A Computational Chemistry Investigation of the Mechanism of the

Article pubs.acs.org/JPCA

A Computational Chemistry Investigation of the Mechanism of the Water-Assisted Decomposition of Trichloroethylene Oxide Jinqing Huang,† Chi Shun Yeung,† Jiani Ma,†,‡ Emma R. Gayner,§ and David Lee Phillips*,† †

Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China College of Chemistry and Materials Science, Northwest University, Xi’an, People’s Republic of China § School of Chemistry, University of Edinburgh, Edinburgh EH9 3JJ, Scotland, United Kingdom ‡

S Supporting Information *

ABSTRACT: Trichloroethylene oxide is a downstream product in the oxidative metabolism of trichloroethylene (TCE) and it may be involved in cytochrome P450 inactivation, protein function destruction, and nucleic acid base alkalization. To explore the hydrolysis mechanism of the decomposition of TCE oxide, an investigation using Second-order Møller−Plesset perturbation theory in conjunction with density functional theory has been conducted to analyze the effect of the water solvation shell on probable reaction steps. The decomposition of TCE oxide is accelerated by coordinated water molecules (up to seven), which reveals that water molecules can help to solvate the TCE oxide molecule and activate the release of the Cl− leaving group. After the opening of the epoxide ring, several pathways are proposed to account for the dehalogenation step along with the formation of CO as well as three carboxylic acids (formic acid, glyoxylic acid, and dichloroacetic acid). The predominant pathways were examined by comparing the computed activation energies for the formation of the products to each other for the possible reaction steps examined in this work. After rationally analyzing the computational results, the ring-opening reaction has been identified as the rate-determining step. The rate constant estimated for the TCE oxide decomposition from the calculations performed here was found to be reasonably consistent with previous experimental observations reported in the literature.

■

INTRODUCTION Epoxides are versatile intermediates in organic synthesis and in reactions associated with human metabolism.1−6 The triangular ring strain provides an active site for a variety of reagents like electrophiles, nucleophiles, acids, bases, proteins, and possibly DNA.7−9 The thermal decomposition of polyhalogenated alkene epoxides had been studied in organic solvents and was shown to be dominated by halide migration.2,10 However, the hydrolytic reactions are more complex mainly due to extensive C−C scission, which may be highly relevant to associated biology and toxicology reactions but it is still unclear how the hydrolytic reactions occur. About 34% of the drinking water supplies in the United States have been found to be contaminated by trichloroethylene (TCE) via leaching into groundwater from landfill sites, evaporation during use of TCE, and directly into the water system from industrial wastewater.11 When contaminated water is consumed, the human body may generate TCE oxide1,8 and the oxidative metabolism of TCE with P450 occurs primarily in the liver during the process of detoxification.2 Studies of the microsomal oxidation of TCE suggest that TCE oxide is a genotoxic carcinogen with protein and nucleic acid base alkalization reactions able to occur.1,12,13 Hence, there has been a lot of research on TCE oxide. In 1978, Van Duuren and co-workers reported the synthesis of TCE oxide as well as thermodynamic studies that CHCl2COOH was the only hydrolysis and thermolysis product.14 Henschler and coworkers later reported that in the hydrolysis process, TCE © 2014 American Chemical Society

oxide is rearranged to CHCl2COOH or hydrolyzed to CO, HCOOH, or glyoxylic acid.15 Guengerich and co-workers also examined the rearrangement of TCE oxide under various conditions and found that TCE oxide did not rearrange to form chloral, in contrast to the proposals of Byington, Leibman, and Henschler and co-workers.2,15,16 Hydrolysis and rearrangement mechanisms of TCE oxide have been proposed to account for the various experimental observations. It was suggested that C− C scission of TCE oxide occurred under neutral and basic conditions, in accordance with the C−C scission of the analogue vinylidene chloride epoxide.17 Product analysis and isotopic tracer measurement provided strong evidence for a heterogeneous type of decay.18 Scheme 1 illustrates the different reaction pathways for the decomposition of TCE oxide that end with the formation of glyoxylic acid, dichloroacetic acid, CO and formic acid.18 The kinetic investigations on TCE oxide hydrolysis were carried out by Guengerich, indicating the rate law for the hydrolysis of TCE oxide with two terms: a pH-independent term, kwater (6.9 × 10−3 s−1) and a hydronium ion-dependent term, kH (3.3 × 10−2 M−1s−1).18 The mechanism proposed for the hydronium ion-dependent hydrolysis of TCE oxide is very similar to the pH-independent hydrolysis except for the first step, which involves a hydronium ion attacking TCE oxide to form a TCE oxide cation intermediate. The experimental and theoretical studies on Received: February 6, 2014 Published: February 7, 2014 1557

dx.doi.org/10.1021/jp501310z | J. Phys. Chem. A 2014, 118, 1557−1567

The Journal of Physical Chemistry A

Article

activation energy barrier. To better understand how solvation influences the reaction, theoretical calculations have been employed to investigate the dehalogenation reactions of TCE oxide in both the gas and aqueous phases. The results presented here confirm that the presence of water accelerates the decomposition reactions, which can be further accelerated by introducing more water molecules. Rate constants were used to compare the calculation results to available experimental data. The mechanisms of the water-catalyzed decomposition reactions are briefly described and followed by a discussion of a water-assisted HCl elimination model for the aqueous decomposition of polyhalogenated epoxides.

Scheme 1. Possible Mechanisms for Hydrolysis of TCE Oxide in Aqueous Solution18

■

COMPUTATIONAL METHODS Since water molecules are involved in the reaction, and the hydrogen bond effect may make an important contribution to the activation of the reaction,30,31 high-level theory and large basis sets are likely required to be included in the calculations. This may require extended basis functions and high computational cost. Methods including second-order Møller−Plesset perturbation theory (MP2) and density functional theory (DFT) are thought to be appropriate candidates to better describe the reaction of interest.32 MP2 and B3LYP approaches were used to study water-assisted reactions such as the decomposition of halogenated hydrocarbons in our previous studies, and these results were found to be in good agreement with experimental results.25,33 The DFT method with the M062X functional was recommended in some reports for analyzing intramolecular hydrogen bonds and proton-transfer reactions, and those results were found to be comparable to results from MP2 calculations.32 Since the reaction systems here have similar characteristics, the M06-2X method may be an alternative way to obtain reasonably accurate values. To better simulate the cooperative hydrogen system, a high level treatment of the electron correlation with a large basis set is essential to describe the weak hydrogen bonds between the water molecules and TCE oxide. Some reports suggested that diffuse functions are important to study weak hydrogen bonds.34−36 Therefore, a large basis set, namely 6-311+ +G(2df,2pd), was used at the M06-2X level of theory.32 At this time, it is still too computationally intensive with the resources available to us to employ all of these three methods to the complex hydrolysis mechanism of TCE oxide. Therefore, we only compared the results using all three of these methods for the first reaction step, and for the other reaction steps we compared the activation barrier using one method to determine the predominant reaction pathway. We investigated three major reaction schemes to explore the hydrolysis of TCE oxide. Scheme 2 is the ring-opening reaction of TCE oxide 1 that proceeds to form 2-chloro-2-hydroxyacetyl chloride 2 with water. This reaction then proceeds by dehalogenation of 2 to make glyoxylic acid 5 through the intermediate chloroglyoxal 3 as shown below. Scheme 3 involves the same ring-opening reaction of TCE oxide 1 to form 2-chloro-2-hydroxyacetyl chloride 2 and then it forms CO and formic acid 7 via different pathways. One pathway is dehalogenation of 2 to chloroglyoxal 3, followed by decomposition of 3 to CO and 7 directly. The decomposition of 3 through the 2-dihydroxyacetyl chloride 6 intermediate to CO and 7 is another possible pathway. It is also possible that the reaction pathway proceeds from 2 to CO and formyl chloride 4 that subsequently becomes 7 during hydrolyzation as shown below.

acid-catalyzed hydrolysis of epoxides have been well established and have indicated the possibility of epoxide conversion to a protonated aldehyde in the presence of a water molecule.19−22 Nonetheless, there has been little computational work performed to examine the mechanism(s) of TCE oxide hydrolysis. Competing with hydrolysis, the reactions between the epoxide and the nucleophilic sites in DNA and RNA have been studied by some computational methods, and water molecules were speculated to assist (or catalyze) these reactions.23 This type of behavior will be used to help extend the previous work of the water-assisted decomposition of TCE oxide to better understand the effect of water molecules on the reaction steps and mechanisms. It has been reported that ethylene epoxide reacted with the nucleotide bases adenine, guanine, and cytosine, assisted by a hydrogen-bonded network with six water molecules.24 By employing density functional theory methods, the activation energies of the ring-opening steps were found to be 28.06 kcal/mol, 28.64 kcal/mol, and 28.37 kcal/mol for the epoxide−adenine−water system, the epoxide−guanine−water system, and the epoxide−cytosine− water system, respectively. Without water, these reactions have significantly higher activation energies: 53.51 kcal/mol, 55.76 kcal/mol, and 56.93 kcal/mol for the epoxide−adenine system, the epoxide−guanine system, and the epoxide−cytosine system, respectively. Additionally, further theoretical and experimental studies suggested that water molecules are able to catalyze various reactions (SO3 hydration, dehalogenation of CBr4 and other polyhalomethanes, H2O2 formation, hydrolysis of acids, etc.)25−28 as well as to act as an optimal promoter to induce epoxide opening cascades.29 Increasing the number of water molecules involved can promote reaction rates by lowering the 1558



Article

(TS), and product complexes (PC) were optimized for all of the reactions. RCijn, TSijn, and PCijn represent the structures determined from the calculations, where i is the number of the reactants, j is the number of the products, and n is the number of the water molecules in the reaction. For instance, (RC)362 represents the reaction complex of 3 to 6 with two water molecules, i.e., the reaction complex of OHCCClO + 2H2O → HC(OH) 2CClO + H2O (3−6). The stationary structures for all of the RC, TS, and PC were fully optimized without symmetry constraints (C1 symmetry). The 6-311++G(2df,2pd) basis set was used in the DFT (M06-2X) calculations and the 6311G(d,p) basis set was utilized in the MP2 and DFT (B3LYP) calculations employing the Gaussian 09 program suite for both the optimization and the frequency calculations. Analytical frequency calculations were performed to confirm that the optimized structures are either a minimum or a first order saddle point, as well as to obtain the zero-point energy correction for all of the reactions. Intrinsic reaction coordinate (IRC) calculations were conducted to confirm that the optimized TS correctly connect the relevant reactants and products. In addition to the explicit coordination of the solvent water molecules in the reactions, bulk solvation effects were also examined by employing the integral equation formalism variant Polarizable Continuum Model (IEFPCM) utilized for water (λ = 78.39).

Scheme 2. Decomposition of Trichloroethylene Oxide to Glyoxylic Acid

Scheme 3. Decomposition of Trichloroethylene Oxide to CO and Formic Acid

■

RESULTS AND DISCUSSION A. Decomposition of Trichloroethylene Oxide to Glyoxylic Acid. a. TCE Oxide + nH2O → ClCH(OH)CClO + HCl + (n − 1)H2O (1−2). Figure 1 shows the activation barriers of the first reaction step are about 34.3 kcal/mol for n = 1 and 27.0 kcal/mol for n = 2, and then a slight decrease to 22.8 kcal/ mol for n = 3. The activation energy decreases when more water molecules participate in the reaction system. As the number of water molecules reaches six and seven, the reaction barriers become 14.3 and 13.3 kcal/mol, respectively. The

Scheme 4 is the intramolecular rearrangement (Cl− shift) of TCE oxide 1 to generate dichloroacetyl chloride 8 followed by decomposition of 8 to dichloroacetic acid 9 as shown below. The effect of water clusters was investigated by adding water molecules one by one into the reactant complexes. The structures of the reactant complexes (RC), transition states Scheme 4. Decomposition of Trichloroethylene Oxide to Dichloroacetic Acid

Figure 1. Relative energy profiles (in kcal/mol) obtained from the MP2/6-311G(d,p) calculations for the TCE oxide + nH2O → ClCH(OH)CClO + HCl + (n − 1)H2O (1−2) (n = 1, 2, 3, 4, 5, 6, 7) reaction are shown. RC12n, TS12n, and PC12n represent the structures determined from the calculations, where 1 is TCE oxide, 2 is ClCH(OH)CClO, and n is the number of water molecules in the reaction. 1559



Article

incorporation of additional water molecules slowed down the decreasing trend of activation barriers. Since the TCE oxide has been shown to be saturated by the water cluster, it is not necessary to further increase the number of water molecules. The catalytic effect by addition of water molecules can be accounted for by the increase of the hydrogen bonds between the water molecules and the chloride species as the leaving group. For a better understanding of this water solvation effect, an investigation has been carried out in terms of the structural and charge changes caused by adding water molecules into the reaction system. The structures presented in Figure 2 are those that give the lowest activation barrier among the different reaction complex orientations with a certain number of water molecules involved in the reaction system. By considering steric effects and electric repulsion in the n = 1 system, a less sterically hindered carbon is attacked by a water molecule and the C−O bond is elongated from 1.40 to 2.04 Å. This leads to the splitting of the epoxide ring and the formation of a new CO bond in the product, which are consistent with the high activation energy needed for the reaction to proceed. As to n = 2 and n = 3, the changes of the C−O bond on the epoxide ring show an identical trend. In addition, the water molecules are connected with the leaving group H−Cl through cyclic hydrogen bonds. An increase in the number of water molecules is accompanied by a smaller structural change from the RC to the TS, leading to a lower activation barrier. Addition of the number of water molecules from n = 4 to 5 reduces the energy significantly from 20.6 to 17.8 kcal/mol. There is less distortion of the water cluster with the TCE oxide from RC125 to TS125 compared with that for the four water molecules reaction system. This suggests that less energy is required for C−Cl bond cleavage during the reaction. In the latter stage of the reaction, six and seven water molecules are involved. The TCE epoxide is surrounded by water molecules and the whole structure maintains almost the same from RC to TS, where elongations of the C−O bond on the epoxide with n = 6 and n = 7 are 0.51 and 0.52 Å, respectively. The water clusters help to stabilize the O on the epoxide and the attacking water molecule. They build the water bridge in two circles and cover two sides of TCE oxide. Moreover, the changes in the C−Cl bond length from RC126 to TS126 and RC127 to TS127 are the same (0.07 Å). This indicates that an increase in the number of water molecules enhances the hydrogen bonding between the water molecules and the chloride leaving group. These interactions also help to stabilize the leaving Cl atom by spreading the charge over the whole water cluster. The hydrogen bond interactions between water molecules also limit the flexibility of the water cluster. To examine the charge distribution among the atoms in the transition from RC to TS and PC, natural orbital analyses (NBO) were performed for most of the stationary structures. A large amount of the charge redistribution occurs upon going from the RC to the associated TS. For instance, the charge of the leaving Cl atoms in the RC127 is slightly negative (−0.002), while it becomes much more negative (−0.061) for the corresponding TS127. Moreover, the charge differences between RC12n and TS12n become smaller. According to previous work on halide elimination reactions,25,33 it is suggested that watersolvated clusters can help to stabilize the negative charge on the leaving Cl atom and spread the charge over the nearby water molecules in the cluster reaction system, which prominently reduces the activation barriers.

Figure 2. The optimized geometries (bond distance given in Å) for all of the RC12n, TS12n, and PC12n obtained from the MP2/6-311G(d,p) calculations for the TCE oxide + nH2O → ClCH(OH)CClO + HCl + (n − 1)H2O (1−2) (n = 1, 2, 3, 4, 5, 6, 7) reaction are shown.

In this ring-opening reaction of TCE oxide, compared with the mechanism proposed by Guengerich and co-workers,18 we prefer a intermediate 2-chloro-2-hydroxyacetyl chloride 2 to a zwitterionic intermediate depicted in Scheme 1. Because of the stereoseletivity shown in Figure 2, the substituted Cl could easily be attracted by water to form an H−Cl leaving group. Hence, the zwitterionic intermediate is unstable and resembles the transition state in the formation of 2-chloro-2-hydroxyacetyl chloride 2. As shown in Figure 1, the nucleophilic ring-opening reactions of epoxides are remarkably accelerated in water. Moreover, the reaction is exothermic in all cases. The results 1560



Article

Table 1. NBO Charges on the Leaving Cl Atom for the Reaction 1−2 Cl

n=1

n=2

n=3

n=4

n=5

n=6

n=7

reactant complex (RC) transition state (TS) product complex (PC) QTS−QRC QPC−QTS

−0.018 −0.276 −0.290 −0.258 −0.272

0.006 −0.193 −0.365 −0.199 −0.371

0.012 −0.218 −0.397 −0.230 −0.410

−0.009 −0.139 −0.442 −0.130 −0.434

−0.018 −0.125 −0.760 −0.107 −0.742

0.013 −0.062 −0.760 −0.075 −0.773

−0.002 −0.061 −0.670 −0.059 −0.669

show the effect of the stabilizing ability of water molecules. Significant stabilization is offered to make this reaction become more exothermic and therefore more thermodynamically favorable. With reference to previous work on water cluster calculations,25,26,28,32−34,37−39 various models for the reaction complexes have been developed. In our results, the ringopening reaction of TCE oxide is assisted by the hydrogen bonded network of water molecules and the solvation model for the ring-opening reaction of TCE oxide was studied by adding explicit water molecules. DFT calculations were done to compare with the results computed at the MP2 level of theory. The energy profiles of the M06-2X/6-311++G(2df,2pd) and B3LYP/6-311G(d,p) calculations are shown in Figures 1S and 2S, and a similar catalysis trend is observed by increasing the number of water molecules incorporated into the reaction system. An estimation of the aqueous solvation effects obtained by using IEFPCM is shown in Figure 3S. The activation energies calculated by the IEFPCM model show the same trend with the DFT and MP2 calculation results in the gas phase with explicitly solvated water molecules. When seven water molecules are involved, the activation energy is 8.8 kcal/mol using the IEFPCM model and 6.9 kcal/mol using the B3LYP gas phase calculation. This is consistent with the watercatalyzed character of these reactions where the water molecules couple the proton transfer from the reactant molecule to the solvation of the Cl− leaving group in the HCl elimination reactions. This therefore has the largest effect on the reaction pathway and the activation energy. Further addition of water solvent molecules has little effect on the reaction pathway and the activation energy, as they do not directly participate in coupling the proton transfer. Due to the release of the HCl molecules, the surrounding aqueous environment will suffer a change in pH and an increase in its local acidity levels. It would be possible to determine the water-assisted nature of the TCE oxide decomposition reaction by assessing it under acidic and basic conditions. As is shown in Figure 3, the activation energy for the ring-opening of TCE oxide is 7.1 kcal/mol involving one hydronium ion and one water molecule. Compared with the calculation results of the pH-independent mechanism (13.3 kcal/mol for n = 7), it is much easier to have a ring-opening reaction with the help of the hydronium ion. Under basic conditions, the hydroxyl ion attacked the less substituted carbon of TCE oxide, which is the same with the pH-independent mechanism. It is confirmed by our computational results that the water is added preferentially to the less sterically hindered carbon atom with respect to basecatalyzed and pH-independent mechanisms for asymmetric epoxides.40 The activation energy (5.8 kcal/mol for n = 4) is lower than that under neutral conditions as the hydroxyl ion is more reactive than the water molecules. These results suggest that the change in pH resulted in the activation of the halogen atoms, changing the reactivity in the solution. b. ClCH(OH)CClO + nH2O → OHCCClO + HCl + nH2O (2− 3). Figure 4 shows the activation barriers for the reaction step

Figure 3. Relative energy profiles (in kcal/mol) obtained from the MP2/6-311G(d,p) calculations for the TCE oxide + nH2O → ClCH(OH)CClO + HCl + (n − 1)H2O (1−2) (n = 1, 4, 7) reactions are shown.

Figure 4. Relative energy profiles (in kcal/mol) obtained from the MP2/6-311G(d,p) calculations for the ClCH(OH)CClO + nH2O → OHCCClO + HCl + nH2O (2−3) (n = 1, 2, 3) reactions are shown. RC23n, TS23n, and PC23n represent the structures determined from the calculations, where 2 is ClCH(OH)CClO, 3 is OHCCClO, and n is the number of water molecules in the reaction.

2−3. When only one water molecule is involved, the activation energy is 20.1 kcal/mol. By increasing the number of involved water molecules to two, there is a significant decrease of the reaction barrier to 15.2 kcal/mol. Addition of further water molecules gradually decreases the reaction barrier to 5.3 kcal/ mol for n = 3. This trend is similar to the results found for the 1561



Article

first reaction step discussed in the previous section. The catalytic effect associated with addition of water molecules is due to the increased hydrogen bonding between the water molecules and the leaving chloride species. In this step, the activation barriers are low, especially when three water molecules are included in the reaction model. Therefore, 2-chloro-2-hydroxyacetyl chloride 2 would change into chloroglyoxal 3 immediately after the ring-opening reaction of TCE oxide. 3 is the major intermediate in the decomposition of TCE oxide, which is potentially reactive with nucleophiles and may be highly relevant to the associated biology and toxicology effects of TCE oxide decomposition. This is consistent with the experiment results from the reaction of TCE oxide with lysine that demonstrated the existence of 3 as a major intermediate.12,18 Owing to this fast reaction step in forming 3, TCE oxide itself may not be the intermediate responsible for irreversible binding to proteins and DNA during the metabolism of TCE. c. OHCCClO + nH2O→ OHCCOOH + HCl + (n − 1)H2O (3− 5). The energetics of the step 3−5 can be discussed with reference to the energy profile diagram shown in Figure 5. The

subsequently becomes 7 during hydrolyzation. The predominant pathway was explored by comparisons between these possible reaction mechanisms. The activation barriers for the direct decomposition from chloroglyoxal 3 to CO and formic acid 7 are shown in Figure 6,

Figure 6. Relative energy profiles (in kcal/mol) obtained from the MP2/6-311G(d,p) calculations for the OHCCClO + nH2O → HCOOH + CO + HCl + (n − 1)H2O (3−7) (n = 1, 2, 3, 4, 5, 6) reactions are shown. RC37n, TS37n, and PC37n represent the structures determined from the calculations, where 3 is OHCCClO, 7 is HCOOH, and n is the number of water molecules in the reaction.

and these can be compared with those for the decomposition from chloroglyoxal 3 through intermediate 2-dihydroxyacetyl chloride 6 to CO and formic acid 7 shown in Figure 7. Similar to the previous cases, the decomposition reaction of interest will be catalyzed by adding water molecules one by one to the reactant complexes, and the activation energies can be described by a decreasing trend in the activation barriers with increasing water molecules. The activation barrier for direct decomposition of chloroglyoxal 3 to CO and formic acid 7 is 17.2 kcal/mol (n = 6), which is much higher than that of 6.3 kcal/mol (n = 7) for the reaction of chloroglyoxal 3 to intermediate 2-dihydroxyacetyl chloride 6, followed by C−C cleavage to form CO and formic acid 7 with an activation energy of 7.9 kcal/mol (n = 4). Besides, considering the steric and electronic effects, the pathway of 3 to 6 is also favorable. The formation of a diol destroys the conjugated structure of 3 and leads to the structure of a tetrahedral carbon that provides an easy cleavage of the C−C bond. These calculated results are well supported by classic organic reactions as well as abundant experimental data.41,42 Halogens are electronegative atoms and their attachment to the carbon atoms next to the carbonyl group can increase the extent of the hydration by the inductive effect, according to the number of halogen substituents and their electron-withdrawing power. They increase the polarization of the carbonyl group, which already has a positively polarized carbonyl carbon, and make it vulnerable to water attack. Since both the addition of water to a carbonyl functional group and the elimination of water from the resulting diol are fast, a rapid exchange of the oxygen isotope may occur to form formic acid with three 18O, which is shown in the H218O incorporation experimental data.18 Therefore, it is most likely

Figure 5. Relative energy profiles (in kcal/mol) obtained from the MP2/6-311G(d,p) calculations for the OHCCClO + nH2O→ OHCCOOH + HCl + (n − 1)H2O (3−5) (n = 1, 2, 3) reaction are shown. RC35n, TS35n, and PC35n represent the structures determined from the calculations, where 3 is OHCCClO, 5 is OHCCOOH, and n is the number of water molecules in the reaction.

energy barriers for the reaction decrease with an increasing number of water molecules (27.2 kcal/mol for n = 1, 18.5 kcal/ mol for n = 2, and 10.4 kcal/mol for n = 3). According to the mechanism, two water molecules are added in the pathway for forming glyoxylic acid 5. This is in good agreement with the product analysis and H218O incorporation results that 90% of OHCCOOH contained two 18O.18 B. Decomposition of Trichloroethylene Oxide to CO and Formic Acid. After the same ring-opening reaction of TCE oxide 1 to 2-chloro-2-hydroxyacetyl chloride 2, there are three possible pathways to form CO and formic acid 7. One pathway is 2 to chloroglyoxal 3, followed by decomposition of 3 to CO and 7 directly. The decomposition of 3 through intermediate 2-dihydroxyacetyl chloride 6 to CO and 7 is another possible pathway. It is also possible that the reaction pathway proceeds from 2 to CO and formyl chloride 4 that 1562



Article

Figure 7. Relative energy profiles (in kcal/mol) obtained from the MP2/6-311G(d,p) calculations for the OHCCClO + nH2O → HC(OH)2CClO + (n − 1)H2O (3−6) (n = 1, 2, 3, 4, 5, 6, 7) and HC(OH)2CClO + nH2O → HCOOH + CO + HCl + nH2O (6−7) (n = 1, 2, 3, 4) reactions are shown. RC36n, TS36n, PC36n, RC67n, TS67n, and PC67n represent the structures determined from the calculations, where 3 is OHCCClO, 6 is HC(OH)2CClO, 7 is HCOOH, and n is the number of water molecules in the reaction.

difference becomes smaller (from −0.278 to −0.171) as the number of cubic water molecules involved in the reaction systems increase. The lower charge transfer is consistent with a lower activation energy observed for the reaction system. Additionally, 2-chloro-2-hydroxyacetyl chloride 2 would also be able to cleave into CO and formyl chloride 4 directly. Our previous studies show a possible O−H insertion reaction of formyl chloride 4 in water to produce chloromethanoldiol (CHCl(OH)2) which can then proceed by decomposition into formic acid 7 and HCl.33 However, the activation energies in forming CO and HCl are lower than that of producing HCOOH and HCl.33 According to the H218O incorporation experiment, the O of CO is most likely from the epoxide rather than 4.18 Therefore, this pathway is not favored, which is consistent with the relative higher activation barriers compared with the other pathways. In summary, the predominant pathway is the ring-opening reaction of TCE oxide in the first step, and the 2-chloro-2hydroxyacetyl chloride 2 would then form chloroglyoxal 3, followed by decomposition to CO and formic acid 7 through the intermediate 2-dihydroxyacetyl chloride 6. By comparison of the activation energies for all of the possible pathways considered here, the ring-opening reaction of TCE oxide is found to be the rate-determining step. Our results are in good agreement with the experimental reports that the rate constant for the decomposition of TCE oxide (about 6.9 × 10−3 s−1) is slower than the rate constant for formation of CO (about 8.0 × 10−3 s−1) in aqueous solution.18 C. Decomposition of Trichloroethylene Oxide to Dichloroacetic Acid. Dichloroacetic acid is also an important product from the hydrolysis of TCE oxide. From the calculated results of the intramolecular rearrangement mechanism, the activation barrier is 48.6 kcal/mol and it is endothermic by 29.0 kcal/mol. Inspection of Figure 9 shows the process of this chloride shift. The distances between Cl and the two carbon atoms are 1.74 and 2.80 Å, while the distances between the O and the two carbon atoms on the epoxide are 1.40 and 1.43 Å. In the transition state, the chloride leaves both of the carbon atoms to the distance of 2.00 and 2.62 Å, respectively. One of

that most of chloroglyoxal 3 decomposes to CO and formic acid 7 through intermediate 2-dihydroxyacetyl chloride 6. To better understand the predominant pathway and how the water molecules assist the reaction, the structures presented in Figure 8 are chosen from those which give the lowest activation barriers among the different reactions involved in the reaction system. In the case of n = 1, 2, and 3, the reactions can be regarded as two-dimensional cyclic model reactions, in which all of the RC, TS, and PC have similar cyclic configurations. In the case of n = 4 and 5, the reactions can be regarded as the transition from the two-dimensional to the three-dimensional solvated reaction models, in which the TS and PC proceed to become cage-like three-dimensional structures. This process can be regarded as a partially solvated model reaction. In the case of n = 6 and 7, the reactions can be regarded as a fully solvated three-dimensional reaction systems (for the first water solvent shell), in which all of the RC, TS, and PC have cubic or cubic-like structures. The cubic-like water-solvated reaction model is the most efficient reaction pathway in a solution phase system.39,43,44 For the seven water molecule reactions, the seven water molecules occupy seven corners of the cube, while the O atom from chloroglyoxal 3 occupies the remaining corner. The cubic water cluster has been well studied both theoretically and experimentally, showing that the cubic cluster appears to be the most stable with a large binding energy per water molecule compared with those of hexamer and heptamer water clusters. The interactions of O from water molecules and C from chloroglyoxal substrate change from RC367 to TS367 with a difference of 0.65 Å. The elongation of the CO bond (by about 0.05 Å) would help to compensate for the energy required for partial cleavage of the H−O bond from another water molecule. In addition, the extensive hydrogen bonding in the cubic structure imposes a constraint on the structural changes that take place upon going from RC367 to TS367. This less flexible water-solvated cubic structure spreads the charge over the water cluster. This effect can be better understood by undertaking a charge distribution analysis, shown in Table 1S. From the charge difference between the transition states and the reaction complexes, there is a general trend that the charge 1563



Article

Figure 9. The optimized geometries (bond lengths are in Å) for all of the RC180, TS180, and PC180 obtained from the MP2/6-311G(d,p) calculations of the rearrangement mechanism for TCE oxide + nH2O → Cl2CHCClO + nH2O (1−8) (n = 0) reactions are shown.

Additionally, since the concentration of aqueous chloride is increased by chloride elimination during hydrolysis, the epoxide may be attacked by the chloride in solution. This is another possible pathway to produce Cl2CHCOOH. We built up the water cluster with seven water molecules involved in the reaction system as shown in Figure 10, and found the activation

Figure 10. The optimized geometries (bond lengths are in Å) for all of the RC187, TS187, and PC187 obtained from the MP2/6-311G(d,p) calculations of the chloride ion exchange mechanism for the TCE oxide + nH2O + Cl− → Cl2CHCClO + nH2O + Cl− (1−8) (n = 7) reactions are shown.

energy to be 12.3 kcal/mol. The water molecules are positioned around the oxygen atom of the epoxide and from there, they attack the chloride. This indicates that the increase in the number of water molecules enhances the hydrogen bonds for stabilization and these interactions also help to spread the charge over the whole water cluster. Epoxides behave as bases in the presence of catalytic quantities of halide ions, and the specific effects of the chloride ion on epoxides are well studied.45−47 The well-known epoxide formation from 2haloalcohols and hydroxide ions is a reversible reaction.46 The reversing hydroxyl bonding between O from epoxide and H from water molecule would assist the leaving of the chloride by chloride elimination to form dichloroacetyl chloride 8. After that, dichloroacetyl chloride 8 is expected to react rapidly with water to form dichloroacetic acid 9 and HCl. D. Discussion of the Water-Catalyzed HCl Elimination Model for Aqueous Decomposition of Polyhalogenated Epoxides. It is useful to compare our computed thermodynamic results, shown in Table 2S, to the experimental data available in the literature. For this comparison, the data set of the MP2/6-311G(d,p) and B3LYP/6-311G(d,p) computational results are used to estimate the rate constant kn using Eyring’s equation. Our calculation results predict the rate constant for the decomposition of TCE oxide to be 127.90 s−1 by MP2 and 1.7 × 107 s−1 by B3LYP, which are smaller than the pH-independent rate constant for the formation of CO and formic acid 7. This implies that the first step of the TCE oxide ring-opening is the rate-determining step for CO formation. According to the experimental results, the decomposition of TCE oxide with the rate constant of 6.9 × 10−3 s−1 is also smaller than the rate constant for CO formation with 8.0 ×

Figure 8. The optimized geometries (bond lengths are in Å) for all of the RC36n, TS36n, and PC36n obtained from the MP2/6-311G(d,p) calculations for the OHCCClO + nH2O → HC(OH) 2CClO + (n − 1)H2O (3−6) (n = 1, 2, 3, 4, 5, 6, 7) reactions are shown.

the C−O bonds is elongated by 0.79 Å, while simultaneously, the other is shortened by 0.17 Å to form CO from RC to TS. Despite extensive efforts, an optimized transition state with incorporation of one water molecule into the reaction could not be found. From previous theoretical investigations, it is expected to be more thermodynamically favorable than the waterless pathway. However, it is also reasonable that the chloride would be stabilized by water molecules to cause O−H insertion on TCE oxide during the zwitterionic transition state. 1564



Article

10−3 s−1 within the pH range 0−14. To compare with the experimental value, the calculated rate constants have to be convert to the “effective rate constants” Kn by the expression Kn = kn × [(H2O)n], where [(H2O)n] represents the water cluster concentration. The chance of several water molecules colliding together to initiate the reaction is rare. Therefore, the probability of the formation of the water clusters before reacting with TCE oxide is critical for the water-assisted reaction to proceed. Additionally, the discrepancy between simulated and experimental value is probably due to the interpretation of the experimental rate constant and an insufficient representation of a more accurate model of the actual cooperative hydrogen bond system. The experimental reaction rate reflects the overall effect of all of the reaction pathways in the system. As shown in Figure 1S and Figure 2S, a similar catalysis trend is observed by using M06-2X/311+ +G(2df,2pd) and B3LYP/6-311G(d,p). Most of the energies computed are lower than the energies obtained from the MP2 calculations as the DFT level of theory usually underestimates weak hydrogen bond interactions. However, the overall trend of the B3LYP calculations behaves similarly to the results of the MP2 calculations. Therefore it is still an alternative method to save computational cost. Our results indicate that water molecules catalyze the TCE oxide decomposition via assistance to the intermediates, for which decomposition rates become greater in aqueous solution. Computations focused on explicitly coordinated water molecules as well as bulk water in the system were used to obtain decomposition rates for TCE oxide. These results were found to be in excellent agreement with the experimental data from the literature. During the HCl elimination of TCE oxide, water catalysis occurs by a simultaneous proton transfer via the water molecules and solvation of the leaving Cl atom of the molecular species by H−Cl interactions with the water solvent molecules. Thus, the water assisted HCl dissociation promotes the elimination of HX (X = Cl, Br, I), which is exothermic in aqueous environments. This allows cleavage of the O−H and C−Cl bonds in all of the intermediates with low barriers in aqueous solution. Since C−Br and C−I bonds are weaker than the C−Cl bond and the HX dissociation processes in aqueous solution are similar, we believe that this type of hydrolysis might be a general phenomena for the HX elimination reactions of halocarbons in aqueous environments. On the basis of literature results, we expect that this type of water catalysis will also occur in HX elimination reactions of other molecules which may be subjects of further investigations.

aqueous solutions as well as previous theoretical studies on water clusters and water-assisted dehalogenation reactions of other systems. Our present results provide new insight into the decomposition of TCE oxide in aqueous solutions and may be useful for future investigations on TCE oxide in the environment and in designing methods to minimize the impact of environmental pollution related to the TCE family of molecules. Our present results also have some interesting implications for the risk assessment of TCE and its metabolites. As is known, carcinogenesis is a complex pathological process and this process is associated with chemical modifications of DNA involving a series of chemical reactions. The direct toxicological risk from TCE oxide may be low because of the rapid hydrolysis. One of the major intermediates, chloroglyoxal 3, may be responsible for the irreversible binding to proteins and DNA during the metabolism of TCE, which requires further investigation. In many of the experimental cases this process is unstable and difficult to detect.12,13 It is therefore a major challenge to understand and model these processes.

■

ASSOCIATED CONTENT

S Supporting Information *

Relative energy profiles (in kcal/mol) obtained from the M062X/6-311++G(2df,2pd) and B3LYP/6-311G(d,p) calculations for the TCE oxide + nH2O → ClCH(OH)CClO + HCl + (n-1) H2O (1−2) (n = 1, 2, 3, 4, 5, 6, 7) reaction are shown. Relative energy profiles (in kcal/mol) obtained from the B3LYP/6311G(d,p) calculations using IEFPCM for reactions 1−2 are shown. NBO Charges on the O Atom for reactions 3−6 are presented. B3LYP/6-311G(d,p) energies (ΔE‡, kcal/mol), enthalpies (ΔH‡, kcal/mol), free energies (ΔG‡, kcal/mol), entropies (ΔS‡, kcal/mol), zero-point energies(ΔZPE, kcal/ mol), rate constants (k1, s−1), and MP2/6-311G(d,p) calculated rate constants (k2, s−1) for reactions 1−2 are presented. The Cartesian coordinates of the stationary points of reaction 1−2 and reactions 3−6 with B3LYP/6-311(d,p) calculation are provided. The full versions of the Gaussian program suite are given. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

■

The authors declare no competing financial interest.

■

CONCLUSIONS An ab initio and DFT study of TCE oxide dehalogenation in the presence of water has been presented. Up to seven water molecules were explicitly included in the reaction systems to investigate the effect of hydrogen bonding from the water molecules on the reaction steps of interest. The decomposition reaction of TCE oxide was found to be remarkably catalyzed by the presence of water molecules and the decomposition rate becomes faster as the number of water molecules involved in the reaction system increased. This computational study indicates that water molecules help to solvate TCE oxide and facilitate the release of the solvated Cl− leaving group. The computational results found here for the decomposition of TCE oxide in the presence of water were briefly discussed in relation to previous literature reports including a recent experimental study on the decomposition of TCE oxide in

ACKNOWLEDGMENTS This work was supported by a grant from the Research Grants Council of Hong Kong (HKU 7035/13P) and the University Grants Committee Special Equipment Grant (SEG-HKU-07) to D.L.P. Support from the University Grants Committee Areas of Excellence Scheme (AoE/P-03/08) is also gratefully acknowledged.

■

REFERENCES

(1) Fontana, E.; Dansette, P. M.; Poli, S. M. Cytochrome P450 Enzymes Mechanism Based Inhibitors: Common Sub-Structures and Reactivity. Curr Drug Metab. 2005, 6, 413−454. (2) Miller, R. E.; Guengerich, F. P. Oxidation of Trichloroethylene by Liver Microsomal Cytochrome P-450: Evidence for Chlorine Migration in a Transition State not Involving Trichloroethylene oxide. Biochemistry 1982, 21, 1090−1097.

1565



Article

(3) RajanBabu, T. V.; Nugent, W. A. Selective Generation of Free Radicals from Epoxides Using a Transition-Metal Radical. A Powerful New Tool for Organic Synthesis. J. Am. Chem. Soc. 1994, 116, 986− 997. (4) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Asymmetric Catalysis with Water: Efficient Kinetic Resolution of Terminal Epoxides by Means of Catalytic Hydrolysis. Science 1997, 277, 936−938. (5) Trost, B. M. Atom EconomyA Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way. Angew. Chem., Int. Ed. Engl. 1995, 34, 259−281. (6) Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley: Weinheim/Chichester, 2006; p 1. (7) Ou, J. S.; Ou, Z. J.; McCarver, D. G.; Hines, R. N.; Oldham, K. T.; Ackerman, A. W.; Pritchard, K. A. Trichloroethylene Decreases Heat Shock Protein 90 Interactions with Endothelial Nitric Oxide Synthase: Implications for Endothelial Cell Proliferation. Toxicol. Sci. 2003, 73, 90−97. (8) Yoshioka, T.; Cai, H. L.; Guengerich, F. P. Reaction of Trichloroethylene and Trichloroethylene Oxide with Cytochrome P450 Enzymes: Inactivation and Sites of Modification. Abstr. Pap. Am. Chem. Soc. 2001, 222, 299. (9) Parker, R. E.; Isaacs, N. S. Mechanisms of Epoxide Reactions. Chem. Rev. 1959, 59, 737−799. (10) Uehleke, H.; Poplawski, S.; Bonse, G.; Henschler, D. Spectral Evidence for 2,2,3-Trichloro-Oxirane Formation during Microsomal Trichloroethylene Oxidation. Xenobiotica 1977, 7, 94−95. (11) Gist, G. L.; Burg, J. R. Trichloroethylene - A Review of the Literature from a Health-Effects Perspective. Toxicol. Ind. Health 1995, 11, 253−307. (12) Cai, H. L.; Guengerich, F. P. Acylation of Protein Lysines by Trichloroethylene Oxide. Chem. Res. Toxicol. 2000, 13, 327−335. (13) Cai, H. L.; Guengerich, F. P. Reaction of Trichloroethylene Oxide with Proteins and DNA: Instability of Adducts and Modulation of Functions. Chem. Res. Toxicol. 2001, 14, 54−61. (14) Kline, S. A.; Solomon, J. J.; Van Duuren, B. L. Synthesis and Reactions of Chloroalkene Epoxides. J. Org. Chem. 1978, 43, 3596− 3600. (15) Henschler, D.; Hoos, W. R.; Fetz, H.; Dallmeier, E.; Metzler, M. Reactions of Trichloroethylene Epoxide in Aqueous Systems. Biochem. Pharmacol. 1979, 28, 543−548. (16) Byington, K. H.; Leibman, K. C. Metabolism of Trichloroethylene in Liver Microsomes. II. Identification of the Reaction Product as Chloral Hydrate. Mol. Pharmacol. 1965, 1, 247−54. (17) Liebler, D. C.; Guengerich, F. P. Olefin Oxidation by Cytochrome P-450: Evidence for Group Migration in Catalytic Intermediates Formed with Vinylidene Chloride and Trans-1-phenyl1-butene. Biochemistry 1983, 22, 5482−5489. (18) Cai, H.; Guengerich, F. P. Mechanism of Aqueous Decomposition of Trichloroethylene Oxide. J. Am. Chem. Soc. 1999, 121, 11656−11663. (19) Antoniotti, S.; Antonczak, S.; Golebiowski, J. Acid-Catalysed Oxidative Ring-Opening of Epoxide by DMSO. Theoretical Investigation of the Effect of Acid Catalysts and Substituents. Theor. Chem. Acc. 2004, 112, 290−297. (20) Muniz, R. C. D.; de Sousa, S. A. A.; Pereira, F. D.; Ferreira, M. M. C. Theoretical Study of Acid-Catalyzed Hydrolysis of Epoxides. J. Phys. Chem. A 2010, 114, 5187−5194. (21) Sayer, J. M.; Yagi, H.; Silverton, J. V.; Friedman, S. L.; Whalen, D. L.; Jerina, D. M. Conformational Effects in the Hydrolyses of Rigid Benzylic Epoxides: Implications for Diol Epoxides of Polycyclic Hydrocarbons. J. Am. Chem. Soc. 1982, 104, 1972−1978. (22) Santosusso, T. M.; Swern, D. Chemistry of epoxides. XXXI. Acid-Catalyzed Reactions of Epoxides with Dimethyl Sulfoxide. J. Org. Chem. 1975, 40, 2764−2769. (23) Borosky, G. L. Theoretical Study Related to the Carcinogenic Activity of Polycyclic Aromatic Hydrocarbon Derivatives. J. Org. Chem. 1999, 64, 7738−7744.

(24) Vijayalakshmi, K. P.; Mohan, N.; Ajitha, M. J.; Suresh, C. H. Mechanism of Epoxide Hydrolysis in Microsolvated Nucleotide Bases Adenine, Guanine and Cytosine: A DFT Study. Org. Biomol. Chem. 2011, 9, 5115−5122. (25) Yeung, C. S.; Ng, P. L.; Guan, X.; Phillips, D. L. Water-Assisted Dehalogenation of Thionyl Chloride in the Presence of Water Molecules. J. Phys. Chem. A 2010, 114, 4123−4130. (26) Kwok, W. M.; Zhao, C.; Li, Y.-L.; Guan, X.; Wang, D.; Phillips, D. L. Water-Catalyzed Dehalogenation Reactions of Isobromoform and Its Reaction Products. J. Am. Chem. Soc. 2004, 126, 3119−3131. (27) Chu, J. W.; Trout, B. L. On the Mechanisms of Oxidation of Organic Sulfides by H2O2 in Aqueous Solutions. J. Am. Chem. Soc. 2004, 126, 900−908. (28) Nguyen, M. T.; Raspoet, G.; Vanquickenborne, L. G.; VanDuijnen, P. T. How Many Water Molecules are Actively Involved in the Neutral Hydration of Carbon Dioxide? J. Phys. Chem. A 1997, 101, 7379−7388. (29) Vilotijevic, I.; Jamison, T. F. Epoxide-Opening Cascades Promoted by Water. Science 2007, 317, 1189−1192. (30) Clark, T.; Hennemann, M.; Murray, J.; Politzer, P. Halogen Bonding: The σ-Hole. J. Mol. Model. 2007, 13, 291−296. (31) Alkorta, I.; Elguero, J. Non-Conventional Hydrogen Bonds. Chem. Soc. Rev. 1998, 27, 163−170. (32) Zhao, Y.; Truhlar, D. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−241. (33) Phillips, D. L.; Zhao, C.; Wang, D. A Theoretical Study of the Mechanism of the Water-Catalyzed HCl Elimination Reactions of CHXCl(OH) (X = H, Cl) and HClCO in the Gas Phase and in Aqueous Solution. J. Phys. Chem. A 2005, 109, 9653−9673. (34) da Silva, J. B. P.; Silva, M. R.; Ramos, M. N. Hydrogen Bonds Between Pyrazine and HX Linear Acids (X = F, NC, CN and CCH): A Theoretical Study. J. Brazil. Chem. Soc. 2005, 16, 844−850. (35) Halkier, A.; Klopper, W.; Helgaker, T.; Jorgensen, P.; Taylor, P. R. Basis Set Convergence of the Interaction Energy of HydrogenBonded Complexes. J. Chem. Phys. 1999, 111, 9157−9167. (36) Del Bene, J. E. Hydrogen Bonding: Methodology and Applications to Complexes of HF and HCl with HCN and CH3CN. Int. J. Quantum Chem. 1992, 44, 527−541. (37) Thomas, C. R.; Hose, G. C.; Warne, M. S.; Lim, R. P. Effects of River Water and Salinity on the Toxicity of Deltamethrin to Freshwater Shrimp, Cladoceran, and Fish. Arch. Environ. Contam. Toxicol. 2008, 55, 610−8. (38) Ignatov, S. K.; Sennikov, P. G.; Razuvaev, A. G.; Schrems, O. Ab-initio and DFT Study of the Molecular Mechanisms of SO3 and SOCl2 Reactions with Water in the Gas Phase. J. Phys. Chem. A 2004, 108, 3642−3649. (39) Sadlej, J.; Buch, V.; Kazimirski, J. K.; Buck, U. Theoretical Study of Structure and Spectra of Cage Clusters (H2O)(n), n = 7−10. J. Phys. Chem. A 1999, 103, 4933−4947. (40) Okumoto, S.; Yamabe, S. A Computational Study of BaseCatalyzed Reactions between Isocyanates and Epoxides Affording 2Oxazolidones and Isocyanurates. J. Comput. Chem. 2001, 22, 316−326. (41) Clayden, J. Organic Chemistry; Oxford University Press: Oxford/ New York, 2001; p 1508. (42) Clayden, J.; Greeves, N.; Warren, S. G. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford/New York, 2012; p 1234. (43) Lee, H. M.; Suh, S. B.; Lee, J. Y.; Tarakeshwar, P.; Kim, K. S. Structures, Energies, Vibrational Spectra, and Electronic Properties of Water Monomer to Decamer. J. Chem. Phys. 2001, 114, 3343−3343. (44) Gruenloh, C. J.; Carney, J. R.; Hagemeister, F. C.; Zwier, T. S.; Wood, J. T.; Jordan, K. D. Resonant Ion-Dip Infrared Spectroscopy of Benzene−(Water)9: Expanding the Cube. J. Chem. Phys. 2000, 113, 2290−2303. (45) Whalen, D. L.; Ross, A. M. Specific Effects of Chloride Ion on Epoxide Hydrolysis. The pH-Dependence of the Rates and 1566



Article

Mechanisms for the Hydrolysis of Indene Oxide. J. Am. Chem. Soc. 1976, 98, 7859−7861. (46) Buddrus, J. Basic Behavior of Epoxides in the Presence of Halide Ions. Angew. Chem., Int. Ed. Engl. 1972, 11, 1041−1050. (47) Ross, A. M.; Pohl, T. M.; Piazza, K.; Thomas, M.; Fox, B.; Whalen, D. L. Vinyl Epoxide Hydrolysis Reactions. J. Am. Chem. Soc. 1982, 104, 1658−1665.

1567


A Computational Chemistry Investigation of the Mechanism of the

Recommend Documents