Computational Studies of Versatile Heterogeneous Palladium

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Computational Studies of Versatile Heterogeneous PalladiumCatalyzed Suzuki, Heck and Sonogashira Coupling Reactions Pitchaimani Veerakumar, Pounraj Thanasekaran, Kuang-Lieh Lu, King-Chuen Lin, and Seenivasan Rajagopal ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b00922 • Publication Date (Web): 24 Aug 2017 Downloaded from http://pubs.acs.org on August 24, 2017

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ACS Sustainable Chemistry & Engineering

Computational Studies of Versatile Heterogeneous PalladiumCatalyzed Suzuki, Heck and Sonogashira Coupling Reactions Pitchaimani Veerakumar,*,†,§ Pounraj Thanasekaran,*,‡ Kuang-Lieh Lu,‡ King Chuen Lin,†,§ and Seenivasan Rajagopal*,∥ †

Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 10617, Taiwan Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan § Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan ∥School of Chemistry, Madurai Kamaraj University, Madurai 625021, India ‡

* P. Veerakumar. E-mail: [email protected]. *P. Thanasekaran. E-mail:[email protected]. *S. Rajagopal. E-mail:[email protected]. ABSTRACT: This perspective focuses on the mechanistic insights and complexity, which are difficult to acquire from pure experimental techniques, through the computational studies of Pd-catalyzed Suzuki, Heck and Sonogashira carbon-carbon bond-forming reactions. These reactions consist of three fundamental steps including oxidative addition (OA), transmetalation (TM) and reductive elimination (RE) for the generation of carbon–carbon bonds from the bond-forming reactions of aryl halides (R1X) and organometallic species (R2M). Computational studies of these coupling reactions allow us to understand specific reaction pathways in the analysis of OA (resolving the linkage between coordination number and selectivity in Suzuki reaction), TM (the function of the base in the Suzuki reaction and various mechanistic options in the Sonogashira reaction), and RE (way of efficient β-hydride elimination in Heck reaction). In addition, the reaction pathways and complexities in the full catalytic cycle of each reaction along with the future perspective are also discussed. KEYWORDS: C-C cross-coupling, Density functional theory, Heterogeneous, Mechanism, Palladium, Suzuki, Heck, and Sonogashira reactions

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INTRODUCTION Palladium-based catalysts remain the most useful transition metal catalysts and become a pivotal tool for the synthesis of organic molecules carrying carbon-carbon bonds. This is because of selectivity of the reaction, tunability of the catalyst and the choice of ligand towards reactivity and selectivity. Further, these reactions proceed with a high TON (turnover number) and TOF (turnover frequency) using a small amount of Pd (ppb to ppm) species under green reaction conditions.1−4 These reactions find applications frequently on the synthesis of organic molecules with biological and pharmaceutical importance. Among the main bond-forming reactions by Pd-catalysts, the Suzuki, Heck and Sonogashira reactions, which occur between a nucleophile (organometallic reagents, alkenes or alkynes) and an electrophile (aryl or alkyl halides), highlight some of the most practical and important applications of palladium nanoparticles (PdNPs) in the chemical industries. In palladium-catalyzed Suzuki, Heck and Sonogashira carbon-carbon bond-forming reactions, competing pathways appear to be involved in many steps containing similar energy barriers, thus making their mechanism difficult.5 For example, since most of the intermediates are short-lived species that are difficult to be detected, developing a coherent mechanism for these reactions using experimental technique is a challenging task. It is known that various chemical reactions are facilitated by heterogeneous catalysts through change in the surface charge of the catalyst. Recent interest is the application of density functional theory (DFT) as a better approach to understand the mechanism of these reactions.6 However, to date only limited efforts have been made to use computational techniques based on DFT to screen improved catalysts in heterogeneous systems. The nature of the active Pd catalysts in solid supports for the carbon-carbon bond-forming reaction is a subject of considerable debate. There are two extremes where either the reaction is catalyzed by heterogeneous Pd catalysis (Pd/support, Pd clusters, Pd surface) or the leaching of active Pd species occurs from the supporting solid and catalyzes the reaction homogeneously. Determining whether a bond-forming reaction proceeds exclusively homogeneously or heterogeneously is very difficult task. It is likely that both homogeneous and heterogeneous catalysis may occur at the same time or consecutively (Scheme 1).

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Scheme 1. General Mechanism for the Heterogeneous and Homogeneous Bond-Forming Reactions Catalyzed by Pd Species

If the catalysis occurs at the same time, it would be extremely difficult to characterize.7 Usually, the mechanism of Pd catalyzed carbon-carbon bond-forming reactions is similar to the mechanism proposed for homogeneous catalysis. However, a clear picture on the mechanism of heterogeneous catalysis is yet to emerge. We report herein on recent developments in computational studies of Pd-catalyzed carbon-carbon bond-forming reactions, which could provide readers with some guidance for designing Pd nanocatalysts with desirable catalytic activities. Most of the empirical and computational studies on the mechanism of carbon-carbon bond-forming reactions catalyzed by Pd species have involved the use of homogeneous catalysts.8-10

General Pd-mediated Suzuki, Heck and Sonogashira Catalytic Cycles for Carbon-Carbon Bond-Forming Reactions. Pd-mediated Suzuki carbon-carbon bond-forming reactions usually involve the reaction of aryl halides (or triflate), R1-X, with a boronic acid, R2-B(OH)2, in the presence of a base and take place through three steps viz. OA, TM, and RE in the catalytic cycle. Other Pd-mediated Heck and Sonogashira carbon-carbon bond-forming reactions have various steps that are in common with the Suzuki bond-forming reaction. Both Suzuki and Heck reactions begin with the oxidative addition of an aryl halide to a Pd(0) in the catalytic cycle to produce a more soluble σ-aryl Pd(II) complex. The addition of a base intends to replace the halide of the σ-aryl Pd(II) in a ligand substitution reaction. The resulting 3



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σ-aryl Pd(II) complex reacts with an aryl boronate in the Suzuki reaction, while an alkene or alkyne is preferred in the Heck or Sonogashira reaction, respectively. Reductive elimination then produces the unique product for each reaction and regenerates Pd(0) catalytically active species to begin the catalytic cycle again (Scheme 2). In the past decades, computational chemists have primarily focused on solving chemically related problems in the catalytic cycles for carbon-carbon bond-forming reaction catalyzed by Pd species. Hybrid B3LYP,11 M0612 and BP8613 functionals are applied for these reactions. Among them, B3LYP shows promise and is thus extensively used to understand the mechanism of these catalyzed reactions.

Scheme 2. Similarities in the Catalytic Cycle Between the Suzuki and Heck Reactions

Oxidative Addition. In coupling reactions, the first step is OA, which is determined to be the rate-determining step. When the coupling reaction occurs between electron-rich Pd(0)Ln(n = 1–4) and an electrophile organic halide R−X, not only bond breaking takes place in between the aryl and the halide groups in R−X but also generating two bonds in Pd(0)Ln, where the oxidation state of Pd species is increased from 0 to +2 (Scheme 3).

Scheme 3. General Scheme for the Oxidative Addition Reaction

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Although reaction appears to be reversible, the use of strong electron donating ligands may lead the equilibrium to be shifted to the oxidative addition (OA) product. For this step, two mechanisms, i.e., concerted mechanism and an SN2 mechanism are proposed (Scheme 4).

Scheme 4. The Concerted and SN2 Mechanisms for OA Reaction

The concerted mechanism involves the formation of a three-centered transition state (TS), in which the R1-X binds firstly to the Pd center, and then the cleavage of R1-X bond and the generation of new Pd-R1 and Pd-X bonds take place simultaneously. This mechanism induces the retention of configuration at a stereogenic center in the case of chiral R1-X molecule. In contrast, the SN2 mechanism is an associative bimolecular reaction, involving two pathways. In this reaction, the R1 of R1-X is encountered by the Pd(0)Ln and the X− is released, resulting in the formation of a [Pd–R]+ intermediate. Finally, both charged species combine to yield the coupling product. This second mechanism results in the inversion of configuration of a stereogenic center. The first computational studies by Low and Goddard proposed three models (three-coordinate (one ligand removed from metal center), four-coordinate and five-coordinate (one ligand added to metal center)) in OA reactions that involved the use of Pd dialkylbis(phosphino ligands).14 They reported that the RE barrier follows the order: three-coordinate complex ˃ four-coordinate complex ˃ five-coordinate complex. Although the OA process has been investigated in some depth, the more reactivity of Pd species carrying bulky and electron-rich ligands is not clearly realized. This might be due to the more rapid OA reaction of monoligated [PdL] species 5



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compared to the bis-ligated compound, [PdL2]. When relatively inert aryl chlorides are used as substrates, the carbon-carbon bond-forming reactions become more facile in the presence of bulky and electron-rich phosphine ligands. A detailed DFT study on the Ph-X (X = Cl, Br, I) OA to a [Pd(PMe3)2] complex reveals that aryl halides, ArCl and ArBr, assist the OA reaction through the promoting monoligand pathway when the bulky and hemilabile ligands are used (Scheme 5).15

Scheme 5. Reaction Mechanism for the Aryl Halide Addition to [Pd(PMe3)2]

But, when the OA involves electron withdrawing groups (EWGs) containing ArI, a less sterically hindered ligands are proposed. The choice of the bulky ligand might be less important for ArI derivatives compared with other halogen derivatives owing to their weak C–I bond and viable process with a few energy barriers in both pathways. These results clearly explained the use of electron-rich, and sterically hindered ligands in bond-forming reactions of ArBr, ArCl, and ArI using Pd-catalysts.15 Jutand et al. reported that the mechanism of the addition of an aryl halide to a PdL2 complex was influenced by the nature of the ligand (L) size.16 In another computational study, Norrby et al. reported that, with PdL2 complexes, the OA of Ar-X occurred more fastly due to low energy barriers involved compared with PdL complexes.17 Phosphine ligands performed a significant contribution on the reactivity and selectivity in the Suzuki bond-forming reaction of dibromo sulfoxide mediated by Pd-catalyst.18 The less hindered phosphine PPh3 ligand was linked with a bisphosphine 6


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catalyst, which favored an SN2 pathway through bromoaryl group activation, while bulky P(1-napthyl)3phosphine complex was associated with the monophosphine catalyst, which promoted a concerted pathway through bromoaryl moiety activation. DFT and DFT/MM calculation studies showed that the coordination number of the catalyst played a key role for the reaction selectivity. Bisphosphine catalysts preferred sp3 carbon coupling where the substrate occupied only one site around Pd center. In the case of monophosphine catalysts, they favoured coupling at the sp2 carbon, in which the substrate occupied more portions around Pd center. The OA of mono-, and bis-ligated forms of the [Pd(L)] and [Pd(L)2] catalysts was postulated and computed. As monoligated catalyst possessed a lower energy barrier to the progress of the reaction, the ligand dissociation energy from the Pd complex was responsible for the prevalence of one or the other in the cycle.19,20 The mechanistic study of the addition of PhX to [Pd(PR3)2] and PdPR3(R = Me, Et, i-Pr, t-Bu, Ph) was carried out using DFT studies.21 These calculations showed that a 12-electron monophosphine species PdPR3 catalyst was more active compared with bisphosphine Pd(PR3)2. Interestingly, the computed free-energy barriers did not show any differences in the addition reaction of PhCl to the [Pd(PR3)] catalyst (< 2 kcal mol−1), among different PR3 ligands, indicating that the organic group R was independent. In contrast, the dissociation energy of one P from the parent Pd complex showed a significant difference. The dissociation energies derived from computational studies for the different PR3 ligands showed the energy values ranging from 26.0 (R = Me) to 19.4 kcal mol−1 (R = t-Bu) and followed the order R = Me > Et > PPh3 > i-Pr > t-Bu. It was suggested that the choice of phosphine ligands can significantly affect the energetics of the OA process. It is noteworthy that P(t-Bu)3 had a unique ability in the bond-forming of aryl chlorides, which was attributed to energy barrier difference. The Pd coordination number and the nature of ligands in a solvent or the gas phase determine the fate of the addition reaction. For example, Senn and Ziegler used DFT calculations to investigate the OA of Ph-X (X = Cl, Br, or I) to [Pd(PP)] (PP = 1,2-bis-(dimethylphosphino)ethane or (P)-2,2’-bis(dimethylphosphino)-1,10-biphenyl) in THF solution.22 In this study, the authors were not able to locate concerted TS in solution state but in gas phase. The halide dissociation and its recombination with phenyl complex were strongly exothermic and barrier-free, leading a facile process in solution. However, Schoenebeck and co-workers successfully located the transition 7



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states using DFT approach for the addition reaction of C-Cl and C-OTf to Pd(PtBu3), Pd(PtBu3)(MeCN), and Pd(PtBu3)F− in MeCN.23 Legault et al. theoretically studied the OA of polyhalogenated heterocyclic compounds to Pd(PH3)2, and showed that both C–X bond strength and the frontier molecular orbital (MO) interactions controlled regioselectivities. The frontier interaction is related to the TS structure in which the interaction occurs between PdL2 and η2-Ar–X. For example, in the case of 2,5-dibromo-7-methoxybenzofuran, the C(2)–Br is first activated since it is a stronger bond than that of C(5)–Br. As the C(2) is linked nearby hetero oxygen atom, its π* orbital gets lower energy, leading to generate d-π* backbonding.24 It was also found that anionic Pd species such as Pd(PR3)2Cl− and [Pd(PMe3)2]OAc− promoted the addition process even in the presence of anionic additives.25,26 A different mechanism for the addition of organic iodides to [Pd(PMe3)2OAc]− using BP86/LANL2DZ theory was proposed (Scheme 6). Gooßen and co-workers reported that OAc− stabilized the structure of the four-coordinate anionic intermediate over the five-coordinate intermediate through a ligand exchange between OAc− and I−.27

Scheme 6. Formation of Intermediate Species in the OA of ArI with Anionic Pd(L)2(OAc)

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This mechanism was based on previous work reported by Amatore and Jutand, in which [Pd(0)L2X]− was generated instead of Pd(0)L2 from the reaction of Pd(II) precursor with phosphines to initiate the OA reaction.28 Table 1 lists selective OA reactions of arylhalides with [Pd(PP)] and [Pd(L)2].15,21,25,29,30 Some important results can be summarized from these items. (i) the barriers of arylhalides towards the addition reaction increases in the order ArI < ArBr < ArCl, which is consistent with the order of aryl halides reactivity. (ii) since aryl halides containing EWGs impart smaller barriers compared to those of electron-rich arylhalides, they offer higher addition rates, (iii) the calculated energy barriers for R1Br are found to decrease in the order R1 = Me >benzyl> Ph >vinyl. In fact, C(sp3)–X bonds are less reactive compared to C(sp2)–X bonds in this step.31 Table 1. Activation Barriers ∆G‡(∆E‡) and Reaction Energies (∆ ∆G,∆ ∆E) for 1 1 1 1 PdL2 + R X → cis-PdL2(R )(X) and Pd(PP) + R X → cis-Pd(PP)(R )(X) L or (PP) R1X Ref ∆G‡(∆E‡)a (∆G,∆E)a PPh3 Ph-Cl 21b 34.4 (−) 6.9 (−) 21 Ph-Br 1.5 (−) 25.0 (−) Ph-I 18.6 (19.4) 29c − (−) 15d PMe3 Ph-Cl 33.2 (21.1) 0.5 (−15.4) Ph-Br 27.6 (15.3) 15 −4.5 (−19.0) 15 Ph-I 22.5 (10.1) −5.1 (−21.6) p-MeOPh-Cl 34.7 (22.4) 15 0.7 (−15.3) 15 p-MeOPh-Br 29.4 (16.3) −3.1 (−18.9) p-MeOPh-I 23.3 (10.6) 15 −4.8 (−21.0) p-NCPh-Cl 29.3 (16.5) 15 −3.1 (−18.9) 15 p-NCPh-Br 24.4 (11.4) −6.3 (−22.5) p-NCPh-I 19.4 (6.9) 15 −9.1 (−24.9) Ph-Br 23.8 (13.4) 30c PH3 1.0 (−10.2) vinyl-Br 19.4 (9.2) 30 0.8 (−11.0) MeBr 32.7 (23.6) 30 0.7 (−9.8) BnBr 28.8 (18.4) 30 −1.2 (−13.0) H2P(CH2)2PH2 Ph-Cl 25c − (9.7) − (−19.3) H2P(CH2)4PH2 Ph-Cl 25 − (17.2) − (−14.7) H2P(CH2)6PH2 25 Ph-Cl − (21.6) − (−8.5) a

kcal mol−1.bB3PW91/LANL2DZ + p calculations to obtain the geometries. c B3LYP/LACVP* and the Poisson-Boltzmann self-consistent reaction field continuum solvation model with DMF as the solvent. dB3LYP gas-phase 9



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calculations.

The π* orbitals of aryl halides give a better reactivity, and (iv) the length of the alkyl chain and the larger bite angles of the ligands are the critical parameters for the addition barriers of aryl halides to Pd-phosphine complexes. Hong et al.32 computationally examined OA processes related to the mechanism of the Suzuki bond-forming reaction of PhCl and phenyl boronicacid with diimine, diphosphine, and diamine ligands. More accurate energies of the optimized structures were calculated and were resembled with the metal coordination geometries in these reactions. However, the use of a IM ligand was found to be more favorable than that of other ligands, including P’ or AM’ (Table 2).

Table 2. Computed Relative Energies of Various Ligands with Respect to Reactants energy (kcal mol−1) entry ligand (L∧L) transition statea product 1 14.1 (241i) P −13.3 2 11.9 (165i) PM −26.3 3 IMc 9.1 (184i) −22.6 4b P’d 17.6 (246i) −12.1 5 AM’e 11.9 (132i) −29.8 6 10.2 (162i) IM’ −28.3 7 10.1 (172i) IM-Me −23.6 8 9.0 (217i) IM-F −12.5 9 9.7 (173i) IM-Me’ −24.8 10 8.6 (205i) IM-F’ −17.9 11 10.5 (161i) IM-Cy −24.5 12 10.5 (191i) IM-Ph −19.7 a b 2 Imaginary frequencies in parentheses. Phenyl chloride is η –coordinated to Pd via C2 and C3 atoms. cDiimine, dDiphosphine. eDiamine. Especially, the introduction of trifluoromethyl functional groups on IM ligand lowered the activation energies of this process. Upon chelating diphosphine P into Pd metal center, the energy was greatly affected by chelate ring size, while methylene unit on the backbone of P ligand increased the activation energy. For diimine ligands, 10


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ring size had no significant effect on the activation energies (Table 2). Therefore, the activation energies increased along the order IM (diamine) < AM (diamine) < P (diphosphine) for the OA process of these reactions. Cis-trans Isomerization. On the basis of concerted mechanism, OA generally results in the generation of a square planar cis-Pd(II)L2(R1)(X) complex. Experimentally, trans-Pd(II)L2(R1)(X) isomers are obtained from the reaction of organohalides with Pd(0) complexes. It is commonly believed that a fast isomerization occurs leading to the formation of a cis-isomer (eqn (1)) → 1

Three major potential mechanisms have been identified including (i) a ligand assisted process, (ii) direct ligand rearrangement, and (iii) dissociative mechanism for the cis-trans isomerization (Scheme 7).

Scheme 7. Possible Mechanisms for Cis-trans Isomerization

Computational results showed that the ligand assisted process is kinetically favored33 and the calculated barrier is 20 kcal mol−1.33,34 The ligand dissociation from a cis-Pd(II) 11



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complex, pathway (iii), also involves a barrier >20 kcal mol−1.35 Many factors including solvent, ligand and temperature can have a significant influence on the isomerization mechanism and its rate. Transmetalation. In the carbon-carbon bond-forming reactions involving the TM step, the organic group R2 attached with electropositive moiety “m” is transferred to Pd(LnR1)X catalyst without any change in the oxidation state of Pd (Scheme 8).

Scheme 8. Transmetalation Reaction of Electronegative Organic Group with Pd Catalyst

The mechanism for the TM step has been less studied because of the difficulty involved in the isolation and characterization of reaction intermediates, when the reaction is carried out experimentally. Among the different mechanistic studies attempted so far, Suzuki bond-forming reactions are probably the most studied.36-38 Issues like role of the base, R-X and boronic acid, R-B(OH)2 on the TM step in the Suzuki–Miyaura reaction have been addressed and several proposals emerged.39 Two important roles were proposed for these species (Scheme 9).

Scheme 9. Role of Base in the TM Process of Suzuki Reaction

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Pathway A involves the binding of the base with the boronic acid to form organoboronate, but in the pathway B the base substitutes the leaving group X in the coordination sphere of the catalyst. Braga et al.40 postulated a direct mechanism in the absence of a base (pathway 0) apart from pathways A and B for a model reaction. In the absence of a base, pathyway 0 requires a greater energy barrier (44 kcal mol−1) compared to the energy barrier (21 kcal mol-1) involved in the presence of OH− (pathways A and B). These results show the importance of adding the base in accordance with the experimental results. Therefore, the final conclusion is that the catalytic cycle likely proceeds through the low energy barrier pathway A or B. The results observed by Braga et al. were also valid when the PH3 or vinyl ligands were replaced with PPh3 or phenyl groups, respectively.41 Hence, the authors suggested that both pathways may be operative and competitive.42-45 In 2008, Cid and co-workers reported the mechanistic studies of the reaction of 2(4)-bromopyridines with phenylboronic acid. 1H and

31

P NMR spectral techniques

were used to monitor the reaction at various stages. Bromopyridine first reacted with Pd(PPh3)4 to give the trans-(Ph3P)2Pd(II)(Ar)(Br). As experimental studies gave little informations, DFT studies were performed to identify the structure of intermediates of this reaction. Scheme10 displays the energy profile showing that a TM step is involved for this system.46

Scheme

10.

B3LYP

Ph-B(OH)3− and

Energy

Profile

for

the

TM

Trans-[PdBr{C5H3N(4-C6H5)-C2}(PH3)2].

Structures are Labeled as I or TS.

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Reaction All

Between Computed


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Table 1 lists the B3LYP energy profiles (in kcal mol−1) for the TM reaction between Ph-B(OH)3− and trans-[PdBr{C6H5}(PH3)2] or trans-[PdBr{C6H5}(PH3)2] in the gas phase and toluene, respectively. After realizing the role of the base in this reaction, the next issue was to find out the number of phosphine ligands involved, one or two, in the mechanism of the reaction. The effect of vinyl bromide with bis- and monophosphine ligated Pd complexes in the presence of H2C=CHB(OH)2 within the full cycle of Suzuki bond-forming reaction was computationally analyzed by Braga and co-workers.40,41 In addition, an alternative mechanism was also considered, depending on whether the isomer around the Pd center was cis or trans isomer. The authors began by mapping the Suzuki reaction, then diverged into investigating whether or not the Suzuki reaction proceeded via a monophosphine reaction pathway (Scheme 11) or biphosphine reaction pathway (Scheme 12). The Pd-P dissociation energy for the reaction was originally calculated using two phosphine ligands. Its energy barrier would then be compared to that for the reaction where one phosphine ligand was used. However, monophosphine species are very solvent dependent. Large entropy differences would cause difficulties in accurately modeling ligand dissociation energies. They found that both biphosphine and monophosphine reaction pathways could be involved in the TM step but were not able to distinguish which 14


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pathway was preferred. An interesting result from Scheme 11 and Scheme 12 is that the energy barriers never exceeded 25 kcal mol−1, indicating that the reaction involves a low heat and could proceed at room temperature.

Scheme 11. Mechanistic Details for Monophosphine Pd Catalysts Derived from the Theoretical Analysis Carried Out by Maseras et al19

Scheme 12. Mechanistic Details for Bisphosphine Pd Catalysts Derived from Theoretical Analysis Carried Out by Maseras et al19

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The authors extended their work to the study of the participation of aryls in the same overall mechanism.41 The role of monophosphine complexes in the Suzuki reaction mechanism was also explained.47,48 The efficiency and selectivity of Suzuki reaction were improved by dialkyl and biaryl phosphine ligands.49,50 Baillie et al.51 experimentally investigated the effect of introducing P(biphenyl)nPh3-n type ligands, and among the biphenylphosphine ligands, P(biphenyl)Ph2 gave the highest conversions and turn overs. On the basis of theoretical study on the use of P and N containing ligands with Pd catalysts in the Suzuki reaction, Hong et al.32 proposed two reaction pathways for this TM step (Scheme 13).

Scheme 13. Two Probable Pathways (Dissociative Pathway (Route 1) and Associative Pathway (Route 2)) for the TM Process

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Since the first step of the dissociative pathway (Route 1) was highly endothermic, Route 2 leading to the formation of a stable biaryl Pd complex as a reaction intermediate was favored. The activation energy for the TM process was lower in the presence of EWG, but higher in the presence of EDG. Thus, the diimine ligands appear to act as an excellent coordinating ligands for the Pd-catalyzed Suzuki reaction. The reaction rate was observed to be slow in the absence of a base. In order to realize the steric and electronic effects on the Suzuki-Miyaura reaction, computational study has been carried out using phosphine ligand (PMe3) and its analogues. In TM step, tetracoordinated Pd complex is transformed to a four-membered TS due to the chelation of the boronate, resulting in the formation of a Pd complex as shown in Scheme 14.

Scheme 14. Effect of Phosphine Ligands in the TM Reaction Pathway Analyzed by Harvey et al52

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The conclusion reached from the computational studies is that both steric and electronic effects were important and their energy barrier were in the order: P(CF3)3 < PPh3 < PMe3 < P(t-Bu3). Furthermore, π-acceptor phosphine ligands lowered the energy barrier for this step. It was rationalized by these facts that phosphine ligands had an ability to stabilize the electron density at the Pd center due to the nucleophilic attack of the boronate phenyl group on Pd.53

Reductive Elimination. A reductive elimination (RE) process is required in order for full catalytic cycle to be completed in addition to the OA and TM steps, but it is less studied in depth computationally because this step continues very easily.54 Concerted mechanism was the most probable mechanism for this step. This last step features a cyclic TS, which accompanies to the carbon-carbon bond forming reaction, and the concomitant reformation of the PdL2 catalyst through a cyclic TS can be explained as shown in Scheme 15.

Scheme 15. Generally Accepted Mechanism for the RE Step

Bulky and bidentate ligands with a big bite angles and Pd at higher oxidation state facilitate the reaction which is usually irreversible. Apart from these facts, the solvent and additive used, temperature, and ligand features give significant effects on this step.55 In the RE reaction, the reaction rate is accelerated by the sterically bulky phosphine ligands as the repulsive interaction arises between L and the R groups in the parent R2PdL2 complex that influences the two groups in a close manner, thus facilitating this RE step. Three-coordinated complex generated by the leaving of a phosphine atom from the parent R2PdL2 accounts for the improved reactivity.56,57 The 18


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RE rate is enhanced by phosphine ligands carrying electron-donating groups. Pd(II) complexes with more electrophilic character than Pd(0) complexes become highly stable with electron donating phosphine ligands. Hence, these ligands maintain R2PdL2 complex to become more stable, thus enhancing their barrier for this step. Contrary to this, diphosphine ligands with a wide bite angles stabilize the TS, resulting in the accelerated rate of the reaction.58 Ananikov et al.59-61 theoretically demonstrated the effects of different X ligands and alkyl groups on the RE of [Pd(CH=CH2)2Xn] (X = Cl, Br, I, NH3, PH3) and cis-[Pd(R1)(R2)(PH3)2] complexes (R1 or R2= Me, vinyl, Ph, ethynyl), respectively. The rate of C-C bond formation increased in the order Cl ˂ Br ˂ NH3 ˂ I ˂ PH3, and the energy barrier for the carbon-carbon bond formation from the symmetrical R2Pd(PH3)2 complex enhanced in the order: R = vinyl < Ph < ethynyl < Me. Furthermore, the exothermic values and energy barriers for asymmetrical R1–R2 coupling in R1R2Pd(PH3)2 were close to the averages of their corresponding values for symmetrical R1–R1 and R2–R2 coupling in R12Pd(PH3)2 and R22Pd(PH3)2, respectively. In the ONIOM approach, Me–Me bond-formation from [PdR2Ln] (L = PPh3, PCy3, PMe3, and PH3; n = 1, 2) complexes was studied. The calculations showed that the parent complex energy is influenced by steric effect, but the TS energy is affected by electronic effects. The RE barriers followed in the order PPh3< PH3< PCy3< PMe3, and therefore, different reaction pathways may be involved upon changing the different types of L ligands, as shown in Scheme16.

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Scheme 16. Simplified Reaction Mechanisms for the RE Step from PdR2L2

For example, the use of PCy3 resulted in an increased reactivity through the mono-ligated reaction pathway, whereas the PMe3 ligand decreased the reactivity with respect to RE by stabilizing the four-coordinated complexes. Alternatively, the PPh3 ligand showed a good reactivity for both mechanisms, and therefore, it is treated as a more universal choice. The study of the effect of ancillary ligand L (L = acetonitrile, ethylene, maleic anhydride (ma)) on the C-C coupling reaction of [PdMe2(PMe3)L) showed that the reaction barrier at DFT-B3LYP level increased in the order: maleic anhydride < “empty” < ethylene < PMe3 ≈ MeCN, confirming that the barrier decreased with the nature of π-accepting L.62 The bond-forming reaction was easier for the four coordinated species with “ma” than that of the three-coordinated complex (∆G#= 13.2 kcal mol−1 for L = empty and 8.6 kcal mol−1 for L = ma), owing to its better π-acceptor ability. The four coordinated complex with “ma” had an easier coupling compared to the three coordinated complex. It, thus, appears that the reaction will be accelerated with strong π-accepting additives ability. The authors concluded this result with the features of RE in cis-[Pd(η1-allyl)2(PMe3)(L)],63 where Csp2-C’sp2 elimination is favored.

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Hong et al. used IM, P’ and AM’ ligands for the Suzuki–Miyaura bond-forming reaction of Ph-Cl with phenyl boronic acid.32 It is interesting to note the reverse order of the energy barrier calculated for the RE reaction (AM ˃IM ˃P) compared to the OA step. The values of activation energies collected in Table 3 clearly established the trend. Furthermore, the energy barrier for the RE reaction was in the order: electron-withdrawing group on the diamine ligand ˂ unsubstituted ligand ˂ ligand carrying electron-donating group.

Table 3. Computed Relative Energies of Various Ligands with Respect to Reactants energy (kcal mol−1) No. ligand (L∧L) transition statea Products b 1 P 9.0 (309i) −26.5 c 2 AM 15.7 (330i) −9.4 d 3 IM 13.2 (329i) −14.6 4 10.1 (313i) P’ −27.9 5 17.7 (332i) AM’ −6.6 6 16.6 (327i) IM’ −9.0 7 13.6 (323i) IM-Me −12.3 8 8.5 (315i) IM-F −24.0 9 14.4 (325i) IM-Me’ −12.3 10 10.9 (314i) IM-F’ −20.2 11 13.7 (322i) IM-Cy −11.3 12 10.4 (316i) IM-Ph −15.8 a b c Imaginary frequencies are given in parentheses. Diphosphine. Diamine. dDiimine. Full Catalytic Cycle. All the DFT studies performed so far were carried out only for homogeneous, and not heterogeneous catalyzed reactions but a very few of them were attempted to study the full catalytic cycle.32,64-71

Suzuki–Miyaura Bond-Forming Reactions. The use of model systems is a common tool in computational chemistry to provide insights into their respective real systems, often yielding a very good results. Braga et al. characterized the different stages in the full catalytic cycle of a Suzuki–Miyaura model reaction of vinyl bromide with vinyl boronic acid by a Pd diphosphine catalyst through calculations of the corresponding intermediates and transition states.33 On the basis of these calculations, different 21



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alternative mechanisms were proposed, and Scheme 17 shows the energy profile for the full catalytic cycle of the model reaction calculated from the Becke3LYP DFT functional.

Scheme 17. Free Energy Profile of the Entire Catalytic Cycle for the Reaction of H2C=CHBr and H2C=B(OH)2 in the Presence of OH− using [Pd(PH3)2] Catalyst According to Becke3LYP DFT Functional

Through an exothermic reaction, a cis-CH2=CHPdBr(PH3)2 was formed due to the oxidative addition of vinyl halide to linear Pd0(PH3)2 complex and this reaction was proposed as the rate-determining step of the catalytic cycle. The alternative paths, either the dissociation or association of phosphine external ligand, were difficult to compute because of high barriers involved. According to Scheme 17, the energy difference between the reference point and TSOA, i.e.,∆G# was the energy barrier for the rate controlling step.

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Heck Bond-Forming Reactions. In the Heck reactions (eqn.2), R1 from an aryl halide can attach to the α- or β-carbon of the alkene, and the migratory insertion step determined the regioselectivity.

(2)

The reaction barriers for the insertion of olefin into the Pd(II)–(CH=CH2) bond in [Pd(PH3)(I)(CH=CH2)(RHC=CH2)] and cationic [Pd(H2PCH2PH2)(CH=CH2) (RHC=CH2)]+ complexes depended mostly on the regiochemistry of the system.72 For different substituents R under cationic and neutral conditions, the order of selectivity followed in the order:

Cationic: COOMe < CN < CF3 < Ph

Computational Studies of Versatile Heterogeneous Palladium

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