Ligand Exchanges and Hydroxypalladation Reactions of the Wacker

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Ligand Exchanges and Hydroxypalladation Reactions of the Wacker Process in Aqueous Solution at High Cl- Concentration Nisanth N. Nair Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India ABSTRACT: Reaction mechanisms and associated free energies of various reaction steps involved in the Wacker process in aqueous acidic conditions at high Cl- concentration were investigated using accelerated ab initio molecular dynamics techniques. Several ligand exchange reactions of the catalytic precursor [PdCl4]2- and nucleophilic attack of water at Pdcoordinated ethene (hydroxypalladation) were looked at in great molecular level detail. This work underlines the key role of the trans effect of Pd-coordinated ethene in the structure and dynamics of solvated Pd(II) complexes. Irrespective of Cl or water ligation at the trans position, the hydroxypalladation proceeds through an anti mechanism where an outer-sphere water attacks an ethene carbon atom in an anti fashion. Extensive molecular dynamics simulations were used to analyze various reaction mechanisms and unravel the stereochemistry of the crucial hydroxypalladation step.

1. INTRODUCTION The Wacker reaction involves oxidization of an olefin to carbonyl compounds by reaction with water in the presence of a PdCl2/CuCl2 catalyst mixture and an oxidizing agent under acidic aqueous conditions.1-3 This reaction remains as a classic textbook example of dual catalysis and catalyst regeneration.1,4 Improvised and original Wacker-type oxidation reactions are still used in industrial and laboratory chemistry, including total synthesis of natural products.5-8 There are three main steps for the Wacker process in the oxidation of ethene: (a) under acidic aqueous conditions, ethene reacts with a Pd(II) salt, giving acetaldehyde, Pd(0), and two protons; (b) reoxidation of Pd(0) coupled with the reduction of Cu(II) to Cu(I); (c) reoxidation of Cu(I) to Cu(II) salt by molecular oxygen. See Figure 1 for an overview on the mechanism. In the mechanistic scheme in Figure 1, and in the reactions followed in this work (see Figure 2), [PdIICl4]2- is taken as the catalyst precursor. Reaction steps involved in the formation of acetaldehyde begin with the ligand exchange of Pd(II)-coordinated chloride ions by ethene (or any primary olefin) and solvent water molecules. Subsequently, a nucleophilic attack of water takes place at the coordinated ethene. After some steps of H rearrangements, 6 is formed and release of acetaldehyde follows, with the reduction of Pd(II) to Pd(0). The latter is then oxidized back to Pd(II) coupled with the reduction of Cu(II) to Cu(I). Several theoretical9-17 and experimental18-21 works in the literature were dedicated to scrutinizing the mechanistic aspects of the Wacker reaction; see also refs 5 and 8 for more related review and references. Although there is a consensus in the general characteristics of the Wacker reaction, the precise mechanistic details are still under debate. In particular, the detailed mechanism of hydroxypalladation (step C) in which r 2011 American Chemical Society

the nucleophilic addition of water occurs remains as a matter of discussion.22 This particular step can proceed via an anti or outersphere addition of water to alkene:

Alternatively, a syn or inner-sphere addition of hydroxide to alkene could also take place:

It is now believed that anti vs syn mechanisms compete with each other, and the preference of one over the other depends on the reaction conditions, chiefly on [Cl-] and [CuCl2]. Kinetic and stereochemical studies have prompted the syn route at low [Cl-] and [CuCl2]23 and the anti route at high [Cl-] and [CuCl2];21,24,25 see also ref 18. Under the above extreme conditions, the rate expressions derived are also different. Most of the theoretical works have performed gas-phase computations of the reaction mechanism and energy barriers and concluded that the free energy barrier for the anti route is Received: October 24, 2010 Revised: December 14, 2010 Published: February 18, 2011 2312

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The Journal of Physical Chemistry B lower than that for the syn route. Siegbahn13 noted the importance of accounting for finite solvent effects in the theoretical models used for computations of the Wacker reaction. Using a finite water cluster model, he concluded that a chain of (at least

Figure 1. Reaction scheme for the Wacker process. Reprinted with permission from ref 5. Reverse arrows are avoided for clarity. The dotted line for step G includes the oxidation of Pd(0) by CuCl2 and is not elaborated here. The pink shaded area within the thin dotted lines highlights the reaction steps (A-C) investigated in the present work.

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three) water molecules bridging the negative Cl- ion and the point of attack on the olefin14 has to be used. Recently, Goddard and co-workers26 have found that the free energy barrier(s) for hydroxypalladation along the cis route is lower than that of the anti route, but only marginally. More interestingly, while including the CuCl2 interactions with the Pd complex, they have observed the prevalence of the anti route over the syn addition. Thus, their computations agree with the experimental observations related to concentration dependence on the stereochemistry of hydroxypalladation. All previous calculations on this topic used static methods with or without including a few explicit water molecules and/or incorporating the solvent effects by implicit models. As solvent directly participates in the chemical reaction steps of the Wacker process, it is, however, crucial to consider the solvent explicitly. The stabilization energies of charge-separated structures by solvation (as in the bulk) contribute substantially to the free energies. To a much larger extent, the dynamics of the water molecules, thereby entopic effects, have to be taken into account. It is noted in passing that it is not only the vibrational contributions to entropy that are crucial in condensed matter systems, but also the dynamics of the solvation shells, attachment/detachment dynamics of water at the axial coordination sites of the planar Pd complex, and structure/dynamics of H3Oþ/OH-. Thus, a proper treatment requires a periodic box with several water molecules simulating a bulk water environment and their dynamics at finite temperature. Ab initio molecular dynamics27

Figure 2. Detailed reaction steps followed in this work and associated free energy barriers (kJ/mol). Numbers assigned for structures are written in bold, while the numbers (in blue) above the arrows are the estimated free energy barriers. Some reaction pathways are marked with “” (in red), showing them inaccessible on the basis of structural and energetic reasons. 2313

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The Journal of Physical Chemistry B enables one to simulate such complex chemical reactions in silico while explicitly incorporating the solvent effects and dynamics. During the last stages of preparing this paper, another work28 was reported on the stereochemistry of nucleophilic addition of water at low [Cl-] using ab initio molecular dynamics simulations. This work is discussed in the Discussion and Conclusions. Other than that, no ab initio molecular dynamics simulation investigation has been reported in finding the mechanism and free energy barriers of the Wacker process. The aim of the current study is to investigate some crucial reaction steps of the Wacker process at aqueous acidic conditions and high [Cl-] using reactive ab initio molecular dynamics techniques.27 Finite solvent and temperature effects as in a true condensed matter environment are included in the calculations. The mechanisms and associated free energies of all the steps involved in ethene and water ligand exchange reactions in the [PdIICl4]2- catalyst precursor and the nucleophilic attack of a water molecule at Pd-coordinated ethene are presented; i.e., steps A-C in Figure 1.

2. METHODS AND MODELS To obtain the detailed mechanism and free energies associated with steps A-C, a metadynamics technique29,30 in the framework of ab initio molecular dynamics27 is employed. The metadynamics technique is helpful for an unbiased sampling of the underlying free energy surfaces of chemical reactions, thereby obtaining reaction mechanisms along the minimum free energy pathway; for details see reviews in refs 31-33. All computations in this work were performed using planewave periodic density functional theory (DFT) with its pseudopotential formalism27 as implemented in the CPMD34 program package. The PBE35 exchange-correlation functional was used together with ultrasoft pseudopotentials36 with a plane-wave cutoff of 30 Ry. Fictitious masses for the orbitals were set to 700 au, and a molecular dynamics time step of 0.145 fs was used in all the simulations. To have stable Car-Parrinello dynamics by maintaining an adiabatic separation between nuclear and orbital degrees of freedom, hydrogen masses in the system were substituted by deuterium masses. Nose-Hoover chain thermostats37 were used for both nuclei and electronic orbitals. To model the bulk-water system, 32 water molecules were taken in a periodic supercell of size 10.0 Å 10.0 Å 10.0 Å, roughly reproducing the density of water at ambient conditions. For constructing the initial configuration of step A, three water molecules were replaced by [PdCl4]2-, one Hþ, and a CH2d CH2 entity. The starting structure in the metadynamics simulation for reaction step A was obtained after 2 ps of equilibration, thermalizing each degree of freedom at 300 K by coupling them with individual Nose-Hoover chain thermostats. In the case of steps B and C, the starting structures were taken from the metadynamics trajectory of A and B, respectively. The released Cl- in step A was removed before the simulation of step B was started. In all other cases, the expelled Cl- ions were maintained while the subsequent reaction steps were started. This way, effectively a high [Cl-] is created in the simulation. An extended Lagrangian-type metadynamics procedure30 was used for the presented calculations. The metadynamics technique enhances the exploration of the system on a free energy landscape constructed along a selected set of collective coordinates that are analytical functions of the nuclear coordinates. Accelerated exploration is achieved by slowly growing repulsive potentials along the trajectory of a set of auxiliary variables (or

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collective variables), which are coupled strongly to the collective coordinates by a harmonic potential. Four different types of collective coordinates were used in this work. The coordination number between two atom types, A and B, is defined by C½A - B ¼

XX

cðI - JÞ

ð1Þ

I ∈AJ ∈B

where cðI - JÞ ¼

0 1 - ðRIJ =RA-B Þp 0 1 - ðRIJ =RA-B Þp þ q

ð2Þ

Here RIJ is the distance between atoms I and J belonging to atom types A and B, respectively, and R0A-B is a cutoff bond distance parameter depending on atom types A and B. In eq 2, p and q are constant even integer numbers, and their values were set to 6 and 6, respectively, to achieve appropriate smoothness for the function c(I-J). For each pair of atoms I and J, the function c(I-J) is nearly 1.0 when the bond distance RIJ < R0A-B and is nearly 0.0 when RIJ > R0A-B. Another type of collective coordinate used is an associated coordination number, CA[A-B-C], defined as CA ½A - B - C ¼

XX I ∈AJ ∈B

cðI - JÞ

X

cðJ - KÞ

ð3Þ

K∈C

where c(I-J) is defined according to eq 2 and the indices I, J, and K run over all atoms of types A, B, and C, respectively. The above equation is a conditional sum since both c(I-J) and c(J-K) have to be nonzero to have a nonzero contribution from a given I, J, and K. The third type of collective coordinate used in this work is the distance between two atoms: d½A - B ¼ jRA - RB j

ð4Þ

A distance difference collective coordinate, Δd, was also used, where Δd[A-B-C] = d[A-B] - d[B-C]. More details of the collective coordinates will be discussed while the results are presented in the next section (wherever necessary). The choice of metadynamics parameters is now discussed. The coupling constant in the harmonic potential of the metadynamics Hamiltonian30 for C[A-B] and CA[A-B-C] was 2.0 au, and that for d[A-B] and Δd[A-B-C] was 0.4 au. Masses for all the collective variables were assigned as 50.0 amu. Repulsive potentials were in the form of spherical Gaussian functions with their heights varied between 1 and 2 kBT depending on the extend of the reaction, while the width parameter was fixed to a constant value of 0.05. To avoid “hill surfing” problems,38 Gaussians were added only when the displacement from the previous Gaussian center was more than or equal to 0.075. The fictitious kinetic energy of the collective variables was kept within a temperature window of (200 K from the target temperature of 300 K using velocity scaling. Free energy surfaces were constructed by the negative sum of all the deposited Gaussian potentials. The minium energy path (MEP) was obtained after this procedure, and the structures along the minimum energy path are used to elucidate the reaction mechanism. Further refined free energy values are conceivable by performing umbrella sampling with overlapping windows along the MEP that is rendered by metadynamics. 38 Alternatively, a transition-state sampling39 approach can be used to refine the 2314


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obtained reaction pathways and free energies.40 However, these procedures are computationally intensive for complex free energy landscapes and the large number of reaction steps studied here and are thus not employed. For the metadynamics setup employed here, an error of about (2kBT41 is expected in the free energy estimates.

3. RESULTS All the reaction steps investigated in this work are given in Figure 2, together with the corresponding free energy barriers. Labeling for various structures is followed from Figures 1 and 2. 3.1. Step A: Cl- Exchange by Ethene in [PdCl4]2-. The first step of the Wacker reaction involves the replacement of one of the chlorine atoms from the coordination sphere of Pd by ethene. For simulating this reaction, the [PdCl4]2- and ethene in water system was prepared and equilibrated for nearly 2 ps. This was followed by metadynamics simulation using two reaction coordinates: (a) coordination number of Pd to ethene carbon atoms, C[Pd-C]; (b) coordination number of Pd to all Cl atoms in the system, C[Pd-Cl]. The coordination number is defined using eq 1 with cutoff distance R0Pd-C = 2.6 Å and R0Pd-Cl = 2.9 Å, as required by the first and second collective coordinates, respectively. The coordination number spans over all the Cl atoms equally, and thus, a particular Cl atom need not be selected in advance for simulating the exchange reaction. In the simulation, it was observed that ethene approaches the complex along the axial direction. In the transition-state structure, ethene is semiaxial and tilted toward a Cl which was exchanged with ethene subsequently. The expelled Cl is also semiaxial in the transition-state structure; see 1* in Figure 3. Successively, Cl- detaches along the axial position, and ethene approaches the equilibrium structure nearly simultaneously with the C-C bond aligned perpendicular to the PdCl 3 plane. This reaction is nearly an SN2 type, which is also obvious from the topology of the reconstructed free energy surface (Figure 3). The forward barrier going from 1 to 2 is 45 kJ/mol. It is also clear from Figure 3 that the product 2 is more stable than the reactant. The reverse barrier for 2 f 1 cannot be obtained from this simulation as the calculation was not continued until a 2 f 1 transition was observed. However, it can be predicted that the reverse barrier is larger than 65 kJ/mol. In the last part of this metadynamics run, it was also seen that the eliminated Cl- exchanges with another coordinated Cl-. This exchange happens after the approach of the Cl- along the axial position of the Pd complex. The exchanged Cl- was trans to ethene within the complex. This is expected due to the strong trans effect of the ethene moiety.42 3.2. Step B: Cl- Exchange by Bulk Water in [Pd(Cl3) (CH2dCH2)]-. In this particular step, one of the three chloride

ions will be replaced by a solvent water molecule. The starting structure was 2, and the end product can be either 3.1 or 3.10 . In the first set of metadynamics simulations performed, the following collective coordinates were used: (a) coordination number of all three Cl- ions to Pd, C[Pd-Cl], and (b) coordination number of all oxygen atoms in the system to Pd, C[Pd-Owat]. The coordination numbers were defined using eq 1 with both R0Pd-Cl and R0Pd-O set to 2.9 Å. It is stressed here that the coordination number gives the flexibility that one particular Cl- or water molecule need not be selected prior to the simulation, but it includes all Cl- or water molecules equally.

Figure 3. (a) Reconstructed free energy surface and snapshots from trajectories for the reaction 1 f 2 (step A). See Figure 2 for labeling. Color code of atoms: brown (Pd), green (Cl), black (C), red (O), and white (H). (b) Free energy profile (kJ/mol) for the reaction based on the reconstructed free energy landscape.

Such general definition is crucial for a correct incorporation of entropic effects. With the current set of collective coordinates, a cis or trans (to ethene) Cl- could be exchanged with a bulk water molecule, resulting in 3.10 or 3.1 depending on the lowest free energy pathway. In the metadynamics simulation, the trans-Cl- was first replaced by water. The exchanged water molecule approached axially and weakly bound to Pd. The positions of this water oxygen and the detaching trans-Cl along the reactive trajectory 2315



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Figure 4. Reconstructed free energy surface and snapshots from trajectories of the reaction 2 f 3. (b) Positions of O of the reacting water (small glossy spheres) and the expelled Cl- (big glossy spheres) along the reactive trajectory. The color of these O and Cl spheres varies from red to gray to blue with increasing extent of reaction. Other solvent water molecules are excluded for clarity. (c) Reconstructed free energy surface of cis-Cl exchange in 3 by a solvent water (3 f 3.1). (d) Free energy profile (kJ/mol) for 2 f 3 f 3.1. See Figure 2 for labeling and Figure 3 for atom color codes.

are mapped in Figure 4b. This figure clearly indicates that the water oxygen bends toward the trans position once axially coordinated to Pd, simultaneously pushing the trans-Cl below the PdCl3 plane. This is also obvious from the transition-state structure 2* in Figure 4a.

The free energy surface obtained from this simulation is given in Figure 4a. The exchange of trans-Cl- with a bulk water molecule has to surmount a free energy barrier of about 60 kJ/ mol. In our simulations, a reverse reaction is also observed, and thus, the reverse barrier for the replacement of coordinated trans2316



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Figure 5. (a) Reconstructed free energy surface of deprotonation of the cis-water of 3.1 by a solvent water molecule. (b) Free energy profile (kJ/mol) for 3.1 f 3.2. See Figure 2 for labeling and Figure 3 for atom color codes.

water by Cl- (3 f 2) can be estimated. The reverse free energy barrier is nearly twice as high as the forward barrier. It is interesting to note that the minimum energy path goes via a high-energy basin which is about 30 kJ/mol higher than the reactant state. This intermediate state corresponds to the axially water coordinated complex. Due to the fact that there is no effective reverse free energy barrier, it immediately dissociates back to the reactant well of 2. Again, the observation of water exchange at the trans position (to ethene) is not surprising because of the strong trans effect of ethene and is in agreement with the experimental works on exchange reactions in Zeise’s salt.42 To confirm the fact that the free energy required to replace a cis-Cl- is larger than that of a trans-Cl-, another metadynamics simulation was launched where the same collective coordinates were used as before, except modifying the first collective coordinate by excluding the trans-Cl atom. It was expected that the cis-Cl ions would only be replaced by water; thus, the free energy barrier for this process can be estimated. However, in the simulations, the trans-Cl was first replaced by bulk water and followed by the cis-Cl atom. This implies that 2 f 3.1 goes through 3. To have a proper estimation of the free energy barriers for 3 f 3.1, another metadynamics simulation was carried out starting with 3. The collective coordinates were C[Pd-Cl] and C[Pd-Owat] as discussed above. From this simulation it was quantified that the replacement of cis-Cl in 3 requires a free energy barrier of about 125 kJ/mol to be overcome; see Figure 4c. It was also noticed that, during this exchange process, the Pd-Clcis bond breaks away (distance Pd-Cl > 3 Å), and then water attacks in a subsequent step, unlike in a simultaneous manner as in the case of trans-Cl exchange. Whenever a water approaches along the axial position, it bends toward the trans-water and undergoes exchange with the latter. This exchange process results in a broad

free energy well for 3 in Figure 4c. Since the approaching water molecule prefers to exchange with the trans-water rather than the cis-Cl, the free energy barrier for 3 f 3.1 has large entropic contributions, thus resulting in high free energy barriers. 3.3. Step C: Nucleophilic Attack of Water on Ethene. At this point it is clear that water exchange with the cis-Cl is not an energetically preferred route. However, if a cis-water has to attack ethene along the syn route, a cis-Cl has to be exchanged with water. Thus, for verifying the mechanism and free energy barriers of cis-water attack, a simulation was commenced starting with the 3.1 structure irrespective of the large free energy barriers involved in its formation. 3.3.1. Deprotonation of cis-Water. Before simulation of the syn water attack, the deprotonation of the cis-water was looked at. This is important because the syn type of water attack may involve the deprotonation of cis-water as the first step. The starting structure of this simulation was 3.1, and the chosen collective coordinates were (a) the coordination number of ciswater O to all H atoms, C[Ocis-H], and (b) the distance between Pd and cis-water O, d[Pd-Ocis]. A hard-wall potential was applied to the second collective coordinate at 2.5 Å so that the water coordinated with Pd was not allowed to leave the coordination sphere. The cutoff distance R0O-H used for the first collective coordinate is 1.6 Å. Deprotonation of cis-water was simulated successfully in the metadynamics simulations. Deprotonation occurs by a proton transfer to the bulk solvent water. A reconstructed free energy plot (Figure 5) shows that the free energy barrier for deprotonation of cis-water in 3.1 is only about 25 kJ/mol. However, there is essentially no reverse barrier for the reprotonation of the cishydroxyl group in 3.2, so it reverts back to 3.1. This implies that 3.2 occurs only as a transient structure while going from 3.1 to 4. Therefore, nucleophilic attack of water was simulated starting with 3.1 instead of 3.2. 2317



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Figure 6. Reconstructed free energy surface for the anti attack of water on ethene in 3.10 to form 40 . The three-dimensional free energy surface is generated by making a cut along the first collective coordinate CA[Pd-O-H] = 4.0. Here 3.10 * is a representative snapshot near the transition state. (b) Free energy profile (kJ/mol) for the reaction 3.10 f 40 . See Figure 2 for labeling and Figure 3 for atom color codes.

3.3.2. Attack of Water: Simulation 1. To verify the syn attack of water, structure 3.1 was initially taken, as discussed above. Three collective coordinates were used to incorporate a syn mode of water attack. The first coordinate is an associated coordination number, CA[Pd-O-H], as given by eq 3. This collective coordinate counts the number hydrogen atoms associated with all the oxygen atoms coordinated to Pd. This coordinate was chosen for sampling the deprotonation of the cis-water before/ during its nucleophilic attack at the olefin. Before a water molecule attacks ethene, it will take a (semi) η1 coordination structure, resulting from a “slipping” motion from the equilibrium η2-type coordination.43 For sampling such (slow) slipping motions, the difference in two Pd-C distances, Δd[C-Pd-C], was taken as a collective coordinate; see eq 4 . In the η2 case, these two bond distances are nearly the same, and thus, Δd ≈ 0. On attaining an η1-type coordination, Δd becomes largely positive or negative, depending on the direction at which the ethene “slips”. The third coordinate is the coordination number of all water oxygens, including the Pd-coordinated water, to both carbon atoms of ethene, C[C-Owat]. This coordinate samples the water coordination with the carbon atoms of ethene. It is important to note that, using the same coordinates as above, even an anti-type attack of water can occur in the simulation if that reaction route has the lowest free energy pathway. Surprisingly, during the initial phase of the simulation, the trans-water molecule was exchanged with one of the two Cl-

ions from the solution, forming structure 3.10 . Later the reaction 3.10 f 40 proceeds by a bulk water molecule attacking the ethene in an anti mode; i.e., an outer-sphere mechanism. The reconstructed free energy surface and the representative snapshots along the minimum energy pathway are shown in Figure 6. It is clear from the reconstructed free energy surface that the slipping motion of ethene had been nicely sampled using the Δd coordinate. Moreover, the reaction occurs when both the slipping movement and the water coordination to ethene occur simultaneously. The barrier for the anti attack of water is nearly 74 kJ/mol; see Figure 6 for the reconstructed free energy surface and snapshots along the minimum free energy pathway. Soon after the coordination of water, the latter deprotonates and the detached proton migrates to bulk water subsequently. As no syn route is observed in the current simulation, this reaction pathway should be associated with a higher free energy barrier. 3.3.3. Attack of Water: Simulation 2. Independent of the above, another simulation was carried out where the starting structure was the same, but using a different set of collective coordinates. The main aim was to resolve the mechanism and free energy estimates better than simulation 1 using more specific collective coordinates for the anti mode of water attack. Three collective coordinates were chosen for this metadynamics simulation: The first coordinate is an associated coordination number, CA[C-O-H], as given by eq 3. This collective coordinate counts the number hydrogen atoms associated with 2318



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Figure 7. (a) Reconstructed free energy surface for the anti attack of water on ethene in 3.1 based on simulation 2. The five-dimensional free energy surface is visualized here as volumetric data for free energy isovalues -7 kJ/mol (red), -47 kJ/mol (yellow), and -83 kJ/mol (green). Here -7, -47, and -83 kJ/mol are the free energies of 4, 3.1*, and 3.1, respectively. 3.1* is the transition-state structure. (b) Free energy profile (kJ/mol) for the reaction 3.1 f 4. See Figure 2 for labeling and Figure 3 for atom color codes.

the water oxygen connected to the ethene carbon atoms. This may be crucial if the deprotonation of the anti-attacking water happens to be a slow coordinate. The second and third collective coordinates were the same as those for the previous simulation. During the simulation, an exchange of trans-water with Cl- ion from the bulk was not observed; i.e., structure 3.1 was retained throughout the simulation. However, on several occasions, trans-water had exchanged with the bulk water. The reaction proceeded in a fashion very similar to that of simulation 1. The free energy barrier for the anti attack of water from this simulation is 76 kJ/mol, which is nearly the same compared to the estimate from simulation 1; see Figure 7. A difference of about 2 kJ/mol is within the metadynamics error bars of about 5 kJ/mol. Thus, the mechanism and the associated free energy barriers are essentially identical for 3.10 f 40 and 3.1 f 4.

3.3.4. Attack of Water: Simulation 3. Water attack can occur in an alternative way in which a bulk water molecule coordinates axially to Pd and thereafter attacks ethene in a syn mode. Pd to bulk-water coordination is slow and may become decisive in driving the reaction along the syn route. To verify this possibility, a simulation was launched starting from the 3.10 structure, but with explicitly taking the Pd to water O coordination number, C[Pd-Owat]. The second and third collective coordinates were Δd[C-Pd-C] and C[C-Owat], as in simulations 1 and 2. During the simulation, first an interconversion between 3.1 and 3.10 was observed after a water molecule approached (axially) and replaced the trans-Cl, and vice versa. This process was driven by sampling along the C[Pd-Owat] collective coordinate. From the reconstructed free energy surface (see Figure 8), it is clear that both 3.1 and 3.10 are nearly of the same free energy and are separated by a free energy barrier of about 26 2319



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Figure 8. (a) Reconstructed free energy surface for the anti attack of water on ethene in 3.10 based on simulation 3. The five-dimensional free energy surface is visualized here as volumetric data for free energy isovalues -9 kJ/mol (red), -29 kJ/mol (white), -41 kJ/mol (yellow), and -81 kJ/mol (green). Here -9, -29, -41, and -81 kJ/mol are the free energies of 3.1/3.10 , 4.1, 4, and 3.1*, respectively. (b) Free energy profile (kJ/mol) based on the above free energy surface. See Figure 2 for labeling and Figure 3 for atom color codes.

kJ/mol. Subsequently, one of the Cl- ions from the solution attacked an ethene C of 3.1 in an anti mode, forming 4.1. The free energy barrier for 3.1 f 4.1 is about 51 kJ/mol, and the reverse barrier is only 11 kJ/mol. Finally, a transition from 3.1 to 4 happened with water attacking again in an anti mode. The barrier for 3.1 f 4 is about 72 kJ/mol, which is nearly the same as that estimated from simulations 1 and 2 (considering the metadynamics error estimate of about 5 kJ/mol). Note that 3.1 f 4.1 is a side reaction. However, a net 3.1 f 4 reaction would happen in reality since the barrier of the reverse reaction 4 f 3.1 is small (4 kBT).

4. DISCUSSION AND CONCLUSIONS Using ab initio molecular dynamics simulations, crucial steps involved in the Wacker process were studied at aqueous acidic conditions and high Cl- concentration. A detailed molecular level picture of the ligand exchanges and hydroxypalladation reaction has been obtained. Ethene exchange with Cl ligands of a solvated [PdCl4]2- precursor occurs rapidly, and the estimated free energy barrier is only about 30 kJ/mol. Further substitution of Cl by a bulk water preferably happens at the trans position due to the strong trans effect of the ethene ligand. In all trans ligand exchanges, ligands attach and detach along the axial positions simultaneously. A cis-water substitution happens only after a

trans substitution since the former has a free energy barrier (125 kJ/mol) 2 times larger than the latter. In the vital step of nucleophilic attack of water at Pd-coordinated ethene, the anti (or outer-sphere) mode of water attack is preferred over the syn (inner-sphere) route. It has also been shown that the stereochemistry of nucleophilic attack of water at ethene is independent of trans substitution. The estimated free energy barrier for anti attack of water is between 72 and 76 kJ/mol. The mechanism along the minimum energy pathway has revealed that the anti attack of water is associated with the formation of a semi-η1 coordination of ethene with simultaneous attack of water. The syn attack involves structural strain in the transfer of a cis-water of the Pd complex to the ethene carbon atoms. This structural strain is large when ethene is in the semiη1 form as the Pd-water interactions become even more stronger than those at equilibrium. In addition, the anti route is entropically favored as several solvent water molecules are available near ethene; an addition of a solvent water to a carbon atom of the semi-η1-ethene is more probable than the Pd-coordinated cis-water. Another observation is that deprotonation of water which attacks ethene in the hydroxypalladation step occurs after the attack, but spontaneously. More significantly, simulations reveal that, at high [Cl-], cisCl exchange with bulk water is substantially slower than the hydroxypalladation step, and thus, it can be concluded that the latter process occurs without advancing through the former route. In that case, the anti vs syn problem becomes dispensable, 2320


The Journal of Physical Chemistry B and the reaction prefers to proceed from 3 to 400 directly. The barrier going from 3 to 400 is expected to be very similar to that of 3.1 f 4.1.

At high [Cl-], Cl- attack is preferred (ΔFq = 51 kJ/mol) over the water attack (ΔFq = 72-76 kJ/mol) on Pd-coordinated ethene. However, the reverse barrier (11 kJ/mol ≈ 4 kBT) for the former reaction is small, and therefore, a net hydroxypalladation reaction could happen in reality. The observation that the anti mode is preferred over the syn route at high [Cl-] conditions is in accordance with the experimental observations.18,21,24,25 However, what is surprising is that no direct effect of [Cl-] is seen in the mechanism of hydroxypalladation, which would enforce precedence of one mode of water attack over the other. Interestingly, during the last stage of preparation of this paper, another independent report28 appeared on the stereochemistry of the hydroxypalladation step at low [Cl-] employing ab initio metadynamics simulations. This technically different work supports most of the key conclusions of this work. Critically, the preference of the anti (or outer-sphere) mechanism of water addition and the large barrier involved in the cis substitution of water were also seen in their study. Of large consequence, ref 28 and the current work underline that the above two observations are independent of the Cl- concentration. This calls for more detailed experimental and theoretical studies to understand the observed kinetics and reaction mechanism of the Wacker process.

’ ACKNOWLEDGMENT All the calculations were performed using the computer cluster installed at the Department of Chemistry, Indian Institute of Technology Kanpur, procured under the DST-FIST program. This work is supported by CSIR, India (Project No. 01(2418)/ 10/EMR-II.). ’ REFERENCES (1) Cotton, F. A.; Murillo, C. A.; Bochmann, M. Advanced Inorganic Chemistry, 6th ed.; Wiley-Interscience: New York, 1999. (2) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; R€uttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176–182. (3) Jira, R. Angew. Chem., Int. Ed. 2009, 48, 9034–9037. (4) Rothenberg, G. Catalysis: Concepts and Green Applications; WileyVCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008. (5) Takacs, J. M.; Jiang, X. Curr. Org. Chem. 2003, 7, 369–396. (6) Tsuji, J. Synthesis 1984, 369–384. (7) Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9289–9346. (8) Cornell, C. N.; Sigman, M. S. Inorg. Chem. 2007, 46, 1903–1909. (9) Beyramabadi, S. A.; Eshtiagh-Hosseini, H.; Housaindokht, M. R.; Morsali, A. J. Mol. Struct.: THEOCHEM 2009, 903, 108–114. (10) Beyramabadi, S. A.; Eshtiagh-Hosseini, H.; Housaindokht, M. R.; Morsali, A. Organometallics 2008, 27, 72–79. (11) Keith, J. A.; Oxgaard, J.; Goddard, W. A., III. J. Am. Chem. Soc. 2006, 128, 3132–3133. (12) Nelson, D. J.; Li, R.; Brammer, C. J. Am. Chem. Soc. 2001, 123, 1564–1568. (13) Siegbahn, E. M. J. Am. Chem. Soc. 1995, 117, 5409–5410. (14) Siegbahn, E. M. J. Phys. Chem. 1996, 100, 14672–14680. (15) Kragten, D. D.; van Santen, R. A.; Lerou, J. J. J. Phys. Chem. A 1999, 103, 80–88.

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Ligand Exchanges and Hydroxypalladation Reactions of the Wacker

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