parts of VX separately, we propose them as possible fragmentation pathways of real VX. 3.3. Fluoride Affinity. The results of calculated fluoride affinity of VX molecule are summarized in Table 2 and the corresponding optimized structures (F1-F25) are shown in Figure 9-11. The electron affinity of VX molecule is less than that of F, and hence, F1-F18 are simple ion-molecule complexes. These structures can be classified into three types (A type, B type, and AB type). In the ion molecule complexes the F- is attracted by the different H atoms of VX, the structures in which F- is attracted by H atom(s) in the upper part of VX (i.e., 3H-7H and 12H-14H) is referred as A type and same by the lower part of VX (i.e., 18-21H, 26-32H, and 36-42H) is B type and for AB type structures the attraction to F- ion is shared by the H atoms of both upper and lower part of VX molecule. There are six unique A-type structures (F1-F6, Figure 9), six B-type structures (F7-F12, Figure 10), and six AB-type structures (F13-F18, Figure 11). A-Type Structures. Twelve fluorination paths converged to six A-type structures (F1-F6). Among them, the largest fluoride affinity, -∆E ) 31 kcal/mol, was found at F6 in which F- is

Proton and Fluoride Affinity of Nerve Agent VX

Figure 9. Fluorinated A-type structures.

Figure 10. Fluorinated B-type structures.

Figure 11. Fluorinated AB-type structures.

bound by 7H and 13H. This is only about 4 kcal/mol higher than the most stable fluoridation product to be discussed below. Structures with coordination to two H atoms (F4-F6) tend to have larger fluoride affinity compared to singly coordinated species (F1-F3). Attraction from the terminal CH3 group (3H, 4H, and 5H) is weak, and all optimizations starting from around them converged to other attraction sites. In singly coordinated species (F1-F3), H-F- distances vary depending on attachment

J. Phys. Chem. A, Vol. 114, No. 50, 2010 13195 sites. For F1 structure, F- is bound to H in O-CH2- and the H-F- distance 1.70 Å is relatively long. Correspondingly, the fluoride affinity of the F1 structure is the lowest. For F2 and F3 the F- is bound to H in P-CH3 from different directions and these have similar fluoride affinity values and similar H-Fdistances of 1.48 and 1.52 Å, respectively. In all the doubly coordinated species (F4-F6), F- is bound to H atoms in O-CH2- and P-CH3. The H-F- distances between F- and H in O-CH2-/P-CH3 are 1.97/1.61 Å, 1.87/1.61 Å, and 1.82/ 1.75 Å, respectively for F4, F5, and F6 structure. The two H-Fdistances are the closest in the most stable species F6 and the farthest in the least stable species F4. B-Type Structures. Twenty-two fluorination paths converged to the B-type structures (F7-F12, Figure 10). In F7, F- is attracted by 38H and 42H with H-F- distances 2.01 and 2.00 Å, respectively. Similarly for F8, F- is attracted by 18H, 30H, and 37H with H-F- distances 2.05, 2.00, and 2.10 Å, respectively. In F9, F- is attracted by 21H and 36H with H-Fdistances 1.87 and 2.18 Å, respectively. In F10 F- is attracted by 29H, 31H, 39H, and 41H with H-F- distances 2.01, 2.28, 2.07, and 2.23 Å, respectively. For nearly the same structure F11 and F12, F- is attracted by 20H, 27H, and 40H with H-Fdistances 1.82, 2.04, and 2.22 Å and 20H, 27H, and 39H with H-F- distances 1.84, 1.95, and 2.34 Å, respectively. Due to the presence of a large number of H atoms in amine moiety at the lower part of VX, the number of paths that converge to B-type structures is about double that of the A type. The largest fluoride affinity in the B type, -∆E ) 30 kcal/mol for F12, is higher by 1 kcal/mol for the most stable A type F6 and about 5 kcal/mol higher than the most stable fluoridation product to be discussed below. The smaller fluoride affinity in the B type is due to the electronegativity of the amine group in VX. AB-Type Structures. Thirty-one fluorination paths converged to the AB-type structures (F13-F18, Figure 11). In F13, F- is shared by 4H and 37H with H-F- distances 2.04 and 1.94 Å, respectively. F- is shared by 6H and 19H with H-F- distances 1.82 and 1.74 Å, respectively, for F14, by 7H and 19H with H-F- distances 1.82 and 1.75 Å, respectively, for F15, by 12H and 19H with H-F- distances 1.75 and 1.78 Å, respectively, for F16, by 12H, 21H, and 36H with H-F- distances 1.70, 1.93, and 2.23 Å, respectively, for F17, and by 7H, 18H, and 26H with H-F- distances 1.91, 1.82, and 2.00 Å, respectively, for F18 structure. The three coordinated species F17 and F18 caught as many as 11 and 14 paths, which implies that these have a wide potential well. Furthermore, the fluoride affinity is largest in these two structures: -∆E ) 35 kcal/mol for F18 and -∆E ) 33 kcal/mol for F19. Hence, we conclude that the ion-molecule VX · F- is most likely to be bound simultaneously to two parts of VX (as F16, F17, and F18). However the ion-molecule complex is not the most stable product of the reaction of F- with VX, as shown in the next section. 3.4. Destruction of VX by Fluorination. The S-P bond cleavagebythefluorinationwasfoundtogiveEt-O-P(dO)(Me)(F) and [S-(CH2)2-N-(iPr)2]-. Seven structures of complexes between the dissociation fragments, F19-F25 (Figure 12), were obtained with different conformations. The initial step is a nucleophilic attack of F- toward 9P in VX. A subsequent charge transfer from F- to 15S induces the P-S bond cleavage. Similar reactions of VX with hydroxide, hydroperoxide, and alkoxide anions have been investigated.1–8 Similarly to the present Fcase, the initial step was a nucleophilic attack of those ions to P in VX, although, in contrast to the present F- case, a hydrogen atom transfer from those ions to S takes place before the P-S bond cleavage.5–8 It turned out that the dissociation channels,

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Bera et al. probably suggesting that such H atom abstraction reactions have certain barrier. The observation of HF in the experiment is demonstrating that such barriers are not very high. Instead of the H atom abstractions, we found S-P bond cleavage pathways to be the most favorable energetically as P19-P25 for the VX molecule. This channel cannot take place in the experiment using the VX surrogates without the S-P bond. Similar reactions of VX with hydroxide, hydroperoxide, and alkoxide anions in basic solutions are known and have been utilized in the detoxification of VX.1–8 Hence, the S-P bond cleavage by F- is consistent with these reactions in real VX. Therefore, we suggest that a signature corresponding to the products of S-P bond cleavage will be found in a CIMS measurement of real VX. 4. Conclusions

Figure 12. Destructed fluorinated VX structures.

in particular F25 among some others, have higher fluoride affinities than the channels leading to ion-molecule complexes without reaction. A justification of an unanticipated low energy of the destruction channel of VX leading to F25, Et-O-P(dO)(Me)(F) + [S-(CH2)2-N-(iPr)2]-, can be given as follows. The relative energy of the most stable VX fluoride product F18 at the RIMP2/cc-pVTZ//B3LYP/6-31G* level is ∆E ) -34.60 kcal/mol (Table 2). To reach F25 from VX, on the other hand, the P-S bond dissociation energy for VX of BE(P-S) ) +63.24 kcal/ mol is required which is compensated by a fluoride affinity of Et-O-P(dO)(Me) of ∆E ) -29.34 kcal/mol and the difference of electron affinity between [S-(CH2)2-N-(iPr)2] and Et-O-P(dO)(Me)(F), ∆EA ) EA[Et-O-P(dO)(Me)(F)] (-18.23 kcal/mol) - EA[S-(CH2)2-N-(iPr)2] (46.01 kcal/mol) ) -64.33 kcal/mol, and the interaction energy between the two fragments of -13.90 kcal/mol, to obtain the relative energy of F25 to be ∆E ) -44.24 kcal/mol. One can clearly see that the energy rise by P-S bond dissociation is more than fully compensated by ∆EA, i.e., EA[Et-O-P(dO)(Me)(F)] is much smaller (even negative, i.e., the anion is less stable than the neutral) than that of [S-(CH2)2-N-(iPr)2], namely, after fluoridization of Et-O-P(dO)(Me) it is advantageous to move an electron from [Et-O-P(dO)(Me)(F)]- to [S-(CH2)2-N-(iPr)2]. Implications for CIMS Detection of VX Using Fluorination Reactions. In the recent experiment for triethylamine,20 an ion-molecule complex [F · (C2H5)3N]- was found to be the major product; the complex should be similar to the B-type structures in Figure 3. While in the experiment for DEMTMP,20 a molecular HF dissociation was observed as the major channel. In this study, F- just coordinated to H atoms forming ion-molecule complexes also in the A-type structures; this is

In this paper, we presented the proton affinity and the fluoride affinity of VX at all possible sites. The B3LYP and RI-MP2 methods were used in geometry optimizations and single point energy calculations, respectively. Eighty protonation paths and 76 fluorination paths were considered and 33 and 25 unique protonated and fluorinated structures were obtained, respectively. Out of all protonation sites considered in this study, the nitrogen site possesses the highest proton affinity of -∆E ) 250.95 kcal/mol (P15). Moreover, the maximum number of paths converged to the nitrogen site, which suggests that its potential well is rather wide and deep. It follows that a protonation of VX most likely gives a protonated structure on the nitrogen site. Some H2 dissociation pathways were also identified at higher energy in protonation reactions around nitrogen of amine moiety, which may be related to an observed H2 generation in a reaction of H3O+ with a VX surrogate molecule where CH4 dissociation or destruction channels are unfavorable or impossible. In addition, CH4 dissociation channels providing [Et-O-P(dO)(Me)-S-(CH2)2N+(iPr))CHMe] (P25-P28) and destruction channels breaking the a C-C bond and forming Et-O-P(dO)(Me)-SMe + CH2dN+(iPr)2 (P32 and P33) were found to be only 9 kcal/ mol above the most stable N-site protonation product and would be possible products of the protonation reaction. Thus, we predict new dissociation pathways involving a C-C bond cleavage for electrophilic attack, which are characteristic to VX, not to its surrogate. A majority of the fluorination paths converged to ion-molecule complexes in which F- coordinates to H atom(s) of alkyl groups via charge-dipole interactions. The fluoride affinity becomes highest (-∆E ) 34.60 kcal/mol) when F- is bound to three H atoms in two different parts of VX (F18). However, the destruction channel (F25) breaking the S-P bond to give Et-O-P(dO)(Me)(F) + [S-(CH2)2-N-(iPr)2]- was found to be energetically most favorable (-∆E ) 44.24 kcal/mol). This is also a characteristic channel to VX, but to a surrogate. Products of these fragmentation reactions for nucleophilic attack are proposed to be important in CIMS detections of VX. Acknowledgment. The present research is in part supported by grants from AFOSR (FA9550-07-1-0395 and FA9550-101-0304). Computer time was provided by a grant under the DoDHigh Performance Computing Program as well as by the Cherry Emerson Center for Scientific Computation. Supporting Information Available: All the stable geometries of protonated and fluorinated structures along with their energies computed at various levels reported in a tabular form. This material is available free of charge via the Internet at http:// pubs.acs.org.

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