Aminolysis of a Model Nerve Agent: A Computational Reaction

Article pubs.acs.org/JPCA

Aminolysis of a Model Nerve Agent: A Computational Reaction Mechanism Study of O,S‑Dimethyl Methylphosphonothiolate Debasish Mandal, Kaushik Sen, and Abhijit K. Das* Department of Spectroscopy, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India S Supporting Information *

ABSTRACT: The mechanism for the aminolysis of a model nerve agent, O,S-dimethyl methylphosphonothiolate, is investigated both at density functional level using M062X method with 6-311++G(d,p) basis set and at ab initio level using the second-order Møller−Plesset perturbation theory (MP2) with the 6-311+G(d,p) basis set. The catalytic role of an additional NH3 and H2O molecule is also examined. The solvent effects of acetonitrile, ethanol, and water are taken into account employing the conductor-like screening model (COSMO) at the single-point M062X/6-311++G(d,p) level of theory. Two possible dissociation pathways, methanethiol and methyl alcohol dissociations, along with two different neutral mechanisms, a concerted one and a stepwise route through two neutral intermediates, for each pathway are investigated. Hyperconjugation stabilization that has an effect on the stability of generated transition states are investigated by natural bond order (NBO) approach. Additionally, quantum theory of atoms in molecules analysis is performed to evaluate the bond critical (BCP) properties and to quantify strength of different types of interactions. The calculated results predict that the reaction of O,S-dimethyl methylphosphonothiolate with NH3 gives rise to parallel P−S and P−O bond cleavages, and in each cleavage the neutral stepwise route is always favorable than the concerted one. The mechanism of NH3 and H2O as catalyst is nearly similar, and they facilitate the shuttle of proton to accelerate the reaction. The steps involving the H2O-mediated proton transfer are the most suitable ones. The first steps for the stepwise process, the formation of neutral intermediate, are the rate-determining step. It is observed that in the presence of catalyst the reaction in the stepwise path possesses almost half the activation energy of the uncatalyzed one. A bond-order analysis using Wiberg bond indexes obtained by NBO calculation predicts that usually all individual steps of the reactions occur in a concerted fashion showing equal progress along different reaction coordinates.

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INTRODUCTION Organophosphorus compounds (OPCs) are considered as the most nefarious synthetic chemical derivatives. They are used as agricultural chemicals such as insecticides, herbicides, etc., and also as chemical warfare agents (CWAs), commonly known as “nerve agents”. The nerve agents exhibit high neurotoxicity as they typically act as potent acetyl cholinesterase (AChE) inhibitors.1−15 Due to the high lethality and danger of CWAs when used either as weapons or stockpiled, sufficient destruction capabilities are required. The nerve agents and pesticides comprise phosphorus(V) compounds with a terminal oxide and three singly bonded substituents, two alkoxyl and one alkyl group, and the derivatives that have inspired a wide variety of studies for their detection and detoxification.16−25 Numerous studies have been performed for the analysis of the natural degradation of OPCs through different processes, e.g., hydrolysis,26−28 oxidation,29 photolysis,30 and biodegradation31 as well as treatments with α-nucleophiles.32,33 A number of theoretical investigations were performed for the thermal unimolecular decomposition,34 hydrolysis,35 and α-nucleophilic destruction36 of such deadly agents. A related organo© 2012 American Chemical Society

thiophosphate compound, VX (S-2-(diisopropylamino)ethyl O-ethyl methylphosphonothiolate) nerve gas, has also shown specific neurotoxicity.37 In some cases, mere destruction of a chemical agent is not adequate because the resulting products can also be highly toxic. Therefore, special attention must be paid to the product distribution to ensure that the agent has been effectively detoxified. In case of VX, alkaline hydrolysis produces two products, a relatively nontoxic ethylmethylphosphonic acid (EMPA) formed via thiolate elimination and a highly toxic and persistent S-[2-(diisopropylamino)ethyl]methylphosphonthioic acid (EA2192) (Scheme 1) formed via ethoxide elimination in a ratio of approximately 7:1, thus favoring the EMPA formation.38 The EA2192 is also a potent neurotoxin and must be further hydrolyzed for complete detoxification. In this report, we have investigated the detoxifying reactions of O,S-dimethyl methylphosphonothiolate (DMPT), a VX as well as EA2192 model compound, with ammonia to provide mechanistic insight into Received: June 18, 2012 Published: July 25, 2012 8382

dx.doi.org/10.1021/jp305994g | J. Phys. Chem. A 2012, 116, 8382−8396

The Journal of Physical Chemistry A

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reactions are also investigated in the presence of NH3 or H2O molecule which gives an opportunity to illustrate the effect of aminolysis in presence of an additional NH3 and in the presence of a specific solvent, H2O. Second, we observe the comparisons and nature of two competitive pathways, P−O and P−S bond cleavages. The biological activity of molecules is known to be crucially dependent on the electronic structure of the active part of the given compound and its conformation. Thus, we initially performed a conformational analysis of DMPT using molecular dynamics (MD) and molecular mechanics (MM) approaches. We then proceeded further and calculated the electronic structure and reaction mechanism using the minimum-energy conformer. The mechanistic details are investigated using a high-level advanced density functional theory (DFT) and the ab initio MP2 method. The potential energy surfaces for all routes have been constructed. An extensive investigation is performed to detect the most favorable pathways for the P−O or P−S fissions as well as to quantify the reaction progress using the most common modern strategies, e.g., activation energy, natural bond orbital (NBO) analysis, Wiberg bond order calculation, and Bader’s atoms in molecules (AIM) approach.

Scheme 1. Possible Competitive Pathways for the Nucleophilic Degradation of VX

the aminolysis reaction of an organothiophosphonate compound. Frequent computational investigations have been conducted to study the aminolysis of ester and ester anhydride.39−41 Theoretical studies have also been reported to compare the reactivity patterns between oxoester and thioester.42 A number of experimental investigations of the aminolysis of different diphosphinates were performed.43−45 Various detoxification procedures for DMPT type of compounds were carefully investigated by experimentally as well as theoretically, e.g., perhydrolysis, solvolysis, and reaction with sodium ethoxide.46−51 But as far as our knowledge goes, no such theoretical study is devoted to establish the decomposition of the aminolysis of organophosphorus compounds with the exception of a theoretical reaction mechanism study of the aminolysis of dimethyl phenylphosphinate.52 However, there is no instance of theoretical investigation for the aminolysis of organothiophosphorus compound. Our computations first provide the mechanistic details of the aminolysis of organothiophosphorus compound. The nucleophilic reaction of DMPT may proceed via two different routes (Scheme 2): (1) elimination of methyl alcohol and (2) elimination of methanethiol.

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COMPUTATIONAL DETAILS For computational investigation of the conformational minima of DMPT, it is subjected to a molecular dynamics (MD) conformational search with an unconstrained MD trajectory via the Verlet velocity algorithm and NVE thermostat using other default parameters in Gabedit V.2.3.8.55 The minimum conformational geometries are obtained using the PM6 semiempirical method as implemented in MOPAC 2009.56 Additional molecular mechanics conformational studies are conducted using the MMFF94 force field and a systematic rotor search using Avogadro V.1.0.3.57 For final validation of the conformational analysis, 25 representative minimum structures are selected from the rigorous conformational search and are treated with density functional theory. The geometries of all the molecular species involved in this study are fully optimized by employing density functional theory (DFT) using M06-2X58 with Pople’s spilt-valence triple-ζ quality 6-311+ +G(d,p) basis set59 and MP260−63 method in conjunction with the 6-311+G(d,p) basis set for all the elements. All calculations have been performed on the low-lying singlet species with restricted wave function. Zhao and Truhlar58 have recently developed the M06 family of local (M06-L) and hybrid (M06, M06-2X) meta-GGA functional that show promising performance for the calculation of barrier height for neutral and radical reactions. The M06-2X is a hybrid meta-DFT method with a high percentage of HF exchange and it is reported that the M06-2X functional gives excellent results for calculating the barrier of a reaction. The MP2 is the second-order Møller− Plesset perturbation theory which includes double excitations. The 6-311++G(d,p) is a valence triple-ζ quality basis set with single polarization and double diffuse functions on all atoms, and the 6-311+G(d,p) basis set includes single polarization and single diffuse function on all atoms. Harmonic vibrational frequencies are determined at the same level of theories to confirm whether the optimized structures are local minima (no imaginary frequency) or transition states (one imaginary frequency) on the potential energy surfaces (PESs) and to evaluate the zero-point vibrational energy (ZPVE) and thermal corrections to the Gibbs free energy at T = 298 K. The connecting first-order saddle points, the transition states

Scheme 2. Possible Competitive Pathways for the Nucleophilic Degradation of DMPT

Addition−elimination processes at phosphorus proceed via a pentavalent intermediate, and elimination preferentially takes place from the apical position. In addition, the more electronegative group prefers to occupy the apical position and as a result in the absence of competing rearrangement processes, the P−O cleavage may be expected to be favored over the P−S cleavage.53,54 On the other hand, the thiolate group is a more potent leaving group compared to the alkoxide group and should favor the P−S over the P−O cleavage. Therefore, determination of the preferred route (sketched in Scheme 2) is quite challenging. The goal of the present work is 2-fold. We first examine the complete reaction mechanism of DMPT with NH3. The 8383



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Figure 1. M062X/6-311++G(d,p) gas-phase-optimized geometries of all the most stable conformer of DMPT with important geometrical parameters.

reveals that the kinetic energy contribution is greater than the potential energy and shows reduction of electronic charge along the bond path which implies a closed-shell electrostatic interaction.73 Additional information on the chemical bond can be obtained through energetic considerations related to the interplay of changes in the potential and kinetic energy. The Laplacian of ρ appears in the local expression of the virial theorem76 as

between the equilibrium geometries, are obtained using synchronous transit-guided quasi-Newton (STQN) method. Parallel intrinsic reaction coordinate (IRC) calculations are performed with all transition states to confirm whether these transition states connect the right minima or not.64,65 The selfconsistent reaction field (SCRF) procedure, the conductor-like screening solvation model (COSMO),66 has been employed to take into account the influence of solvent. The COSMO model is used for single-point (without optimization) calculations at M062X/6-311++G(d,p) level of theory. An NBO analysis is carried out for the evaluation of the bond order and also to check the stability of the transition state. The stabilizing effect, which arises from an overlap of an occupied orbital with another properly oriented neighboring electron-deficient orbital, is carefully analyzed. The significant donor−acceptor interaction, which is measured by the second-order perturbation energy, E (2) , can be obtained by the following expression67−70 E(2) = ΔEij = qi

⎡ ℏ2 ⎤ 2 ⎢ ⎥∇ ρ(r ) = 2G(r ) + v(r ) ⎣ 4m ⎦

The quantity G(r) appearing in this expression is a form of the kinetic energy density of the electrons which is positive everywhere, and v(r) is the potential energy density which is negative everywhere. The electronic energy density H(r), defined as H(r) = G(r) + v(r), is an index of the amount of covalency in the chemical interactions. The sign of H(r) determines whether the accumulation of charge at a given point of r is stabilizing (H(r) < 0) or destabilizing (H(r) > 0). The bond energies, E(x), are calculated by using the following equations:

F[i , j]2 [εi − εj]

where qi is the donor orbital occupancy, εi and εj are diagonal elements (orbital energies), and F(i,j) is the off-diagonal NBO Fock matrix elements. All NBO calculations are performed using the NBO 3.171 program as implemented in Gaussian 09.72 Furthermore, the bonding patterns and stabilization due to intermolecular H-bonding are characterized using Bader’s theory of atoms in molecules (AIM).73−75 The AIM theory is based on the topological analysis of the electron density, ρ(r). Bonds are defined by the presence of bond critical points (BCP), which is necessary for chemical bonding regardless of its nature. The electron density ρ(r) and Laplacian ∇2ρ(r) at the BCP are calculated using the wave function obtained by the M062X/6-31+G(d,p) level of theory. A negative ∇2ρ(r) shows the excess potential energy at the bond critical point. This implies that electronic charge is concentrated in the internuclear region shared by two nuclei and therefore shows covalent interactions. On the other hand, a positive ∇2ρ(r)

E(x) =

1 v (r ) 2

v(r) =

1 2 ∇ ρ(r ) − 2G(r ) 4

Finally, the criterion used here to determine nature of bonds is the ratio −G(r)/V(r). When −G(r)/V(r) > 1, the interaction is noncovalent, while when 0.5 < −G(r)/V(r) < 1, it is partly covalent.77,78 The weak interactions possess positive values for both ∇2ρ(r) and H(r); for medium interactions, ∇2ρ(r) is positive, but H(r) is negative, and for strong interactions, both ∇2ρ(r) and H(r) are negative.79 Here, we use interaction energy to get a clear idea about the bond formation and bond breaking along the progress of reaction. All the topological properties are calculated using AIM 2000 program,80 and electronic structure calculations are performed using the Gaussian 09 suite of quantum chemistry programs.72 8384



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RESULTS AND DISCUSSION The minima for 25 selected conformers of DMPT are finally optimized at B3LYP/6-31+G(d,p) as well as M062X/631+G(d,p) levels of theory. After DFT optimization we get five lower energy structures having large dissimilar spatial arrangement. The optimized geometries are presented in Figure 1, and the energies are collected in Table 1.

zwitterionic pathway is not feasible. So, we now explore the neutral concerted and stepwise pathways in the following discussion. For the concerted pathway, the reaction consists of one step in which all bond-forming and bond-breaking processes occur in (reactant (R) → transition state (TS) → product (P)) concert (first line of Scheme 3). In the case of the concerted mechanism, a proton from the NH3 is shifted to the methoxy oxygen atom simultaneously with a nucleophilic attack of NH3 on the electrophilic phosphorus center, and the breaking of the P−O bond occurs. The optimized geometries of the related species for both pathways are presented in Figures 2, and Figure 3 provides the gas-phase potential energy surface (PES). In this report, all analyses are carried out with respect to the M062X/6-311++G(d,p) energy, unless otherwise mentioned. The necessary energetic parameters, e.g., ΔH and ΔG, are presented in Table 2. We have used the M062X values as well as geometric parameters in successive discussions, unless otherwise mentioned. The separated reactant initially forms a prereactive complex, CRC-O. The CRC-O is situated 2.92 kcal mol−1 below the reactant in the PES. The prereactive complex is mainly stabilized by the H-bond formation through PO--HNH2 with a distance of 2.31 Å. For the production of CRC-O, the NH3 approaches anti to the −SCH3 group and is 3.23 Å (P−N distance) away from the phosphorus of DMPT. The CRC-O then transforms to the concerted transition state, CTSO, containing 50.52 kcal mol−1 activation energy with respect to the separated reactants, which is consistent with the barrier 53.14 kcal mol−1 calculated by the MP2 method. The CTS-O has a four-member ring structure in which the bond-forming P−N distance is 1.90 Å, and bond-breaking P−O distance is 1.97 Å with the transferable H-atom situated 1.39 Å from N atom and 1.10 Å from the O atom. In the case of CTS-O, the P−N and P−O distances are 1.33 Å lower and 0.36 Å higher than those in CRC-O, respectively. The TS, CTS-O, contains an imaginary frequency 696.7 cm−1 and the transition vector for this mode corresponds mainly to the shuttle of proton from the nucleophilic NH3 to the oxygen atom of the methoxy group. The CTS-O finally yields the product complex, CPC-O, which is located 1.31 kcal mol−1 below the reactants in the PES. The product complex is also stabilized by the forming of H-bond through the N---HOCH3 with the interaction distance, 2.04 Å. We now concentrate on the neutral stepwise pathway, the second possibility for the reaction mechanism. This pathway is essentially an addition/elimination mechanism, where the addition and elimination steps are coupled with the proton transfer in order to preserve the neutrality in all of the intermediates depicted in Scheme 3. Between the two addition/ elimination steps, there are three transition states; one of them is related to the rotation of the bonds. In stepwise mechanism, there are two possibilities for the formation of first step prereactive complexes: ammonia can attack on the front side as well as on the backside of the leaving group. Here we observe that the front side attack possesses higher barrier and consequently this mechanism is excluded from the study. In this case, the reaction also starts with the formation of a prereactive complex in which the nucleophile NH3 comes close to the phosphorus through the direction anti to the leaving group (−OCH3) and produces SRC-O which contains 2.65 kcal mol−1 lower energy than the reactant due to the stabilization with formation of the H-bond, PO···H2N. In the case of SRC-O, the P−N distance is 3.38 Å and the H-bond

Table 1. Relative Energies (in kcal mol−1) for All the Conformers at B3LYP/6-31+G(d,p) as Well as M062X/6311++G(d,p) Levels of Theory conformer

B3LYP/6-31G(d,p)

M062X/6-311++G(d,p)

C1 C2 C3 C4 C5

0 1.59 2.53 3.90 8.97

0 1.13 2.407 3.56 8.09

The conformer of lowest energy found here is also identical with that reported by McAnoy et el.46 In the case of the aminolysis of DMPT, there are two possibilities: cleavage of P− OCH3 and P−SCH3 bonds. In an effort to understand the patterns of bond cleavage and to make comparisons between the two pathways, it is first necessary to understand the mechanism and the transition-state structures of the ratedetermining steps of entire reaction channels. The aminolysis reaction has been suggested to proceed through two neutral mechanisms, concerted and stepwise. To determine the favorable one, both routes are also investigated here in detail. Moreover, the aminolysis reactions have been studied in the presence of one additional H2O as well as NH3 molecule as a catalyst. We first analyzed the P−O decomposition pathways. P−O Decomposition Pathways. Uncatalyzed Aminolysis. From the reaction scheme shown in Scheme 3, it is observed that three different pathways may be possible for the uncatalyzed (in the absence of additional NH3 or H2O as a catalyst) aminolysis reaction of DMPT. Scheme 3 shows that a stepwise mechanism through zwitterionic intermediate may be possible. Several attempts have been made to identify the stepwise zwitterionic mechanism, but all are unsuccessful, which reveals that the Scheme 3. Possible Mechanisms for the Methyl Alcohol Leaving Pathways for Uncatalyzed Aminolysis of DMPT

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Figure 2. Optimized geometries with geometrical parameters calculated at the M062X/6-311++G(d,p) and the MP2/6-311+G(d,p) levels in black bold and pink normal faces, respectively, for all the species involved in the P−O decomposition pathway for the aminolysis of DMPT.

STSR-O then transforms to a new intermediate, INT2-O, which is 2.35 kcal mol−1 more stable than the previous intermediate. The forming and breaking of bond also remain same in the second intermediate like the previous one. The last step of the pathway is an elimination reaction which occurs through the transition state, STS2-O, containing the energy barrier, 28.74 kcal mol−1. In this step, the P-OCH3 single bond is broken, and the proton is transferred from the P−O−H moiety to the O atom of the leaving group at the same time the PO bond is restored. The transition state, STS2-O, has a four-member ring structure through O−P−O−H. In STS2-O, the breaking P−OCH3 bond length is 2.21 Å, which is 0.44 Å higher than the previous intermediate. The STS2-O contains an imaginary frequency 489.7 cm−1, which is responsible for the proton-transfer transition vector. The STS2-O is a late transition state and finally produces the product complex, SPC-O, which is also stabilized through the H-bond formation with an interaction distance of 1.85 Å. Comparing the relative

interaction distance (O−H) is 2.26 Å. The SRC-O then transforms to the transition state STS1b-O with 34.09 kcal mol−1 activation barrier. The STS1b-O, the first transition state in the stepwise mechanism, has a four-member ring formed by the P−O−H−N atoms. The imaginary vibrational frequency 1391.4 cm−1 is due to the H-transfer transition vector from N to O atom. The STS1-O then produces a distorted square pyramidal intermediate, INT1-O, with 12 kcal mol−1 lower energy than the TS. In the case of INT1-O, the forming P−N and breaking P−O bonds are 0.28 Å shorter and 0.06 Å longer than those in the TS, STS1-O. The intermediate, INT1-O, is converted to INT2-O through a TS, STSR-O, corresponding to the rotation of H atom around the P−O bond. The STSR-O contains an imaginary frequency 516.6 cm−1 for the change of orientation of H atom due to rotation. The relative energy barrier for STSR-O with respect to the reactant is 28.74 kcal mol−1. In STSR-O, the important bond parameters, e.g., P−N and P−O, remain almost constant like those in INT1-O. The 8386



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Figure 3. M062X/6-311++G(d,p) [(MP2/6-311+G(d,p)] potential energy profile (with ZPE corrected) for the uncatalyzed concerted and stepwise P−O decomposition pathways for the aminolysis of DMPT.

Table 2. Relative Energies (ΔE, kcal mol−1) and ΔH298K and ΔG298K Calculated at M062X/6-311++G(d,p) and MP2/6311+G(d,p) Levels of Theory for All the Species Involved in Uncatalyzed Aminolysis Reaction of DMPT ΔE

ΔH

The results obtained from AIM analysis are reported in Table S4 in the Supporting Information. As shown in Table S4, in SRC-O, there is a weak H-bond ((∇2ρ(r) and H(r) > 0) between H atom of NH3 and O atom on the PO moiety (3.29 kcal mol−1). In STS1-O, this interaction is more prominent with the interaction energy 98.76 kcal mol−1, but the interaction between P and O atoms of the leaving group decreases from 129.18 to 112.15 kcal mol−1. Conversely, reduction of the P−S interaction is not so prominent. Consequently, it clearly establishes the mechanism as well as confirms the P−O bond cleavage. To take into account the influence of solvent (CH3CN, C2H5OH, and H2O) in the reaction mechanism, the conductorlike screening solvation model (COSMO) has been employed. We have estimated the influence of solvent by performing single-point energy calculations using the SCRF (COSMO) method. After implicit treatment of solvent, we find that it has little effect on reactions; sometimes it even proceeds through higher barrier (presented in Tables S1, S2, and S3 in the Supporting Information). This is due to the fact that the separated reactants are more stabilized and possess greater solvation energy in water (16.10 kcal mol−1) than all the transition states (viz., CTS-O possesses 15.60 kcal mol−1). Although this seems to be doubtful, it can be explained by considering the fact that in this reaction the observed transition states are neutral and the charge separation is negligible. Owing to this, we try to find out the influence of solvent and characterize the reaction in the presence of one additional H2O and NH3 molecule explicitly. We first explore the H2O-assisted aminolysis reaction. H2O-Catalyzed Aminolysis. Similar to the uncatalyzed aminolysis, as shown in Scheme 4, the H2O-catalyzed aminolysis reaction can proceed through the two possible neutral mechanisms, concerted and stepwise. The optimized geometries of all the relevant species for both routes are presented in Figure 2, and the ZPVE corrected

ΔG

species

M062X/ BS1

MP2/ BS2

M062X/ BS1

MP2/ BS2

M062X/ BS1

MP2/ BS2

R + NH3 CRC-O CTS-O CPC-O SRC-O STS1-O INT1-O STSR-O INT2-O STS2-O SPC-O CRC-S CTS-S CPC-S SRC-S STS1-S INT1-S INT2-S STS2-S SPC-S

0.00 −2.92 50.50 3.44 −2.65 34.08 22.08 28.74 19.74 27.89 −0.91 −4.85 44.63 −4.16 −4.23 35.35 25.28 23.28 23.11 −7.03

0.0 −1.79 53.14 3.79 −1.69 37.74 27.10 34.54 24.32 30.74 −0.03 −4.31 48.25 −3.43 −3.93 39.56 31.10 29.47 29.27 −6.30

0.0 −3.23 49.17 2.93 −2.86 32.22 20.35 26.89 17.85 26.33 −1.15 −5.06 43.11 −4.57 −4.46 33.85 23.85 22.09 21.08 −8.03

0.0 −1.75 51.89 3.43 −1.66 36.14 25.59 32.85 22.72 29.38 −0.32 −4.31 47.08 −3.70 −3.91 38.09 29.69 28.33 27.89 −6.57

0.0 6.20 61.17 12.18 5.91 45.81 33.72 40.44 31.68 38.94 6.91 4.02 55.54 4.06 3.93 46.70 36.39 33.69 34.82 2.56

0.0 5.82 63.08 11.94 6.08 48.61 38.15 45.70 34.82 41.11 7.83 3.58 57.91 3.75 3.77 50.39 41.93 39.54 39.32 1.38

energy barrier of STS1-O (34.09 kcal mol−1 in M062X and 37.74 kcal mol−1 in MP2) with that of the STS2-O (28.74 kcal mol−1 in M062X and 30.70 kcal mol−1 in MP2), it is clearly established that the first step is the rate-determining step. Again, from the comparison between concerted and stepwise energetics of the uncatalyzed aminolysis, it is recognized that the stepwise pathway is more favorable. 8387



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Scheme 4. Possible Mechanisms for the Methyl Alcohol Leaving Pathways for H2O-Assisted Aminolysis of DMPT

Figure 4. M062X/6-311++G(d,p) [(MP2/6-311+G(d,p)] potential energy profile (with ZPE corrected) for the H2O-assisted concerted and stepwise P−O decomposition pathways for the aminolysis of DMPT.

catalyst to the methoxy oxygen. The forming P−N and breaking P−O distances are 1.89 and 1.86 Å, which are almost similar to those in the CTS-O. In the presence of H2O, the relative energy barrier for the concerted step is 10.78 kcal mol−1 lower than the uncatalyzed aminolysis which clearly illustrates the catalytic effect of H2O. The reason for this is that the CTSb-O involves a six-member cyclic transition state which favors the proton transfer than the CTS-O having a fourmember ring structure. The CTSb-O then produces the preproduct complex, CPCb-O, through an exothermic process with 7.26 kcal mol−1. In the case of stepwise pathway, the first stationary point observed is the prereactive complex, SRCb-O, which is very much stable (−11.79 kcal mol−1) compared to the prereactive complex found in the uncatalyzed pathway. In SRCb-O, the important P−N distance is 3.60 Å. The SRCb-O then transforms to the first transition state, STS1b-O, with

potential energy surface is given in Figure 4. The relative energy, enthalpy, and Gibb’s free energies are shown in Table 3. We first discuss the concerted pathway. According to the findings, the reactants first form a prereactive complex, CRCbO, with 10.92 kcal mol−1 lower in energy than the reactant. The CRCb-O is stabilized through the extent of H-bond formation. In the next step, the CRCb-O is converted to the preproduct complex, CPCb-O, through a six-member cyclic transition state, CTSb-O, that possesses energy of activation 39.74 kcal mol−1. The structure of the concerted transition state, CTSb-O, exposes the catalytic nature of the additional H2O molecule in the hydrogen-transfer process. The imaginary frequency 483.8i cm−1, which is responsible for the transition vector at CTSb-O, consists basically of the transfer of a hydrogen atom from the nucleophile NH3 molecule to the catalytic H2O molecule and a simultaneous transfer of another hydrogen atom from the 8388



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Table 3. Relative Energies (ΔE, kcal mol−1) and ΔH298K and ΔG298K Calculated at M062X/6-311++G(d,p) and MP2/6311+G(d,p) Levels of Theory for All the Species Involved in H2O-Assisted Aminolysis Reaction of DMPT ΔE species R + NH3 + H2O CRCb-O CTSb-O CPCb-O SRCb-O STS1b-O INT1b-O INT2b-O STS2b-O SPCb-O CRCb-S CTSb-S CPCb-S SRCb-S STS1b-S INT1b-S INT2b-S STS2b-S SPCb-S

ΔH

M062X/ BS1

MP2/ BS2

0.00

0.0

−10.92 39.75 −7.26 −11.79 18.74 13.21 10.70 14.22 −10.45 −8.78 42.09 −11.50 −14.31 19.15 14.60 3.53 14.18 −15.13

−9.83 44.32 −6.92 −10.38 25.84 19.62 16.10 20.23 −9.58 −8.62 45.82 −10.63 −13.23 26.51 21.22 9.48 23.22 −13.64

M062X/ BS1 0.0 −11.42 37.06 −8.20 −12.80 15.60 10.82 8.31 11.26 −11.56 −9.29 39.41 −12.49 −15.15 16.19 12.43 1.46 12.01 −16.63

molecule. The second intermediate, INT2b-O, is 2.51 kcal mol−1 more stable than the previous intermediate, INT1b-O. In INT2b-O, the catalytic H2O molecule becomes stable through the formation of two similar H-bonds with interaction distances 1.82 and 1.77 Å. In the final step, the intermediate, INT2b-O, forms the product complex, SPCb-O, through the transition state, STS2b-O, associated with the activation barrier 3.52 kcal mol−1 with respect to the INT2b-O. The STS2b-O basically possesses the cleavage of P−OCH3 single bond and restoration of the PO double bond with simultaneous proton transfer from the P−O(H) to −OCH3 part via the catalytic H2O molecule. It can be seen from the above analysis that the first step of the reaction is the rate-determining step of the entire process. It also shows that the stepwise mechanism is the most favorable one. NH3-Catalyzed Aminolysis. The next step in this study is to investigate the catalytic effect of additional NH3 molecule in the two mechanisms considered for the aminolysis of DMPT. The reaction is sketched in Scheme 5. Comparing with the H 2 O-assisted process, one NH 3 molecule could be designated as a nucleophile while the second NH3 molecule acts as a catalyst. All the optimized geometries are presented in Figure 2, and the activation parameter along with the reaction profile is described in Figure 5. The relative energies, relative free energies and enthalpies are presented in Table 4. A detailed analysis of IRC for the concerted transition state along both sides proves the existence of prereactive and preproduct complexes. Their structures and the existing intermolecular hydrogen bonds are shown in Figure 2. Both complexes are more stable than the separated reactants by 9.54 and 8.04 kcal mol−1. The transition vector illustrates that in CTSc-O proton transfer takes place through a six-member cyclic path associated with 39.83 kcal mol−1 transfer barrier, which is 10.69 kcal mol−1 lower than the uncatalyzed process. In CTSc-O, the forming P−N and breaking P−O distances are 1.83 and 1.82 Å, respectively. In the NH3-assisted stepwise aminolysis of DMPT, the first important critical structure located in the reaction path is the transition state, STS1c-O, associated with activation energy 23.32 kcal mol−1, which is 10.77 kcal mol−1 lower than the uncatalyzed reaction. In STS1c-O, like STS1b-O, the catalytic NH3 molecule forms a typical O···HN bond with the phosphoryl oxygen atom having interaction distance 1.42 Å and a N···HN hydrogen bond (1.35 Å) with the nucleophilic

ΔG MP2/ BS2 0.0 −10.13 41.72 −7.88 −11.10 22.93 17.36 13.86 17.51 −10.52 −8.87 43.12 −11.29 −13.84 23.65 19.08 7.79 20.95 −14.32

M062X/ BS1

MP2/ BS2

0.0

0.0

5.93 59.97 9.85 6.40 39.82 33.59 31.21 35.50 6.74 8.19 62.19 5.72 3.12 39.77 34.40 23.76 33.68 2.89

6.10 64.28 10.10 6.77 46.22 39.53 35.94 40.65 6.80 7.62 65.99 5.24 3.41 46.75 40.82 28.87 42.86 1.67

18.74 kcal mol−1 barrier of activation. The activation energy is significantly lower (15.35 kcal mol−1) in the catalyzed aminolysis than the uncatalyzed one. In STS1b-O, the formation of P−N bond is quite advanced and it possesses a six-member cyclic structure. The transition vector for the imaginary frequency (1202.7 cm−1) mode clearly reveals that the proton transfer is occurred. The transition state, STS1b-O, corresponds to the cleavage of N−H and PO bonds (double to single) and the formation of P−N and O−H bonds. To overcome the transition state, the stable intermediate, INT1bO, is formed. In INT1b-O, the P−N and O−H bonds are completely formed, and the catalytic H2O molecule is situated in a typical orientation stabilized through the H-bond formation in the N−H−O−H extended moiety. Subsequently, the intermediate, INT1b-O, converts to the intermediate, INT2b-O, by rotating the H atom only around the P−O(H) bond with simultaneous rearrangement of catalytic H2O

Scheme 5. Possible Mechanisms for the Methyl Alcohol Leaving Pathways for NH3-Assisted Aminolysis of DMPT

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Figure 5. M062X/6-311++G(d,p) [(MP2/6-311+G(d,p)] potential energy profile (with ZPE corrected) for the NH3-assisted concerted and stepwise P−O decomposition pathways for the aminolysis of DMPT.

Table 4. Relative Energies (ΔE, kcal mol−1) and ΔH298K and ΔG298K Calculated at M062X/6-311++G(d,p) and MP2/6311+G(d,p) Levels of Theory for All the Species Involved in NH3-Assisted Aminolysis Reaction of DMPT ΔE

ΔH

ΔG

species

M062X/BS1

MP2/BS2

M062X/BS1

MP2/BS2

M062X/BS1

MP2/BS2

R + 2NH3 CRCc-O CTSc-O CPCc-O SRCc-O STS1c-O INT1c-O INT2c-O STS2c-O SPCc-O SRCc-S STS1c-S INT1c-S INT2c-S STS2c-S SPCc-S

0.00 −9.55 39.83 −8.04 −8.32 23.33 13.19 10.65 18.00 −8.49 −11.16 23.55 15.77 3.36 12.71 −12.07

0.0 −8.69 43.88 −7.60 −7.61 29.07 19.41 15.98 22.73 −8.12 −10.29 29.66 22.43 9.24 21.59 −10.29

0.0 −9.79 37.40 −8.68 −9.30 20.30 11.29 8.74 15.29 −9.29 −11.48 20.81 14.06 1.40 10.81 −12.72

0.0 −8.72 41.57 −8.15 −7.88 26.25 17.61 14.31 20.04 −8.82 −10.53 27.05 20.84 7.51 19.82 −11.32

0.0 6.85 60.27 7.96 9.51 44.75 33.02 30.38 39.10 8.28 5.53 44.24 35.07 23.82 31.95 4.93

0.0 7.08 63.94 8.19 8.44 49.93 38.81 34.93 43.54 8.37 6.08 49.70 41.14 28.81 40.41 4.56

well as the rate-determining step along the stepwise pathway involves proton shift through six-member cyclic transition states. These structures are characterized by less ring strain than four-member rings in the case of uncatalyzed reaction, and thus lowers the proton-transfer barrier and facilitates the processes. P−S Decomposition Pathways. In the next step, we focus mainly on the elucidation of the mechanism of the P−S bond cleavage during aminolysis in the absence or in the presence of the catalyst molecule. Like the exploration of the P−O decomposition pathway, here we first consider the uncatalyzed process and then consecutively H2O- and NH3-assisted mechanisms.

NH3 molecule. The STS1c-O then transforms into a stable intermediate, INT1c-O, with the transformation of PO to P−O. The INT1c-O then goes to the INT2c-O after a proper orientation of the P−O(H) component and subsequent reorganization with the NH3 molecule. At last the process of elimination takes place via the transition state, STS2c-O, with the restoration of the PO bond and removal of CH3OH. The STS2c-O has the barrier of activation 18.00 kcal mol−1. As expected and also observed from the PES, the neutral stepwise pathway, which is similar to the uncatalyzed and H2O-assisted reactions, becomes the most favorable one. According to the results obtained for the H2O- and NH3assisted reaction, it is obvious that the concerted mechanism as 8390



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Figure 6. Optimized geometries with geometrical parameters calculated at the M062X/6-311++G(d,p) and the MP2/6-311+G(d,p) levels in black bold and pink normal faces, respectively, for all the species involved in the P−S decomposition pathway for the aminolysis of DMPT.

Uncatalyzed Aminolysis. This reaction pathway can be demonstrated by Scheme 3 by simply changing the −OCH3 group to −SCH3. The stepwise mechanism with zwitterionic intermediate is also not found here. The optimized geometry along with geometrical parameters and the ZPVE-corrected gas-phase potential energy profile are presented in Figures 6 and 7, respectively. The relative energies, relative free energies, and enthalpies are presented in Table 1. The IRC calculation proves that the reaction goes by forming a prereactant (CRC-S) and preproduct (CPC-S) complex and possesses 4.84 and 4.16 kcal mol−1 lower in energy than the separated reactants. In this pathway between CRC-S and CPC-S, there exists a fourmember cyclic transition state with 44.63 kcal mol−1 energy of activation. The transition vector for the imaginary frequency (233.2 cm−1) is due to the H shift from the nucleophilic NH3 to S atom. In CTS-S, the forming P−N and breaking P−S bond lengths are 1.91 and 2.73 Å, respectively. In the neutral stepwise pathway, we observed that the first critical stationary point, STS1-S, is the rate-controlling transition state containing 35.35 kcal mol−1 barrier of activation. For this route, there is also a possibility of front side attacking mechanism which passes through a slightly higher barrier and is therefore excluded from the discussion. All other analyses are very similar to the uncatalyzed aminolysis of

P−O bond cleavage pathway and therefore are not so important to mention here; rather, a comparison between the two pathways would be more interesting. The elimination transition state, STS2-S (the final TS for this pathway), is an early TS that possesses geometry like INT2-S, whereas in the case of STS2-O, there is a significant degree of H-shift. The rotational transition state, STSR, could not be located here because of the steric hindrance which may create difficulties. The STS2-S has almost no barrier from the intermediate. From AIM analysis (numerical values are tabulated in Tables S4 and S7 in the Supporting Information), it can be found that in the P−O cleavage pathway of the concerted process the interaction energy of the P−O(L) [L = leaving] bond changes 128.19 to 30.61 kcal mol−1 from reactant to TS. On the other hand, in the case of the P−S decomposition reaction it changes from 43.03 to 7.44 kcal mol−1 from reactant to TS, which clearly suggests that the same degree of breaking of the leaving bond takes place. After investigation of the P−N bond forming interaction energy in the corresponding TS, it is observed that the CTS-O (61.40 kcal mol−1) is more advancing TS than CTS-S (54.08 kcal mol−1). The first step for both stepwise pathways produces similar result but in the case of the second TS, the O(L)−H bond possesses moderate interaction (42.27 kcal mol−1) for STS2-O whereas the S(L)−H bond possesses lower interaction (9.92 kcal mol−1) for STS2-S. From Wiberg 8391



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Figure 7. M062X/6-311++G(d,p) [(MP2/6-311+G(d,p)] potential energy profile (with ZPEC) for the uncatalyzed concerted and stepwise P−S decomposition pathway for the aminolysis of DMPT.

Figure 8. M062X/6-311++G(d,p) [(MP2/6-311+G(d,p)] potential energy profile (with ZPE corrected) for the H2O-assisted concerted and stepwise P−S decomposition pathways for the aminolysis of DMPT.

order energy for LP → BD*(n→σ) and BD → BD*(σ→σ*) type of interactions (see Table S10 in the Supporting Information). It is significant that in the first TS the major charge transfer through n(3)O → σ*N(NH3)-H1 is similar in both STS1-O (180.36 kcal mol−1) and STS1-S (179.58 kcal/ mol) which substantiates the comparable stability of the two TSs independent of the orientation of the −OCH3 or −SCH3 group. For the second TS, we observe that the charge transfer for n(2)O(L) → σ*O(DMPT)-H1 is more prominent (66.76 kcal mol−1) in STS2-O, while in STS1-S comparably lower

bond order analysis (presented in Table S11 in the Supporting Information), it is observed that in STS2-O the breaking P−O bond order changes from 0.4989 to 0.2291, whereas in STS2-S the P−S bond order changes 0.5776 to 0.3262 from reactant to product, respectively. It shows a greater degree of P−O breaking than P−S in the second TS, and consequently we can conclude that for the P−S cleavage early TS is formed, whereas for P−O it produces late TS. Moreover, NBO analysis shows that the first TS in both P− O and P−S pathways are almost comparable due to the second8392



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Figure 9. M062X/6-311++G(d,p) [(MP2/6-311+G(d,p)] potential energy profile (with ZPE corrected) for the ammonia-assisted stepwise P−S decomposition pathway for the aminolysis of DMPT.

value (23.22 kcal mol−1) is obtained for n(2)S(L) → σ*O(DMPT-H1). From the above investigation, it is clear that the two pathways are roughly comparable. H2O-Catalyzed Aminolysis. H2O-assisted aminolysis for the P−S breaking pathways can be represented by the scheme 4 with changing the −OCH3 group to the −SCH3 group. This process is almost similar to the H 2 O-catalyzed P−O decomposition process. The optimized geometry along with the geometrical parameters and the ZPVE-corrected potential energy profile are presented in Figures 6 and 8, respectively, and the enegetic parameters are summarized in Table 2. For the concerted pathway, the reaction goes through the TS, CTSb-S, having energy barrier 42.09 kcal mol−1. For stepwise pathway, the barriers of the first and second transition states are 19.14 and 14.18 kcal mol−1, respectively, which are approximately similar to the transition states of the stepwise H2O-assisted P−O cleavage pathway. From the above analysis, it is confirmed that both P−O and P−S breaking processes during aminolysis are more or less alike. This is also supported by the AIM analysis. The numerical values obtained from AIM analysis are tabulated in Tables S5 and S8 in the Supporting Information. In STS1b-O, the forming P−N bond interaction energy is 37.75 kcal mol−1, whereas for STS1b-S, it is 53.84 kcal mol−1. The most important stabilizing O−H(2) [H(2) means the H atom linked with catalyst molecule] interaction energies are 110.64 and 109.86 kcal mol−1 for STS1b-O and STS1b-S, respectively. On the other hand, the O−H(2) interaction energies for STS2b-O and STS2b-S are 113.43 and 177.03 kcal mol−1, respectively. In the rate-determining steps for the stepwise P−O and P−S cleavages, the Wiberg bond order (presented in Table S12 in the Supporting Information), 0.4404 and 0.8497, for reactant changes to 0.2098 and 0.2473 in TS. So, degree of breaking of the P−S bond is much greater than that of the P−O bond. NH3-Catalyzed Aminolysis. NH3-catalyzed aminolysis for the P−S breaking pathways can be expressed by Scheme 4 by

changing the −OCH3 group to the −SCH3 group. The related geometry, PES, and energetics data are accessible from Figures 6 and 9 and Table 3, respectively. After several attempts we are unable to detect the concerted pathway. However, this is not a problem because in the entire reaction processes the stepwise pathway becomes more favorable. In the stepwise pathway, the conversion of reactant to product needs to overcome two transition states with energy barrier 23.55 and 12.70 kcal mol−1. This process is almost like the methyl alcohol leaving pathway. The AIM parameters tabulated in Tables S6 and S9 in the Supporting Information also establish this fact. After we compare the energy of activation for all the uncatalyzed and catalyzed aminolysis of DMPT, the catalytic role of the second NH3 or H2O molecule is established. The second NH3 or H2O molecule acts as a catalyst influencing typically the proton shuttle processes which prefer to form sixmember ring structure in TS than the four-member ring in the case of the uncatalyzed one. It is important to mention here that the lowering of the barrier height either by H2O or by NH3 does not make significant difference. The stepwise pathway is always favorable, and the first step, the addition step, is the ratelimiting step. This trend remains the same for both the P−O and P−S cleavages. In the second step of the stepwise pathways, as the thio group has greater leaving tendency, the P−S bond breaking becomes lower energetic. Bond Order Analysis. To get more information about the bond-breaking/forming in the aminolysis, the synchronicity parameters have been calculated. The changes in bond order along the aminolysis reaction path are investigated by means of NBO bond order. The Wiberg bond indexes81 are computed using the Gaussian NBO 3.1 program implemented in Gaussian 09. The indexes obtained from the population analysis can be used to estimate bond orders. Bond breaking and making processes involved in the reaction mechanism are monitored by 8393



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outcomes, it can be concluded that the two main disintegration processes are usually parallel. The reaction in the presence of catalyst passes through almost half activation barrier in the stepwise route which indicates that the purely uncatalyzed aminolysis of DMPT is not competitive with the H2O- or the NH3-assisted mechanism. It was established from the previous investigation of hydrolysis as well as nucleophilic reaction of DMPT-type compound that the P−S bond cleavage is more favorable than P−O.47,48 In this study, we have treated both the pathways separately and from the analysis of barrier height we see that the probability of breaking of both bonds is almost parallel. In all the reaction channels, the formation of the first prereactive complex of P−S bond cleavage routes is more exothermic than the P−O cleavage route. Consequently, if we compare the probability of formation of the first prereactive complex that determines the branching ratio of the reaction channels, it is clearly recognized that the P−S cleavage is more prominent than the second one. The present computational investigation provides the quantitative results for the aminolysis of phosphonothiolate type of compound for the first time. The accuracy of these calculations can be anticipated by the use of standard high-level method and basis sets. Although there is no experimental support, our results and predicted reaction mechanisms will serve as useful information and basis for further experimental and computational efforts to understand the reactivities of typical phosphonothiolate compounds in future.

means of the synchronicity parameter (Sy) proposed by Moyano et al.82 Sy can be defined as i=1

Sy = 1 − [∑ |δBi − δBav | /δBav ]/(2n − 2) n

where n is the number of bonds directly involved in the reaction, and the relative variation of bond indexes are obtained from the following relation: δBi =

|BiTS − BiR | |BiP − BiR |

Here the superscripts R, TS, and P denote reactant, transition state, and product, respectively. The evolution in bond changes is calculated using the relation %Ev = (δBi) × 100. The average value for the bond indexes is calculated using the following relation: i=1

δBav = 1/n ∑ δBi n

The progress of the reaction along the reaction coordinate can be monitored using the Wiberg bond indexes, Bi. The synchronicity parameter (S y ) has value 1 for synchronous reactions and 0 for asynchronous stepwise processes. The numerical values regarding the bond-order calculations are demonstrated in Tables S11−S14 in the Supporting Information. For the uncatalyzed concerted process, the Sy values for the P−O decomposition pathway are higher (0.90) than for the P−S cleavage pathway (0.73), which indicates that the former proceeds through less polar and more synchronous TS than the latter. In the stepwise pathway, both have similar and high Sy values (0.94 and 0.95). Therefore, there is usually no difference between the two pathways. In the case of H2O- and NH3-assisted reactions, all processes exhibit high value of Sy and hence no remarkable difference exists. In the second TS of the stepwise pathway, the P−O breakdown reaction possesses higher value than the P−S breaking process. So it can be concluded that the P−O breaking takes place through less polar and more synchronous mechanism.

■

ASSOCIATED CONTENT

S Supporting Information *

Relative free energies in the presence of solvent, numerical parameters for AIM and NBO calculation, Cartesian coordinates for optimized geometries in the gas phase for all the species, ZPVE, thermochemical parameters, and the vibrational frequencies for all the species. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

■

Notes

CONCLUSION The model aminolysis reaction of DMPT has been investigated in the gas phase using the DFT (M062X) as well as ab initio (MP2) method. The solvent effect of CH3CN, C2H5OH, and H2O is taken into account using single-point DFT (M062X) calculation. All the reaction mechanisms are involved in proton transfer. To understand the effect of additional NH3 or H2O molecule, the reaction is studied in the presence of a second NH3 and H2O molecule explicitly. Two competing disintegration pathways (removal of CH3OH and CH3SH) are explored, and two (concerted and stepwise) possible neutral mechanisms for each of the disintegration pathways are intensively investigated. From the outcomes, we can reach to the conclusions that the neutral stepwise pathway is more favorable than the concerted one for all of the aforesaid reactions. The calculated energy barriers for the first step of the stepwise process are always higher than those for the second step and hence the first step is the rate-determining step. The structure and transition vectors of the transition state show that the role of catalyst is to facilitate the proton transfer and also to decrease the energy barriers. It is observed that solvent has little effect on the title reaction. From AIM as well as NBO

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.M. and K.S. are very much grateful to the Council of Scientific and Industrial Research (CSIR), Government of India, for providing Research Fellowships.

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REFERENCES

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