J Mol Model (2016) 22:53 DOI 10.1007/s00894-016-2920-5
ORIGINAL PAPER
Mechanistic investigation of palladium-catalyzed amidation of aryl halides Yun Liang 1 & Ying Ren 1 & Jianfeng Jia 1 & Hai-Shun Wu 1
Received: 1 November 2015 / Accepted: 20 January 2016 # Springer-Verlag Berlin Heidelberg 2016
Abstract A mechanistic investigation using Becke3LYP density functional theory (DFT) was carried out on the palladiumcatalyzed amidition of bromobenzene and tBu-isocyanide. The whole catalytic cycle consists of five steps: oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration. The rate-determining step is oxidative addition, with a small Gibbs free energy of 14.6 kcal mol −1 . In the migratory insertion step, t Buisocyanide provides an important source of carboxy and amino groups to establish the amide group. For anion exchange, path 1a is suggested as the most favorable pathway with the help of the base, and water provides a source of oxygen which is perfectly in line with experimental observations. Finally, in the hydrogen migration step, we illustrate that the six-membered ring path is energetically favored due to the assisting influence of water. In addition, our calculations indicate that using dimethyl sulfoxide as a solvent does not change the rate-determining step.
Keywords Palladium . tBu-isocyanide . Anion exchange . Amidation . DFT
Electronic supplementary material The online version of this article (doi:10.1007/s00894-016-2920-5) contains supplementary material, which is available to authorized users. * Ying Ren [email protected] * Hai-Shun Wu [email protected]
1
School of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, People’s Republic of China
Introduction Amides are of paramount importance as functional groups in organic synthesis, and are common components of abundant natural products and bioactive compounds [1]. The transitionmetal-catalyzed cross-coupling reaction has become a most effective and selective way to form carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds, since it can directly establish the molecular skeletons of these potential precursors from readily available reactants in organic chemistry [2–5]. Previous reports have proposed various transition metal catalysts for amide synthesis reactions, such as Ag nanoparticles [6], and Ru [7] and Rh complexes [8]. Nonetheless, we are particularly interested in palladium-catalyzed cross-coupling reactions [9–11], because these reactions offer diverse perspectives for the formation of carbon–carbon bonds. Palladium catalysts are well known for their extremely strong functional group tolerance and high efficiency; however, lengthy reaction times and the use of the poisonous gas carbon monoxide limit the scope of their use for carbonylation [12, 13]. Isocyanides [14], a series of unsaturated molecule analogous to carbon monoxide, would be the most likely candidates to replace carbon monoxide in palladium-catalyzed coupling reactions, because they can supply not only a carboxy but also an amino group, and react with both nucleophiles and electrophiles on the same carbon atom. Recently, Jiang and coworkers [15] discovered a new and efficient palladiumcatalyzed amidation reaction of aryl halides with t Buisocyanides at moderate temperature to give the stable corresponding amides (Scheme 1). The use of isocyanides not only provides a new and environmentally friendly way to synthesize amides, but also simplifies the initial reaction paths as well as the experiment conditions. Unlike in previous research [16–18], water serves as a nucleophilic reagent and provides a
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Scheme 1 Efficient palladiumcatalyzed amidation of aryl halides with t-Bu-isocyanides
source of oxygen in this reaction. Meanwhile, Jiang and his co-workers [15] assumed a reaction mechanism involving oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration (Scheme 2). To our knowledge, although palladium-catalyzed amidation of bromobenzene with tBu-isocyanides has been achieved successfully, the detailed mechanism still remains ambiguous. Although very few theoretical studies have focused on palladium-catalyzed coupling reactions involving isocyanides, a number of theoretical investigations have been carried out for other palladium-catalyzed C–C coupling reactions. For example, Carvajal et al. [19] studied the mechanism of palladium-catalyzed allyl chloride carbonylation with the help of density functional theory (DFT) calculations. Hu et al. [20] employed the B3LYP level of DFT to investigate the mechanism of sodium alkoxide as the base in palladiumcatalyzed carbonylation of aryl iodides. Recently, we researched the mechanistic details of palladium-catalyzed amidation of bromobenzene and tBu-isocyanides with the help of DFT calculations. Furthermore, several crucial problems were addressed. (1) We proposed four feasible reaction mechanisms and demonstrated that the energy barriers of monophosphine pathways are lower than the bisphosphine ones. (2) We gained an in-depth knowledge of the role of cesium fluoride (CsF), which was illustrated experimentally Scheme 2 Proposed reaction mechanism [15] of palladiumcatalyzed amidation of aryl halides, involving oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration
to increase the corresponding product yield, and theoretically to accelerate the speed of the reaction and make it more exothermic. And, it should be noted that an appropriate base is particularly important. And (3), it was demonstrated that water has an assisting effect on facilitating the catalytic reaction, and serves as a source of oxygen in the product amides. This present report provides a clear understanding of amidation and offers valuable information for studying similar reactions in new catalyst systems. At the same time, the results presented in this article could provide important guidance for the synthesis of natural products and bioactive compounds.
Computational details All the calculations reported in this article were obtained with the Gaussian 09[21] suite of programs. The geometry optimizations and frequency calculations of all stationary points were optimized at the DFT level of theory with the B3LYP hybrid functional [22–25]. The 6-311 + G(d,p) [26] basis set was used for C, H, O, and N atoms. The effective core potential of Hay and Wadt with a double-ξ valence LanL2DZ basis set [27, 28] was chosen to describe Pd, Cs, P, and Br atoms. To verify the accuracy of our computational scheme, further single-point M06 [29]/LanL2DZ calculations were performed
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on all the stationary points optimized at the B3LYP/LanL2DZ level (see Table S1 in the Supporting Information). In addition, polarization functions were also added for Pd(ξf = 1.472) [30], Br(ξ d = 0.428), and P(ξ d = 0.378), respectively. Frequency outcomes were calculated to provide Gibbs free energies at 363.15 K, and to confirm the character of the stationary points as minima with no imaginary frequency, or transition states with only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations [31] were additionally carried out to ensure that transition states were connected to the reactants and products involved in the reaction. In order to support our conclusions, Hirshfeld charge analysis was performed on some selective structures [32]. To consider the solvent effect, the solvation model based on density (SMD) model [33] was employed for single-point calculations on gasphase optimized geometries in dimethyl sulfoxide (DMSO, ε = 47.2) at B3LYP/6-311G+(d,p) (LanL2DZ basis set for Pd, Cs, P, and Br atoms) level.
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Fig. 1 Free energy profiles for oxidative addition. Gas-phase and solvent-corrected Gibbs free energies (the values in parentheses) are given in kcal mol−1
Results and discussion In the DFT calculations, the catalyst [Pd(PPh 3 ) 2 Cl 2 ], bromobenzene, and tBu-isocyanide were used to study the palladium-catalyzed amidation reaction. In the whole reaction, triphenylphosphine (PPh3) is considered to be imitated by PH3 [34, 35]. Not completely considering steric-hindrance effects and electronic effects, the PH3-model is enough to account for the reaction mechanism. The palladium catalyst employed in this reaction goes through a Pd(0)–Pd(II)–Pd(0) catalytic cycle. Relative free energies were used to analyze the hypothetical reaction mechanism. As shown in Scheme 2, five basic steps (oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration) can be studied in the mechanism of amidation reaction. Four possible pathways (two monophosphine and two bisphosphine pathways) for amidation in our hypothetical reaction mechanism are proposed in this article. Based on previous research [34], the monophosphine pathways are superior to the bisphosphine pathways. Since our calculations are consistent with previous work, we moved the bisphosphine pathways to the Supporting Information. So this article depicts in detail mainly the monophosphine pathways. Oxidative addition The whole reaction process initially begins with oxidative addition of bromobenzene to a palladium(0) species. The two possible monophosphine pathways for the oxidative addition step in our assumptive reaction mechanism are shown in Fig. 1, based on palladium-catalyzed C–Br activation reactions. In this process, Pd(PH3)2 is generated from the catalyst precursor [Pd(PH3)2Cl2] in the presence of PH3 and base [36].
Thus, in order to facilitate comparison, we chose Pd(PH3)2 as the reference point of Gibbs free energies for all intermediates and transition states. Some key structures related with this section are illustrated in Fig. 2. The 14-electron unsaturated complex Pd(PH3)2 with two PH3 has a linear geometry. The length of both the Pd–P1 and Pd–P2 bonds is the same, at 2.304 Å. After losing a PH3 ligand to form monophosphine PdPH3, the Pd–P bond of PdPH3 is 0.097 Å shorter than that of Pd(PH3)2 due to the intense trans effect of the PH3 ligand. During the process of d i s s o c i a t i o n , t h e G i b b s f r e e e n e rg y v a r i a t i o n is 12.6 kcal mol−1. In path A, the bromobenzene approaches the Pd center of the 12-electron complex PdPH3, leading to the formation of Pd–C and Pd–Br bonds, and cleavage of the C–Br bond. In this process (PdPH3 → TS1), only a small energy barrier of 2.0 kcal mol−1 must be overcome. The T-shaped complex 2 has a Gibbs free energy of 9.0 kcal mol−1. In another pathway, PdPH3 can react with one molecule of bromobenzene via the three-membered ring transition state TS2 to form tricoordinated complex 3. As shown in Fig. 1, this step is exergonic by 12.1 kcal mol−1, with an energy barrier of 5.0 kcal mol−1. The C–Br bond lengths of TS1 and TS2 are 2.322 Å and 2.159 Å, respectively. These data show that breaking the C–Br bond in TS1 needs less energy than breaking that in TS2. Frontier molecular orbital (FMO) analysis can successfully explain this. As shown in Fig. 3, the molecular orbital from the Pd overlaps with the molecular orbital from benzene, which forms a π-type bonding orbital in TS1. However, in TS2, the overlap generates a π-type antibonding orbital. On the basis of the above analysis, we conclude that TS1 is more stable than TS2. In conclusion, the calculated
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Fig. 2 Geometries of the critical species for oxidative addition. Bond lengths are given in Ångstroms
relative Gibbs free energies illustrate that path A is kinetically favored for oxidative addition. It is can be seen in Fig. 4 that complexes 2 and 3 are isomeric to each other. Complex 2 can transform into complex 3 via a transition state (ts)(2/3). Interestingly, complexes 2 and 3 are in equilibrium, and appear to have a small energy barrier of 2.5 kcal mol −1 , and a slightly exothermic value of 8.5 kcal mol−1. There is a vacant spot on complexes 2 and 3 that can accept an electron-rich substrate, such as tBuisocyanide, to trigger a migratory insertion reaction.
Migratory insertion The migratory insertion of tBu-isocyanide is the most characteristic process of the amidation reaction in the presence of Pd catalyst described in this article. It is concluded that this process can be divided into two steps. Electron-rich t Buisocyanide initially coordinates to the electron-poor Pd(II) center. Subsequently, the tBu-isocyanide carbon rapidly inserts into the adjacent Pd–C2 bond. Figure 5 displays the energy profile of migratory insertion and Fig. 6 describes the detailed structures of intermediates and transition states. This is the reaction stage where tBu-isocyanide closes to form complex 2 and strongly coordinates to the electron-poor Pd(II) center to afford an extremely stable four-coordinate
Fig. 3 Highest occupied molecular orbital (HOMO) of transition state 1 (TS1) and TS2
neutral encounter: complex 4. From the free energy profile, it can be seen that this process is exergonic by 17.3 kcal mol−1. As shown in Fig. 6, four atoms (C1, C2, Br, and P) bond to the Pd(II) in complex 4. In this case, complex 5 derives from the migratory insertion of tBu-isocyanide into the adjacent Pd–C2 bond of complex 4. The energy barrier of the threemembered-ring ts(4/5) is 16.9 kcal mol−1. This step is exothermic by 2.7 kcal mol−1. In ts(4/5), the Pd–C1 bond is decreased to 1.906 Å, and Pd–C2 bond is increased to 2.154 Å compared to 1.961 Å and 2.043 Å in complex 4, respectively. The distance between the C1 and C2 atoms is 1.924 Å. These data show that the Pd–C2 bond is breaking and the C1–C2 bond is bonding. There is an obvious transition vector relevant to the imaginary frequency of ts(4/5) (279.9 I cm−1). Then, in complex 5, the C1 and C2 atoms are bonded to each other with the length of 1.491 Å.
Fig. 4 Free energy profiles for isomerization. Gas-phase and solventcorrected Gibbs free energies (values in parentheses) are given in kcal mol−1
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Fig. 5 Free energy profiles for the migratory insertion. Gas-phase and solvent-corrected Gibbs free energies (the values in parentheses) are given in kcal mol−1
Anion exchange and reductive elimination The reaction was performed efficiently with the addition of cesium fluoride (CsF) and water in the experiment [16]. Due to the impact of water, hydrolysis of CsF forms cesium hydroxide (CsOH) and creates an alkaline environment. Two possible monophosphine paths, 1a and 2a, were found to exist for anion exchange and the reductive elimination in the presence of the Pd catalyst. The assumed mechanisms are shown in Figs. 7 and 10, while the key structures related with this section are depicted in Figs. 8, 9, and 11.
Path 1a Anion exchange The anion exchange is the most significant process in the palladium-catalyzed amidation reaction. In this
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step, CsOH reacts with complex 5 to generate complex 9 along with the formation of cesium bromide (CsBr). The first step of anion exchange begins with the direct coordination of substrate CsOH to complex 5 to afford a more stable encounter: complex 6. The hydroxyl–oxygen coordinates to the center Pd, and the cesium coordinates to the bromine simultaneously. The distance between the Pd and O atoms is 2.236 Å, and there is no bonding between them. This process is exothermic by 23.7 kcal mol−1. Under the weak interaction of CsOH and complex 5, hydroxyl approaches the Pd(II) center under the control of the shortening distance between the Pd and O atoms along the reaction coordinate. At the appropriate orbital interaction, ts(6/7) of this step is formed. The free energy variation of this process is 19.8 kcal mol−1. The coordination sphere of the Pd is a slightly distorted tetrahedron, in which the Pd–Br bond is increased to 2.629 Å compared to 2.593 Å in complex 6. Clearly, the interaction between the Pd and Br atoms becomes weaker. In ts(6/7), the hydroxyl approaches the Pd center with an obvious vibration. The IRC calculation demonstrates that ts(6/7) leads to complex 7. In complex 7, the atoms Pd, Br, Cs, and O form a planar four-membered ring, and the atoms C, P, Pd, Br, Cs, and O are almost coplanar. As shown in Fig. 8, a Pd–O bond is formed, meanwhile the elongated distance between the Pd and Br atoms is beneficial to break in the next step. This process is exothermic by 5.4 kcal mol−1. In the second step, the Br atom gradually leaves the Pd center and finally releases CsBr. Stretching the Pd–Br bond generates ts(7/8). This process is needed to overcome free energy barrier of 19.1 kcal mol−1. For ts(7/8), a plane quadrangle structure is formed, which is composed of the atoms Pd, Br, Cs, and O. Then, complex 8 is formed. This process is endothermic by 18.9 kcal mol−1. The Pd–Br bond is now fully broken. The Cs–O bond is elongated to 2.979 Å compared to 2.885 Å in ts(7/8), which is beneficial for cleavage of the Cs– O bond in the next step. The Hirshfeld charges of the oxygen (−0.689e), palladium (+0.481e), and bromine (−0.606e) atoms in complex 7 are
Fig. 6 Geometries of the critical species for the migratory insertion. Bond lengths are given in Ångstroms
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Fig. 7 Free energy profiles for path 1a. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
increased to −0.835e (O), +0.534e (Pd), and −0.745e (Br) in complex 8. The change in oxygen charge (Δq = 0.146e) is mainly due to Br (Δq = 0.139e) rather than from Pd
(Δq = 0.053e). Consequently, this change in charge results in shortening of the Pd–O bond, and elongation of Cs–O bond compared to 2.099 Å and 2.872 Å in complex 7, respectively.
Fig. 10 Free energy profiles for path 2a. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
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Fig. 8 Geometries of the critical species for anion exchange of path 1a. Bond lengths are given in Ångstroms
With cleavage of the Cs–O bond, complex 9 is generated concomitant with the release of CsBr. Cleavage of the Cs–O bond needs energy of some 9.6 kcal mol−1. Fig. 9 Geometries of the critical species for reductive elimination of path 1a. Bond lengths are given in Ångstroms
Reductive elimination The product-forming step in the majority of Pd(0)-catalyzed coupling reactions, as well as in the amidation reaction described in this article, is reductive
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Fig. 11 Geometries of the critical species for path 2a. Bond lengths are given in Ångstroms
elimination. In the process of reductive elimination, the preamide product 10 is generated from complex 9, with the original palladium-catalyst PdPH3 regenerated. Some relevant structures for the reductive elimination of path 1a are depicted in Fig. 9. The three-centered ts(9/10) is formed by the distance of the C and O atoms reducing to 2.015 Å. The Pd–C and Pd–O bonds are elongated to 2.167 Å and 2.104 Å compared to 2.043 Å and 2.006 Å in 9, respectively. These data show that the elongated Pd–C and Pd–O bonds create conditions beneficial for leaving of the catalyst PdPH3. It can be seen clearly that ts(9/10) has an obvious transition vector along the reaction coordinate with an imaginary frequency of 242.1 I cm−1. The energy barrier of this step is 8.8 mol−1. Subsequently, the hydroxyl–oxygen is coupled directly with the tBu-isocyanide carbon to form a more stable complex 10 with a Gibbs free
energy of −40.4 kcal mol−1. This step is exothermic by 28.8 mol−1. Path 2a Different from the mechanism of path 1a, another assumptive mechanism exists, coupling bromine and the tBu-isocyanide carbon as the first step, while the second step is anion exchange. Reductive elimination As shown in Fig. 10, the reductive elimination of complex 5, in which the bromine couples with the t Bu-isocyanide carbon, generates the threemembered ring ts(5/13). Then, with the cleavage of the Pd– Br and Pd–C bonds, the catalyst PdPH3 and complex 13 are formed. Our calculations indicate that this process is slightly
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endothermic by an effective Gibbs energy of 6.9 kcal mol−1, with a large energy barrier of 20.5 kcal mol−1. Anion exchange In the process of anion exchange, CsOH reacts with complex 13 to afford stable complex 10 along with the release of CsBr. The initial anion exchange step starts with the direct coordination of the substrate CsOH to complex 13 to produce the intermediate complex 14; this process is exothermic by 1.3 kcal mol−1. As shown in Fig. 11, in complex 14, the bromine coordinates to the cesium center. The C–O bond has not formed. Along with cleavage of the C–Br bond and the simultaneous formation of the C–O bond, the four-membered-ring ts(14/15) is then generated with a small energy barrier of 0.8 kcal mol−1. This step is a concerted reaction. In ts(14/15), a plane quadrangle appears that is constructed by the atoms C, Br, Cs, and O. The Cs–Br bond is decreased to 3.665 Å, and the Cs–O and C–Br bonds are increased to 2.847 Å and 2.703 Å in ts(14/15) compared to 3.744 Å, 2.817 Å, and 2.452 Å in 14, respectively. Then, complex 15 is formed. It is noted that this process is exothermic by 41.8 kcal mol−1. In 15, the C–O bond is formed with a distance of 1.370 Å. The Cs–O bond is elongated to 3.176 Å compared to 2.847 Å in ts(14/15), which helps the release of CsBr in the next step. In addition, the C– Br bond is fully broken. This step subsequently yields complex 10 and CsBr, with an elongated distance of the Cs–O bond. This process is endothermic by 6.8 kcal mol−1. Comparing the free energy profiles of paths 1a and 2a, it can be seen that the highest energy points are ts(9/10) and ts(5/13). Their Gibbs free energies are −2.8 kcal mol−1 and 9.5 kcal mol−1, respectively. These results show that path 1a is the energetically favored pathway. As shown in Figs. 7 and 10, ts(9/10) and ts(5/13) have a similar structure. The main difference between them is that the three-membered ring of ts(9/10) is constructed by the atoms C, Pd, and O, while that of ts(5/13) is constructed by C, Pd, and Br. Since hydroxyl has a stronger electron-donating ability than that of bromine, formation of the C–O bond has less energy than that of the C–Br bond. To further demonstrate our point, Hirshfeld charge analysis was performed on ts(9/10) and ts(5/13). It is evident that the oxygen of ts(9/10) carries more negative charge than the bromine of ts(5/13) [−0.513e and −0.131e for ts(9/10) and ts(5/13), respectively]. And the coupling carbons of tBuisocyanide carry positive charge [0.099e and 0.005e for ts(9/10) and ts(5/13), respectively]. Hence, electrostatic interactions between the negatively charged oxygen and the positively charged tBu-isocyanide carbon of ts(9/10) are responsible for stabilizing ts(9/10). These data are enough to support our opinion and demonstrate that path 1a is the favored pathway.
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Hydrogen migration The last step is the hydrogen migration of complex 10 to afford the more stable amide-product 11. Figure 12 clearly shows that this process includes two different competitive paths: the four-membered ring mechanism [10 → ts(10/11a) → 11] and the six-membered ring mechanism [10 → ts(10/ 11b) → 11]. Figure 13 displays the optimized structures of this part. Initial calculations on the four-membered ring mechanism show that hydrogen migrates directly from oxygen to nitrogen. The energy variation from 10 to ts(10/11a) is 28.6 kcal mol−1. The energy barrier of the four-membered ring pathway appears too high to be energetically feasible. In order for this process to happen, we find a six-membered ring transition state, ts(10/11b), with the help of water. Figure 12 shows that the six-membered ring path is kinetically favored over the four-membered ring path. Due to the interaction of water, the six-membered ring path goes through ts(10/11b) with an energy barrier of 13.5 kcal mol−1. As shown in Fig. 13, the atoms C, N, H1, H2, O1, and O2 establish a planar six-membered ring, in which the C–N bond is elongated to 1.305 Å, and the C–O1 bond is shorted to 1.307 Å compared to 1.268 Å and 1.375 Å in 10, respectively. The transition state ts(10/11b) has an obvious transition vector along the reaction coordinate, with an imaginary frequency of 1350.0 I cm−1. The amideproduct 11 is formed with a Gibbs free energy of
Fig. 12 Free energy profiles for hydrogen migration. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
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Fig. 13 Geometries of the critical species for hydrogen migration. Bond lengths are given in Ångstroms
−50.0 kcal mol−1, which is more stable than complex 10 by 9.6 kcal mol−1. The role of CsF To demonstrate the influence of CsF in the process of anion exchange, we also computed the Gibbs free energy variation of base-free pathway. As shown in Fig. 14, the nucleophilic reagent H2O attacks the Pd center of complex 5 to form a tetracoordinated complex 17. In this process, the transition state ts-H 2 O is generated with an energy barrier of 16.6 kcal mol−1. The formation of complex 17 is endothermic by 4.0 kcal mol−1. Then, with the release of hydrogen bromide, complex 9 is formed via ts-Br. This process is Fig. 14 Free energy profiles for base-free pathway. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
exothermic by 4.6 kcal mol−1, with a large energy barrier of 48.9 kcal mol−1. The base-free step is energetically unfeasible. Compared to the free energy profiles of the base-assisted optimal path 1a and the base-free pathway, the data show that the base-free pathway has a higher energy barrier (48.9 kcal mol−1) than the base-assisted pathway. It is safe to say that the reaction does not happen without addition of a base. This result is consistent with the experimental fact that no desired product 11 is detected without any base. Given this situation, we analyzed the key structures of intermediates 7 and 17. It can be seen that 7 and 17 are quite similar. The only difference between them is that the oxygen of 7 bonds to the hydrogen and cesium atoms, while the oxygen of 17 bonds to two hydrogen atoms. To test the role of the base in the anion
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Fig. 15 Free energy profiles for the whole reaction. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
exchange process, calculations were conducted for 7 and 17. Hirshfeld charges on the Cs and Br atoms are +0.818e and −0.606e for 7, while those on the H1 and Br atoms are +0.287e and −0.402e for 17, respectively. It is evident that the Cs atom acts as an electrophile and has a stronger eletrophilicity ability than the H1 atom. The Br atom is a nucleophile. With the eletrophilicity strengthened, the barriers decrease for the base-assisted pathway and increase for the base-free pathway. Consequently, the base-assisted mechanism is more favored both kinetically and thermodynamically than the base-free pathway in the presence of CsF. CsF as the base employed in palladium-catalyzed amidation could promote more efficient anion exchange. In addition, due to the influence of water, the hydrolysis of CsF formed CsOH, which participates in anion exchange. And our calculations demonstrate that water is an oxygen source for the amide product. Jiang and his co-workers’ isotopic tracer method in the experiment provides forceful support for our hypothesis [15].
Conclusions A systematic theoretical study of palladium-catalyzed amidation of bromobenzene and tBu-isocyanide has been presented in this article. All possible pathways were carefully researched, and the minimum energy pathway theoretically located. The Gibbs free energy profile for the overall catalytic cycle is illustrated in Fig. 15. The amidation can be divided into five major stages: oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration. Our calculations lead to the conclusion that the energy
barrier is systematically lower for the monophosphine pathways due to the avoidance of steric interactions between the two phosphine ligands. The oxidative addition of PdPH3 to bromobenzene has the highest activation energy in the whole catalytic cycle, hence becoming the rate-determining step [35] (see Fig. 4S in the Supporting Information). In the migratory insertion, tBu-isocyanide inserts an ortho Pd–C bond and provides a source of both a carboxy and an amino group. Then, the anion exchange is the most valuable process. The following conclusions are drawn: (1) Comparing paths 1a and 2a, Hirshfeld charge analysis of the key transition states ts(9/10) and ts(5/13) demonstrated that path 1a is favored; (2) Our calculations are in accordance with the experimental findings in which water serves as a source of oxygen through O18labeling; and (3) Compared to the base-free and baseassisted pathways, anion exchange pathway accessibly happens with the help of a base, and the base plays a vital role that makes reaction more exothermic in the key step, thereby enhancing path 1a as the best choice. Next, reductive elimination occurs. As far as we known, this is the pre-product forming step in the majority of Pd-catalyzed coupling reactions. Finally, the hydrogen migration step includes two possible pathways. Our calculations indicate that the six-membered ring path is better than the four-membered ring path. Water was demonstrated to facilitate the catalytic reaction. The whole reaction includes both exothermic and exergonic processes. Acknowledgments This work was supported by the Natural Science Foundations of China (21501115, 21373131, and 21571119). Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest.
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References 1. 2. 3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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Qiu GYS, Ding QP, Wu J (2013) Recent advances in isocyanide insertion chemistry. Chem Soc Rev 42:5257–5269 Montalbetti CAGN, Falque V (2005) Amide bond formation and peptide coupling. Tetrahedron 61:10827–10852 Vaidyanathan R, Kalthod VG, Ngo DP, Manley JM, Lapekas SP (2004) Amidations using N, N-carbonyldiimidazole: remarkable rate enhancement by carbon dioxide. J Org Chem 69:2565–2568 Shendage DM, Frohlich R, Haufe G (2004) Highly efficient stereoconservative amidation and deamidation of r-amino acids. Org Lett 6:3675–3678 Baum JC, Milne JEM, Murry JA, Thiel OR (2009) An efficient and scalable Ritter reaction for the synthesis of tert-butyl amides. J Org Chem 74:2207–2209 Shimizu K, Ohshima K, Satsuma A (2009) Direct dehydrogenative amide synthesis from alcohols and amines catalyzed by g-alumina supported silver cluster. Chem Eur J 15:9977–9980 Watson AJA, Maxwell AC, Williams JMJ (2009) Rutheniumcatalyzed oxidation of alcohols into amides. Org Lett 11:2667– 2670 Fujita K, Takahashi Y, Owaki M, Yamamoto K, Yamaguchi R (2004) Synthesis of five-, Six-, and seven-membered ring lactams by Cp*Rh complex-catalyzed oxidative N-heterocyclization of amino alcohols. Org Lett 6:2785–2788 Schoenberg A, Heck RF (1974) Palladium-catalyzed amidation of aryl, heterocyclic, and vinylic halides. J Org Chem 39:1974–3327 Orito K, Miyazawa M, Nakamura T, Horibata A, Ushito H, Nagasaki H, Yuguchi M, Yamashita S, Yamazaki T, Tokuda M (2006) Pd(OAc)2-catalyzed carbonylation of amines. J Org Chem 71:5951–5958 Martinelli JR, Freckmann DMM, Buchwald SL (2006) Convenient method for the preparation of weinreb amides via Pd-catalyzed aminocarbonylation of aryl bromides at atmospheric pressure. Org Lett 8:4843–4846 Ren W, Yamane M (2010) Carbamoylation of aryl halides by molybdenum or tungsten carbonyl amine complexes. J Org Chem 75: 3017–3020 Ren W, Yamane M (2009) Palladium-catalyzed carbamoylation of aryl halides by tungsten carbonyl amine complex. J Org Chem 74: 8332–8335 Gulevich AV, Zhdanko AG, Orru RVA, Nenajdenko VG (2010) Isocyanoacetate derivatives: synthesis, reactivity, and application. Chem Rev 110:5235–5331 Jiang HF, Liu BF, Li YB, Wang AZ, Huang HW (2011) Synthesis of amides via palladium catalyzed amidation of aryl halides. Org Lett 13:1028–1031 Kosugi M, Ogata T, Tamura H, Sano H, Migita T (1986) Palladium catalyzed iminocarbonylation of bromobenzene with isocyanide and organotin compound. Chem Letts 1986:1197–1200 Saluste CG, Whitby RJ, Furber M (2000) A palladium-catalyzed synthesis of amidines from aryl halides. Angew Chem Int Ed 39: 4156–4158 Onitsuka K, Suzuki S, Takahashi S (2002) A novel route to 2,3disubstituted indoles via palladium-catalyzed three-component coupling of aryl iodide, o-alkenylphenyl isocyanide and amine. Tetrahedron Lett 43:6197–6199 Carvajal MA, Miscione GP, Novoa JJ, Bottoni A (2005) DFT computational study of the mechanism of allyl chloride carbonylation catalyzed by palladium complexes. Organometallics 24:2086–2096
20.
Hu YH, Liu J, Lu ZX, Luo XC, Zhang H, Lan Y, Lei AW (2010) Base-induced mechanistic variation in palladium-catalyzed carbonylation of aryl iodides. J Am Chem Soc 132:3153–3158 21. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.02; Gaussian, Inc.: Wallingford CT. 22. Becke AD (1993) A new mixing of Hartree-Fock and local densityfunctional theories. J Chem Phys 98:1372–1377 23. Stephens PJ, Devlin FJ (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J Phys Chem 98:11624–11627 24. Becke AD (1993) Density-functional thermochemistry III. The role of exact exchange. J Chem Phys 98:5648–5652 25. Lee C, Yang W, Parr RG (1988) Development of the colic-salvetti correlation-energy formula into a functional of the electron density. Phys Rev 37:785–789 26. Frisch MJ, Pople JA, Binkley JS (1984) Self-consistent molecular orbital methods 25. Supplementary functions for Gaussian basis sets. J Chem Phys 80:3265–3269 27. Wadt WR, Hay PJ (1985) Ab Initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi. J Chem Phys 82:284–298 28. Hay PJ, Wadt WR (1985) Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J Chern Phys 82:299–310 29. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functional and systematic testing of four M06-class functionals and 12 other functional. Theor Chem Account 120:215–241 30. Ariafard A, Yates BF (2009) Subtle balance of ligand steric effects in stille transmetalation. J Am Chem Soc 131:13981–13991 31. Fuku K (1981) The path of chemical reactions—the IRC approach. Acc Chem Res 14:363–368 32. Hirshfeld FL (1977) Bonded-atom fragments for describing molecular charge densities. Theor Chem Acta 44:129–138 33. Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396 34. Ren Y, Jia JF, Zhang TT, Wu HS, Liu WX (2012) Computational study on the palladium-catalyzed allenylative dearomatization reaction. Organometallics 31:1168–1179 35. Ren Y, Jia JF, Liu WX, Wu HS (2013) Theoretical study on the mechanism of palladium-catalyzed dearomatization reaction of chloromethylnaphthalene. Organometallics 32:52–62 36. Soomro SS, Ansari FL, Chatziapostolou K, Köhler K (2010) Palladium leaching dependent on reaction parameters in Suzuki– Miyaura coupling reactions catalyzed by palladium supported on alumina under mild reaction conditions. J Catal 273:138–146
ORIGINAL PAPER
Mechanistic investigation of palladium-catalyzed amidation of aryl halides Yun Liang 1 & Ying Ren 1 & Jianfeng Jia 1 & Hai-Shun Wu 1
Received: 1 November 2015 / Accepted: 20 January 2016 # Springer-Verlag Berlin Heidelberg 2016
Abstract A mechanistic investigation using Becke3LYP density functional theory (DFT) was carried out on the palladiumcatalyzed amidition of bromobenzene and tBu-isocyanide. The whole catalytic cycle consists of five steps: oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration. The rate-determining step is oxidative addition, with a small Gibbs free energy of 14.6 kcal mol −1 . In the migratory insertion step, t Buisocyanide provides an important source of carboxy and amino groups to establish the amide group. For anion exchange, path 1a is suggested as the most favorable pathway with the help of the base, and water provides a source of oxygen which is perfectly in line with experimental observations. Finally, in the hydrogen migration step, we illustrate that the six-membered ring path is energetically favored due to the assisting influence of water. In addition, our calculations indicate that using dimethyl sulfoxide as a solvent does not change the rate-determining step.
Keywords Palladium . tBu-isocyanide . Anion exchange . Amidation . DFT
Electronic supplementary material The online version of this article (doi:10.1007/s00894-016-2920-5) contains supplementary material, which is available to authorized users. * Ying Ren [email protected] * Hai-Shun Wu [email protected]
1
School of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, People’s Republic of China
Introduction Amides are of paramount importance as functional groups in organic synthesis, and are common components of abundant natural products and bioactive compounds [1]. The transitionmetal-catalyzed cross-coupling reaction has become a most effective and selective way to form carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds, since it can directly establish the molecular skeletons of these potential precursors from readily available reactants in organic chemistry [2–5]. Previous reports have proposed various transition metal catalysts for amide synthesis reactions, such as Ag nanoparticles [6], and Ru [7] and Rh complexes [8]. Nonetheless, we are particularly interested in palladium-catalyzed cross-coupling reactions [9–11], because these reactions offer diverse perspectives for the formation of carbon–carbon bonds. Palladium catalysts are well known for their extremely strong functional group tolerance and high efficiency; however, lengthy reaction times and the use of the poisonous gas carbon monoxide limit the scope of their use for carbonylation [12, 13]. Isocyanides [14], a series of unsaturated molecule analogous to carbon monoxide, would be the most likely candidates to replace carbon monoxide in palladium-catalyzed coupling reactions, because they can supply not only a carboxy but also an amino group, and react with both nucleophiles and electrophiles on the same carbon atom. Recently, Jiang and coworkers [15] discovered a new and efficient palladiumcatalyzed amidation reaction of aryl halides with t Buisocyanides at moderate temperature to give the stable corresponding amides (Scheme 1). The use of isocyanides not only provides a new and environmentally friendly way to synthesize amides, but also simplifies the initial reaction paths as well as the experiment conditions. Unlike in previous research [16–18], water serves as a nucleophilic reagent and provides a
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Scheme 1 Efficient palladiumcatalyzed amidation of aryl halides with t-Bu-isocyanides
source of oxygen in this reaction. Meanwhile, Jiang and his co-workers [15] assumed a reaction mechanism involving oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration (Scheme 2). To our knowledge, although palladium-catalyzed amidation of bromobenzene with tBu-isocyanides has been achieved successfully, the detailed mechanism still remains ambiguous. Although very few theoretical studies have focused on palladium-catalyzed coupling reactions involving isocyanides, a number of theoretical investigations have been carried out for other palladium-catalyzed C–C coupling reactions. For example, Carvajal et al. [19] studied the mechanism of palladium-catalyzed allyl chloride carbonylation with the help of density functional theory (DFT) calculations. Hu et al. [20] employed the B3LYP level of DFT to investigate the mechanism of sodium alkoxide as the base in palladiumcatalyzed carbonylation of aryl iodides. Recently, we researched the mechanistic details of palladium-catalyzed amidation of bromobenzene and tBu-isocyanides with the help of DFT calculations. Furthermore, several crucial problems were addressed. (1) We proposed four feasible reaction mechanisms and demonstrated that the energy barriers of monophosphine pathways are lower than the bisphosphine ones. (2) We gained an in-depth knowledge of the role of cesium fluoride (CsF), which was illustrated experimentally Scheme 2 Proposed reaction mechanism [15] of palladiumcatalyzed amidation of aryl halides, involving oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration
to increase the corresponding product yield, and theoretically to accelerate the speed of the reaction and make it more exothermic. And, it should be noted that an appropriate base is particularly important. And (3), it was demonstrated that water has an assisting effect on facilitating the catalytic reaction, and serves as a source of oxygen in the product amides. This present report provides a clear understanding of amidation and offers valuable information for studying similar reactions in new catalyst systems. At the same time, the results presented in this article could provide important guidance for the synthesis of natural products and bioactive compounds.
Computational details All the calculations reported in this article were obtained with the Gaussian 09[21] suite of programs. The geometry optimizations and frequency calculations of all stationary points were optimized at the DFT level of theory with the B3LYP hybrid functional [22–25]. The 6-311 + G(d,p) [26] basis set was used for C, H, O, and N atoms. The effective core potential of Hay and Wadt with a double-ξ valence LanL2DZ basis set [27, 28] was chosen to describe Pd, Cs, P, and Br atoms. To verify the accuracy of our computational scheme, further single-point M06 [29]/LanL2DZ calculations were performed
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on all the stationary points optimized at the B3LYP/LanL2DZ level (see Table S1 in the Supporting Information). In addition, polarization functions were also added for Pd(ξf = 1.472) [30], Br(ξ d = 0.428), and P(ξ d = 0.378), respectively. Frequency outcomes were calculated to provide Gibbs free energies at 363.15 K, and to confirm the character of the stationary points as minima with no imaginary frequency, or transition states with only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations [31] were additionally carried out to ensure that transition states were connected to the reactants and products involved in the reaction. In order to support our conclusions, Hirshfeld charge analysis was performed on some selective structures [32]. To consider the solvent effect, the solvation model based on density (SMD) model [33] was employed for single-point calculations on gasphase optimized geometries in dimethyl sulfoxide (DMSO, ε = 47.2) at B3LYP/6-311G+(d,p) (LanL2DZ basis set for Pd, Cs, P, and Br atoms) level.
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Fig. 1 Free energy profiles for oxidative addition. Gas-phase and solvent-corrected Gibbs free energies (the values in parentheses) are given in kcal mol−1
Results and discussion In the DFT calculations, the catalyst [Pd(PPh 3 ) 2 Cl 2 ], bromobenzene, and tBu-isocyanide were used to study the palladium-catalyzed amidation reaction. In the whole reaction, triphenylphosphine (PPh3) is considered to be imitated by PH3 [34, 35]. Not completely considering steric-hindrance effects and electronic effects, the PH3-model is enough to account for the reaction mechanism. The palladium catalyst employed in this reaction goes through a Pd(0)–Pd(II)–Pd(0) catalytic cycle. Relative free energies were used to analyze the hypothetical reaction mechanism. As shown in Scheme 2, five basic steps (oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration) can be studied in the mechanism of amidation reaction. Four possible pathways (two monophosphine and two bisphosphine pathways) for amidation in our hypothetical reaction mechanism are proposed in this article. Based on previous research [34], the monophosphine pathways are superior to the bisphosphine pathways. Since our calculations are consistent with previous work, we moved the bisphosphine pathways to the Supporting Information. So this article depicts in detail mainly the monophosphine pathways. Oxidative addition The whole reaction process initially begins with oxidative addition of bromobenzene to a palladium(0) species. The two possible monophosphine pathways for the oxidative addition step in our assumptive reaction mechanism are shown in Fig. 1, based on palladium-catalyzed C–Br activation reactions. In this process, Pd(PH3)2 is generated from the catalyst precursor [Pd(PH3)2Cl2] in the presence of PH3 and base [36].
Thus, in order to facilitate comparison, we chose Pd(PH3)2 as the reference point of Gibbs free energies for all intermediates and transition states. Some key structures related with this section are illustrated in Fig. 2. The 14-electron unsaturated complex Pd(PH3)2 with two PH3 has a linear geometry. The length of both the Pd–P1 and Pd–P2 bonds is the same, at 2.304 Å. After losing a PH3 ligand to form monophosphine PdPH3, the Pd–P bond of PdPH3 is 0.097 Å shorter than that of Pd(PH3)2 due to the intense trans effect of the PH3 ligand. During the process of d i s s o c i a t i o n , t h e G i b b s f r e e e n e rg y v a r i a t i o n is 12.6 kcal mol−1. In path A, the bromobenzene approaches the Pd center of the 12-electron complex PdPH3, leading to the formation of Pd–C and Pd–Br bonds, and cleavage of the C–Br bond. In this process (PdPH3 → TS1), only a small energy barrier of 2.0 kcal mol−1 must be overcome. The T-shaped complex 2 has a Gibbs free energy of 9.0 kcal mol−1. In another pathway, PdPH3 can react with one molecule of bromobenzene via the three-membered ring transition state TS2 to form tricoordinated complex 3. As shown in Fig. 1, this step is exergonic by 12.1 kcal mol−1, with an energy barrier of 5.0 kcal mol−1. The C–Br bond lengths of TS1 and TS2 are 2.322 Å and 2.159 Å, respectively. These data show that breaking the C–Br bond in TS1 needs less energy than breaking that in TS2. Frontier molecular orbital (FMO) analysis can successfully explain this. As shown in Fig. 3, the molecular orbital from the Pd overlaps with the molecular orbital from benzene, which forms a π-type bonding orbital in TS1. However, in TS2, the overlap generates a π-type antibonding orbital. On the basis of the above analysis, we conclude that TS1 is more stable than TS2. In conclusion, the calculated
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Fig. 2 Geometries of the critical species for oxidative addition. Bond lengths are given in Ångstroms
relative Gibbs free energies illustrate that path A is kinetically favored for oxidative addition. It is can be seen in Fig. 4 that complexes 2 and 3 are isomeric to each other. Complex 2 can transform into complex 3 via a transition state (ts)(2/3). Interestingly, complexes 2 and 3 are in equilibrium, and appear to have a small energy barrier of 2.5 kcal mol −1 , and a slightly exothermic value of 8.5 kcal mol−1. There is a vacant spot on complexes 2 and 3 that can accept an electron-rich substrate, such as tBuisocyanide, to trigger a migratory insertion reaction.
Migratory insertion The migratory insertion of tBu-isocyanide is the most characteristic process of the amidation reaction in the presence of Pd catalyst described in this article. It is concluded that this process can be divided into two steps. Electron-rich t Buisocyanide initially coordinates to the electron-poor Pd(II) center. Subsequently, the tBu-isocyanide carbon rapidly inserts into the adjacent Pd–C2 bond. Figure 5 displays the energy profile of migratory insertion and Fig. 6 describes the detailed structures of intermediates and transition states. This is the reaction stage where tBu-isocyanide closes to form complex 2 and strongly coordinates to the electron-poor Pd(II) center to afford an extremely stable four-coordinate
Fig. 3 Highest occupied molecular orbital (HOMO) of transition state 1 (TS1) and TS2
neutral encounter: complex 4. From the free energy profile, it can be seen that this process is exergonic by 17.3 kcal mol−1. As shown in Fig. 6, four atoms (C1, C2, Br, and P) bond to the Pd(II) in complex 4. In this case, complex 5 derives from the migratory insertion of tBu-isocyanide into the adjacent Pd–C2 bond of complex 4. The energy barrier of the threemembered-ring ts(4/5) is 16.9 kcal mol−1. This step is exothermic by 2.7 kcal mol−1. In ts(4/5), the Pd–C1 bond is decreased to 1.906 Å, and Pd–C2 bond is increased to 2.154 Å compared to 1.961 Å and 2.043 Å in complex 4, respectively. The distance between the C1 and C2 atoms is 1.924 Å. These data show that the Pd–C2 bond is breaking and the C1–C2 bond is bonding. There is an obvious transition vector relevant to the imaginary frequency of ts(4/5) (279.9 I cm−1). Then, in complex 5, the C1 and C2 atoms are bonded to each other with the length of 1.491 Å.
Fig. 4 Free energy profiles for isomerization. Gas-phase and solventcorrected Gibbs free energies (values in parentheses) are given in kcal mol−1
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Fig. 5 Free energy profiles for the migratory insertion. Gas-phase and solvent-corrected Gibbs free energies (the values in parentheses) are given in kcal mol−1
Anion exchange and reductive elimination The reaction was performed efficiently with the addition of cesium fluoride (CsF) and water in the experiment [16]. Due to the impact of water, hydrolysis of CsF forms cesium hydroxide (CsOH) and creates an alkaline environment. Two possible monophosphine paths, 1a and 2a, were found to exist for anion exchange and the reductive elimination in the presence of the Pd catalyst. The assumed mechanisms are shown in Figs. 7 and 10, while the key structures related with this section are depicted in Figs. 8, 9, and 11.
Path 1a Anion exchange The anion exchange is the most significant process in the palladium-catalyzed amidation reaction. In this
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step, CsOH reacts with complex 5 to generate complex 9 along with the formation of cesium bromide (CsBr). The first step of anion exchange begins with the direct coordination of substrate CsOH to complex 5 to afford a more stable encounter: complex 6. The hydroxyl–oxygen coordinates to the center Pd, and the cesium coordinates to the bromine simultaneously. The distance between the Pd and O atoms is 2.236 Å, and there is no bonding between them. This process is exothermic by 23.7 kcal mol−1. Under the weak interaction of CsOH and complex 5, hydroxyl approaches the Pd(II) center under the control of the shortening distance between the Pd and O atoms along the reaction coordinate. At the appropriate orbital interaction, ts(6/7) of this step is formed. The free energy variation of this process is 19.8 kcal mol−1. The coordination sphere of the Pd is a slightly distorted tetrahedron, in which the Pd–Br bond is increased to 2.629 Å compared to 2.593 Å in complex 6. Clearly, the interaction between the Pd and Br atoms becomes weaker. In ts(6/7), the hydroxyl approaches the Pd center with an obvious vibration. The IRC calculation demonstrates that ts(6/7) leads to complex 7. In complex 7, the atoms Pd, Br, Cs, and O form a planar four-membered ring, and the atoms C, P, Pd, Br, Cs, and O are almost coplanar. As shown in Fig. 8, a Pd–O bond is formed, meanwhile the elongated distance between the Pd and Br atoms is beneficial to break in the next step. This process is exothermic by 5.4 kcal mol−1. In the second step, the Br atom gradually leaves the Pd center and finally releases CsBr. Stretching the Pd–Br bond generates ts(7/8). This process is needed to overcome free energy barrier of 19.1 kcal mol−1. For ts(7/8), a plane quadrangle structure is formed, which is composed of the atoms Pd, Br, Cs, and O. Then, complex 8 is formed. This process is endothermic by 18.9 kcal mol−1. The Pd–Br bond is now fully broken. The Cs–O bond is elongated to 2.979 Å compared to 2.885 Å in ts(7/8), which is beneficial for cleavage of the Cs– O bond in the next step. The Hirshfeld charges of the oxygen (−0.689e), palladium (+0.481e), and bromine (−0.606e) atoms in complex 7 are
Fig. 6 Geometries of the critical species for the migratory insertion. Bond lengths are given in Ångstroms
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Fig. 7 Free energy profiles for path 1a. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
increased to −0.835e (O), +0.534e (Pd), and −0.745e (Br) in complex 8. The change in oxygen charge (Δq = 0.146e) is mainly due to Br (Δq = 0.139e) rather than from Pd
(Δq = 0.053e). Consequently, this change in charge results in shortening of the Pd–O bond, and elongation of Cs–O bond compared to 2.099 Å and 2.872 Å in complex 7, respectively.
Fig. 10 Free energy profiles for path 2a. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
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Fig. 8 Geometries of the critical species for anion exchange of path 1a. Bond lengths are given in Ångstroms
With cleavage of the Cs–O bond, complex 9 is generated concomitant with the release of CsBr. Cleavage of the Cs–O bond needs energy of some 9.6 kcal mol−1. Fig. 9 Geometries of the critical species for reductive elimination of path 1a. Bond lengths are given in Ångstroms
Reductive elimination The product-forming step in the majority of Pd(0)-catalyzed coupling reactions, as well as in the amidation reaction described in this article, is reductive
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Fig. 11 Geometries of the critical species for path 2a. Bond lengths are given in Ångstroms
elimination. In the process of reductive elimination, the preamide product 10 is generated from complex 9, with the original palladium-catalyst PdPH3 regenerated. Some relevant structures for the reductive elimination of path 1a are depicted in Fig. 9. The three-centered ts(9/10) is formed by the distance of the C and O atoms reducing to 2.015 Å. The Pd–C and Pd–O bonds are elongated to 2.167 Å and 2.104 Å compared to 2.043 Å and 2.006 Å in 9, respectively. These data show that the elongated Pd–C and Pd–O bonds create conditions beneficial for leaving of the catalyst PdPH3. It can be seen clearly that ts(9/10) has an obvious transition vector along the reaction coordinate with an imaginary frequency of 242.1 I cm−1. The energy barrier of this step is 8.8 mol−1. Subsequently, the hydroxyl–oxygen is coupled directly with the tBu-isocyanide carbon to form a more stable complex 10 with a Gibbs free
energy of −40.4 kcal mol−1. This step is exothermic by 28.8 mol−1. Path 2a Different from the mechanism of path 1a, another assumptive mechanism exists, coupling bromine and the tBu-isocyanide carbon as the first step, while the second step is anion exchange. Reductive elimination As shown in Fig. 10, the reductive elimination of complex 5, in which the bromine couples with the t Bu-isocyanide carbon, generates the threemembered ring ts(5/13). Then, with the cleavage of the Pd– Br and Pd–C bonds, the catalyst PdPH3 and complex 13 are formed. Our calculations indicate that this process is slightly
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endothermic by an effective Gibbs energy of 6.9 kcal mol−1, with a large energy barrier of 20.5 kcal mol−1. Anion exchange In the process of anion exchange, CsOH reacts with complex 13 to afford stable complex 10 along with the release of CsBr. The initial anion exchange step starts with the direct coordination of the substrate CsOH to complex 13 to produce the intermediate complex 14; this process is exothermic by 1.3 kcal mol−1. As shown in Fig. 11, in complex 14, the bromine coordinates to the cesium center. The C–O bond has not formed. Along with cleavage of the C–Br bond and the simultaneous formation of the C–O bond, the four-membered-ring ts(14/15) is then generated with a small energy barrier of 0.8 kcal mol−1. This step is a concerted reaction. In ts(14/15), a plane quadrangle appears that is constructed by the atoms C, Br, Cs, and O. The Cs–Br bond is decreased to 3.665 Å, and the Cs–O and C–Br bonds are increased to 2.847 Å and 2.703 Å in ts(14/15) compared to 3.744 Å, 2.817 Å, and 2.452 Å in 14, respectively. Then, complex 15 is formed. It is noted that this process is exothermic by 41.8 kcal mol−1. In 15, the C–O bond is formed with a distance of 1.370 Å. The Cs–O bond is elongated to 3.176 Å compared to 2.847 Å in ts(14/15), which helps the release of CsBr in the next step. In addition, the C– Br bond is fully broken. This step subsequently yields complex 10 and CsBr, with an elongated distance of the Cs–O bond. This process is endothermic by 6.8 kcal mol−1. Comparing the free energy profiles of paths 1a and 2a, it can be seen that the highest energy points are ts(9/10) and ts(5/13). Their Gibbs free energies are −2.8 kcal mol−1 and 9.5 kcal mol−1, respectively. These results show that path 1a is the energetically favored pathway. As shown in Figs. 7 and 10, ts(9/10) and ts(5/13) have a similar structure. The main difference between them is that the three-membered ring of ts(9/10) is constructed by the atoms C, Pd, and O, while that of ts(5/13) is constructed by C, Pd, and Br. Since hydroxyl has a stronger electron-donating ability than that of bromine, formation of the C–O bond has less energy than that of the C–Br bond. To further demonstrate our point, Hirshfeld charge analysis was performed on ts(9/10) and ts(5/13). It is evident that the oxygen of ts(9/10) carries more negative charge than the bromine of ts(5/13) [−0.513e and −0.131e for ts(9/10) and ts(5/13), respectively]. And the coupling carbons of tBuisocyanide carry positive charge [0.099e and 0.005e for ts(9/10) and ts(5/13), respectively]. Hence, electrostatic interactions between the negatively charged oxygen and the positively charged tBu-isocyanide carbon of ts(9/10) are responsible for stabilizing ts(9/10). These data are enough to support our opinion and demonstrate that path 1a is the favored pathway.
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Hydrogen migration The last step is the hydrogen migration of complex 10 to afford the more stable amide-product 11. Figure 12 clearly shows that this process includes two different competitive paths: the four-membered ring mechanism [10 → ts(10/11a) → 11] and the six-membered ring mechanism [10 → ts(10/ 11b) → 11]. Figure 13 displays the optimized structures of this part. Initial calculations on the four-membered ring mechanism show that hydrogen migrates directly from oxygen to nitrogen. The energy variation from 10 to ts(10/11a) is 28.6 kcal mol−1. The energy barrier of the four-membered ring pathway appears too high to be energetically feasible. In order for this process to happen, we find a six-membered ring transition state, ts(10/11b), with the help of water. Figure 12 shows that the six-membered ring path is kinetically favored over the four-membered ring path. Due to the interaction of water, the six-membered ring path goes through ts(10/11b) with an energy barrier of 13.5 kcal mol−1. As shown in Fig. 13, the atoms C, N, H1, H2, O1, and O2 establish a planar six-membered ring, in which the C–N bond is elongated to 1.305 Å, and the C–O1 bond is shorted to 1.307 Å compared to 1.268 Å and 1.375 Å in 10, respectively. The transition state ts(10/11b) has an obvious transition vector along the reaction coordinate, with an imaginary frequency of 1350.0 I cm−1. The amideproduct 11 is formed with a Gibbs free energy of
Fig. 12 Free energy profiles for hydrogen migration. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
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Fig. 13 Geometries of the critical species for hydrogen migration. Bond lengths are given in Ångstroms
−50.0 kcal mol−1, which is more stable than complex 10 by 9.6 kcal mol−1. The role of CsF To demonstrate the influence of CsF in the process of anion exchange, we also computed the Gibbs free energy variation of base-free pathway. As shown in Fig. 14, the nucleophilic reagent H2O attacks the Pd center of complex 5 to form a tetracoordinated complex 17. In this process, the transition state ts-H 2 O is generated with an energy barrier of 16.6 kcal mol−1. The formation of complex 17 is endothermic by 4.0 kcal mol−1. Then, with the release of hydrogen bromide, complex 9 is formed via ts-Br. This process is Fig. 14 Free energy profiles for base-free pathway. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
exothermic by 4.6 kcal mol−1, with a large energy barrier of 48.9 kcal mol−1. The base-free step is energetically unfeasible. Compared to the free energy profiles of the base-assisted optimal path 1a and the base-free pathway, the data show that the base-free pathway has a higher energy barrier (48.9 kcal mol−1) than the base-assisted pathway. It is safe to say that the reaction does not happen without addition of a base. This result is consistent with the experimental fact that no desired product 11 is detected without any base. Given this situation, we analyzed the key structures of intermediates 7 and 17. It can be seen that 7 and 17 are quite similar. The only difference between them is that the oxygen of 7 bonds to the hydrogen and cesium atoms, while the oxygen of 17 bonds to two hydrogen atoms. To test the role of the base in the anion
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Fig. 15 Free energy profiles for the whole reaction. Gas-phase and solvent-corrected Gibbs free energies (values in parentheses) are given in kcal mol−1
exchange process, calculations were conducted for 7 and 17. Hirshfeld charges on the Cs and Br atoms are +0.818e and −0.606e for 7, while those on the H1 and Br atoms are +0.287e and −0.402e for 17, respectively. It is evident that the Cs atom acts as an electrophile and has a stronger eletrophilicity ability than the H1 atom. The Br atom is a nucleophile. With the eletrophilicity strengthened, the barriers decrease for the base-assisted pathway and increase for the base-free pathway. Consequently, the base-assisted mechanism is more favored both kinetically and thermodynamically than the base-free pathway in the presence of CsF. CsF as the base employed in palladium-catalyzed amidation could promote more efficient anion exchange. In addition, due to the influence of water, the hydrolysis of CsF formed CsOH, which participates in anion exchange. And our calculations demonstrate that water is an oxygen source for the amide product. Jiang and his co-workers’ isotopic tracer method in the experiment provides forceful support for our hypothesis [15].
Conclusions A systematic theoretical study of palladium-catalyzed amidation of bromobenzene and tBu-isocyanide has been presented in this article. All possible pathways were carefully researched, and the minimum energy pathway theoretically located. The Gibbs free energy profile for the overall catalytic cycle is illustrated in Fig. 15. The amidation can be divided into five major stages: oxidative addition, migratory insertion, anion exchange, reductive elimination, and hydrogen migration. Our calculations lead to the conclusion that the energy
barrier is systematically lower for the monophosphine pathways due to the avoidance of steric interactions between the two phosphine ligands. The oxidative addition of PdPH3 to bromobenzene has the highest activation energy in the whole catalytic cycle, hence becoming the rate-determining step [35] (see Fig. 4S in the Supporting Information). In the migratory insertion, tBu-isocyanide inserts an ortho Pd–C bond and provides a source of both a carboxy and an amino group. Then, the anion exchange is the most valuable process. The following conclusions are drawn: (1) Comparing paths 1a and 2a, Hirshfeld charge analysis of the key transition states ts(9/10) and ts(5/13) demonstrated that path 1a is favored; (2) Our calculations are in accordance with the experimental findings in which water serves as a source of oxygen through O18labeling; and (3) Compared to the base-free and baseassisted pathways, anion exchange pathway accessibly happens with the help of a base, and the base plays a vital role that makes reaction more exothermic in the key step, thereby enhancing path 1a as the best choice. Next, reductive elimination occurs. As far as we known, this is the pre-product forming step in the majority of Pd-catalyzed coupling reactions. Finally, the hydrogen migration step includes two possible pathways. Our calculations indicate that the six-membered ring path is better than the four-membered ring path. Water was demonstrated to facilitate the catalytic reaction. The whole reaction includes both exothermic and exergonic processes. Acknowledgments This work was supported by the Natural Science Foundations of China (21501115, 21373131, and 21571119). Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest.
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References 1. 2. 3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
J Mol Model (2016) 22:53
Page 12 of 12
Qiu GYS, Ding QP, Wu J (2013) Recent advances in isocyanide insertion chemistry. Chem Soc Rev 42:5257–5269 Montalbetti CAGN, Falque V (2005) Amide bond formation and peptide coupling. Tetrahedron 61:10827–10852 Vaidyanathan R, Kalthod VG, Ngo DP, Manley JM, Lapekas SP (2004) Amidations using N, N-carbonyldiimidazole: remarkable rate enhancement by carbon dioxide. J Org Chem 69:2565–2568 Shendage DM, Frohlich R, Haufe G (2004) Highly efficient stereoconservative amidation and deamidation of r-amino acids. Org Lett 6:3675–3678 Baum JC, Milne JEM, Murry JA, Thiel OR (2009) An efficient and scalable Ritter reaction for the synthesis of tert-butyl amides. J Org Chem 74:2207–2209 Shimizu K, Ohshima K, Satsuma A (2009) Direct dehydrogenative amide synthesis from alcohols and amines catalyzed by g-alumina supported silver cluster. Chem Eur J 15:9977–9980 Watson AJA, Maxwell AC, Williams JMJ (2009) Rutheniumcatalyzed oxidation of alcohols into amides. Org Lett 11:2667– 2670 Fujita K, Takahashi Y, Owaki M, Yamamoto K, Yamaguchi R (2004) Synthesis of five-, Six-, and seven-membered ring lactams by Cp*Rh complex-catalyzed oxidative N-heterocyclization of amino alcohols. Org Lett 6:2785–2788 Schoenberg A, Heck RF (1974) Palladium-catalyzed amidation of aryl, heterocyclic, and vinylic halides. J Org Chem 39:1974–3327 Orito K, Miyazawa M, Nakamura T, Horibata A, Ushito H, Nagasaki H, Yuguchi M, Yamashita S, Yamazaki T, Tokuda M (2006) Pd(OAc)2-catalyzed carbonylation of amines. J Org Chem 71:5951–5958 Martinelli JR, Freckmann DMM, Buchwald SL (2006) Convenient method for the preparation of weinreb amides via Pd-catalyzed aminocarbonylation of aryl bromides at atmospheric pressure. Org Lett 8:4843–4846 Ren W, Yamane M (2010) Carbamoylation of aryl halides by molybdenum or tungsten carbonyl amine complexes. J Org Chem 75: 3017–3020 Ren W, Yamane M (2009) Palladium-catalyzed carbamoylation of aryl halides by tungsten carbonyl amine complex. J Org Chem 74: 8332–8335 Gulevich AV, Zhdanko AG, Orru RVA, Nenajdenko VG (2010) Isocyanoacetate derivatives: synthesis, reactivity, and application. Chem Rev 110:5235–5331 Jiang HF, Liu BF, Li YB, Wang AZ, Huang HW (2011) Synthesis of amides via palladium catalyzed amidation of aryl halides. Org Lett 13:1028–1031 Kosugi M, Ogata T, Tamura H, Sano H, Migita T (1986) Palladium catalyzed iminocarbonylation of bromobenzene with isocyanide and organotin compound. Chem Letts 1986:1197–1200 Saluste CG, Whitby RJ, Furber M (2000) A palladium-catalyzed synthesis of amidines from aryl halides. Angew Chem Int Ed 39: 4156–4158 Onitsuka K, Suzuki S, Takahashi S (2002) A novel route to 2,3disubstituted indoles via palladium-catalyzed three-component coupling of aryl iodide, o-alkenylphenyl isocyanide and amine. Tetrahedron Lett 43:6197–6199 Carvajal MA, Miscione GP, Novoa JJ, Bottoni A (2005) DFT computational study of the mechanism of allyl chloride carbonylation catalyzed by palladium complexes. Organometallics 24:2086–2096
20.
Hu YH, Liu J, Lu ZX, Luo XC, Zhang H, Lan Y, Lei AW (2010) Base-induced mechanistic variation in palladium-catalyzed carbonylation of aryl iodides. J Am Chem Soc 132:3153–3158 21. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.02; Gaussian, Inc.: Wallingford CT. 22. Becke AD (1993) A new mixing of Hartree-Fock and local densityfunctional theories. J Chem Phys 98:1372–1377 23. Stephens PJ, Devlin FJ (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J Phys Chem 98:11624–11627 24. Becke AD (1993) Density-functional thermochemistry III. The role of exact exchange. J Chem Phys 98:5648–5652 25. Lee C, Yang W, Parr RG (1988) Development of the colic-salvetti correlation-energy formula into a functional of the electron density. Phys Rev 37:785–789 26. Frisch MJ, Pople JA, Binkley JS (1984) Self-consistent molecular orbital methods 25. Supplementary functions for Gaussian basis sets. J Chem Phys 80:3265–3269 27. Wadt WR, Hay PJ (1985) Ab Initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi. J Chem Phys 82:284–298 28. Hay PJ, Wadt WR (1985) Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J Chern Phys 82:299–310 29. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functional and systematic testing of four M06-class functionals and 12 other functional. Theor Chem Account 120:215–241 30. Ariafard A, Yates BF (2009) Subtle balance of ligand steric effects in stille transmetalation. J Am Chem Soc 131:13981–13991 31. Fuku K (1981) The path of chemical reactions—the IRC approach. Acc Chem Res 14:363–368 32. Hirshfeld FL (1977) Bonded-atom fragments for describing molecular charge densities. Theor Chem Acta 44:129–138 33. Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396 34. Ren Y, Jia JF, Zhang TT, Wu HS, Liu WX (2012) Computational study on the palladium-catalyzed allenylative dearomatization reaction. Organometallics 31:1168–1179 35. Ren Y, Jia JF, Liu WX, Wu HS (2013) Theoretical study on the mechanism of palladium-catalyzed dearomatization reaction of chloromethylnaphthalene. Organometallics 32:52–62 36. Soomro SS, Ansari FL, Chatziapostolou K, Köhler K (2010) Palladium leaching dependent on reaction parameters in Suzuki– Miyaura coupling reactions catalyzed by palladium supported on alumina under mild reaction conditions. J Catal 273:138–146
