Mechanistic Insights into the Copper-Cocatalyzed Sonogashira Cross

Article pubs.acs.org/Organometallics

Mechanistic Insights into the Copper-Cocatalyzed Sonogashira Cross-Coupling Reaction: Key Role of an Anion Xingbao Wang, Yuming Song, Jingping Qu, and Yi Luo* State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, People’s Republic of China S Supporting Information *

ABSTRACT: The Sonogashira cross-coupling reaction is one of the most important and widely used sp2−sp carbon−carbon bond formation reactions in organic synthesis. Up to now, the exact mechanism of the palladium/copper-catalyzed Sonogashira reaction is far from being fully understood, mainly due to the difficulties in clarifying the combination behavior of the two metal catalysts. In this study, DFT calculations have been performed to elucidate the mechanism of the coppercocatalyzed Sonogashira cross-coupling reaction, where bis(triphenylphosphino)palladium was used as a catalyst and Cs2CO3 was applied as a base. In an agreement between theory and experiment, the Cu cycle could favorably generate an I−-coordinated copper acetylide as the catalytically active species rather than the generally considered neutral copper acetylide. In addition, the transmetalation is calculated to be the ratedetermining step. The results reported herein are expected to have broad mechanistic implications for other bimetal-catalyzed reactions employing metal salts as additives.

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INTRODUCTION In the arena of alkyne chemistry, one of the most significant developments over the past 40 years is the Sonogashira reaction.1−4 The palladium-catalyzed Sonogashira reaction has emerged as the most important and widely used method for preparing arylacetylenes and conjugated enynes.3,4 It is technically simple, efficient, high-yielding, and tolerant toward a variety of functional groups. Its applications cover the field of pharmaceuticals, natural products, organic materials, and nanomaterials.5−9 The general Sonogashira protocol for the coupling of terminal alkynes with aryl or alkenyl halides usually involves an organic solvent, a Pd(0)/Cu(I) catalytic system, and at least a stoichiometric amount of a base, such as Cs2CO3, Et3N, and iPrN2H (Scheme 1).3 Copper salt is used as a cocatalyst in the typical Sonogashira reaction, which is believed to facilitate the reaction rate.4 To date, the study of the Sonogashira reactions is in the ascendant. However, in comparison with the applied studies, the exact mechanism of

the homogeneous Sonogashira reaction is far from being fully understood, with some obscure points and not unequivocally proven assertions still remaining. The copper-cocatalyzed Sonogashira reaction is generally believed to take place through two independent catalytic cycles, as shown in Scheme 2.2−4 In the palladium catalysis (Pd cycle), it is accepted to occur through fast oxidative addition of R1−X to the Pd center and subsequent connection with the copperScheme 2. Copper-Cocatalyzed Sonogashira Reaction Mechanism

Scheme 1. General Pd(0)/Cu(I)-Catalyzed Sonogashira Reaction

Received: January 6, 2017

© XXXX American Chemical Society

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DOI: 10.1021/acs.organomet.7b00010 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

coordinatively unsaturated [Pd(PPh3)] having one phosphine ligand or the two-donor-ligated [Pd(PPh3)2].36 In the monophosphine pathway, as shown in Figure 1, with the interaction of PhI, one phosphine ligand dissociated to give

involved cocatalytic cycle (Cu cycle). The transmetalation generates a [R1Pd(−CCR2)Ln] species, which gives the final coupled alkyne after reductive elimination accompanied by regeneration of the palladium catalyst. So far, the mechanism of the Cu cycle is still poorly understood. In the conventional Cu cycle (left part in Scheme 2), the base is supposed to abstract the acetylenic proton of the terminal alkyne, thus forming a neutral copper acetylide in the presence of the copper salt. In fact, the generally considered in situ formation of a copper acetylide as an intermediate has never been proven, although the copper acetylide had been isolated and did work for the Sonogashira coupling.10 It is a very difficult task to isolate and characterize the active organometallic intermediates or the transition states from a homogeneous mixture to validate a mechanism beyond any doubt. This situation prompted us to clarify the mechanism of the copper-cocatalyzed Sonogashira reaction. During the past decade, some groups have applied computational chemistry to study the mechanism of C−C cross-coupling reactions.11−26 A few theoretical studies have been dedicated to the mechanistic study of the Sonogashira cross-coupling reaction. Sikk27 and Ujaque28 independently reported the mechanism of the Pd-catalyzed copper-free Sonogashira reaction. Recently, a computational study of the copper-cocatalyzed Sonogashira cross-coupling reaction in the gas phase and in dichloromethane solution was reported.29 The mechanism of copper-free Sonogashira cross-coupling catalyzed by Pd-Cy*Phine in the presence of Cs2CO3 as a base was studied by using DFT.30 However, the previous calculations provided no rationale for the hypothesis that the copper acetylide was formed in the Cu cycle. Our recent study on the silver-catalyzed carboxylation of terminal alkynes with CO2 indicated that the anion-coordinated Ag complex is more active than the neutral silver acetylide.31 In addition, some experimental and computational studies indicated that the anions, halides, and acetate played a critical role in the crosscoupling reactions.32−34 Very recently, the importance of anionic ligands involved in catalyst speciation has been recognized in the Au-Pd bimetallic catalysis.35 Inspired by these results, we propose an alternative anionic mechanism (right part in Scheme 2). In contrast to the conventional Cu cycle (left part in Scheme 2), an I−-coordinated copper acetylide is proposed to be generated in situ from acetylene in the presence of base and CuI. Then this highly reactive complex could be involved in the transmetalation with the Pd(II) species (Scheme 2). In this work, the copper-cocatalyzed Sonogashira crosscoupling reaction of iodobenzene with phenylacetylene has been computationally modeled, where bis(triphenylphosphino) palladium ([Pd(PPh3)2]), CuI, and Cs2CO3 are used as catalyst, cocatalyst, and base, respectively.

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Figure 1. Gibbs free energy profiles for oxidative addition pathways (energies in kcal/mol).

2 with a coordinated PhI moiety. This step is achieved through TS(1-2) with an energy barrier of 15.4 kcal/mol. The complex 2 further undergoes oxidative addition via TS(2-3) to yield 3. Finally, the PPh3 ligand recoordinates to 3 to give the squareplanar complex trans-[(PPh3)2Pd(Ph)(I)] (4). In 4, two phosphine ligands are symmetrically coordinated to the palladium center with a P−Pd−P angle of 178.2° and Pd−P bonds of 2.42 Å. In the bis-phosphine pathway, an approach of PhI to the palladium center of [Pd(PPh3)2] leads to the oxidative addition transition state TS(1-5) having Pd···C and Pd···I distances of 2.18 and 2.85 Å, respectively (Figure 1). In comparison with the free forms of PhI and [Pd(PPh3)2], in TS(1-5), the phenyl−I bond is elongated and the P−Pd−P angle is compressed (2.14 vs 2.40 Å and 178.8 vs 121.4°). The free energy barrier of this pathway is 12.3 kcal/mol. Such an oxidative addition leading to the complex cis-[(PPh3)2Pd(Ph)(I)] (5) is exergonic by 18.5 kcal/mol, providing a thermodynamic driving force for this step. In 5, palladium is in a slightly distorted square planar environment with the two PPh3 ligands being cis to each other. The distance between Pd and P atoms trans to phenyl (2.58 Å) is longer than that between Pd and P atoms trans to the I atom (2.38 Å). The subsequent cis to trans isomerization (5 to 4) is known to easily take place.27,37 In addition, 4 is more stable than 5 by 2.3 kcal/mol. These results indicate that the diphosphine pathway is more kinetically favored in comparison with the monophosphine pathway. The more stable oxidative addition product 4 is used for the calculation of the following reaction process. Cu Cycle. The computed Cu cycle is shown in Scheme 3. As shown in this scheme, the formation of complex 7 is energetically much more favorable through the reaction of the CsCO3− anion38 and CuI (ΔG = −25.7 kcal/mol) in comparison to that for complex 8 via the coordination of CuI to phenylacetylene (ΔG = −8.4 kcal/mol). Along path I (Scheme 3), 7 can isomerize to 7′ with I and Cs atoms tilted toward the same side. This process is endergonic by 4.9 kcal/ mol. 7′ further goes through TS(7′-9) leading to 9 and then to anionic 10, accompanied by the liberation of CsI. The transition state TS(7′-9) with an energy barrier of 22.5 kcal/ mol relative to 7 features concerted events: viz., cleavage of Cu−I and formation of Cs−I bonds. The conversion of 7 to 10

RESULTS AND DISCUSSION

Oxidative Addition. The Pd cycle starts with the oxidative addition of PhI to the Pd0 species [Pd(PPh3)2] to give the complex [(PPh3)2Pd(Ph)(I)]. Although this process has been already investigated,27,29,36 for a comparison with the Cu cycle, it is recalculated here on the basis of the current modeling. This is necessary to underline some structural and energetic features that are of relevance to the mechanisms of transmetalation and reduction elimination discussed below. Many reports argue that the active species in the oxidative addition step is either B


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Organometallics Scheme 3. Computed Gibbs Free Energy Profile for Cu Cyclea

a

Energies are given in kcal/mol. The red arrow indicates the most favorable pathway.

accompanied by release of a molecule of CsHCO3 and requires an energy barrier of 10.1 kcal/mol relative to 7 to achieve C−H bond activation. In 14, a rotation of the phenylacetylene moiety around its connected O atom gives the π-alkyne−Cu complex 16. In 16, the Cu atom is closer to C1 (2.08 Å) than to C2 (2.22 Å) and the C−H bond is slightly elongated from 1.10 Å in 14 to 1.14 Å in 16. Therefore, the coordination of the Cu atom to the PhCCH triple bond makes the alkyne proton more acidic. This step is slightly endergonic by 2.4 kcal/mol. The subsequent deprotonation of phenylacetylene via TS(16-17) (Figure 2) is feasible, requiring an activation energy of only 0.8 kcal/mol. TS(16-17) is more stable than TS(13-15) by 1.4 kcal/mol. As shown in Figure 2, in TS(13-15), the acetylenic proton is closer to the O2 atom than to C1. In TS(16-17), however, the proton is closer to C1 than to O1. This suggests that the occurrence of TS(16-17) is earlier than that of TS(1315) along the reaction coordinates and the C−H bond is more activated in TS(13-15). This is understandable because the coordination of Cs to O2 in TS(13-15) made the O2 less nucleophilic and postponed the formation of TS(13-15). These results and the coordination of Cu to the PhCCH triple bond (see TS(16-17) in Figure 2) could account for the stability of TS(16-17). After the C−H bond activation, 17 undergoes an isomerization to give 18. This process is exergonic by 9.3 kcal/mol. In this process, the π-alkyne−Cu interaction disappeared and a Cu−C bond formed instead. 18 could feasibly release CsHCO3 to give 15, which is exergonic by 6.4 kcal/mol. It is noteworthy that, as indicated in path IV, the coordination of CsCO3− to 8 yields 16, which is involved in path III and gradually produces the final species 15 (Scheme 3). However, considering the significant thermodynamic stability of 7 in comparison with 8 (ΔΔG = −17.3 kcal/mol), CuI would first coordinate to the CsCO3− anion rather than phenylacetylene, although the existence of 7 needs further experimental evidence.

is endergonic by 20.8 kcal/mol. An approach of phenylacetylene toward 10 results in complex 11. In 11, the copper atom is coordinated symmetrically to the triple bond of PhC2 C1H (Cu−C1, 1.96 Å; Cu−C2, 1.97 Å). Such a coordination makes linear PhC2C1H bent, as suggested by the compressed angles of C1−C2−C(Ph) (158.9°) and C2−C1−H (153.5°). These geometrical characters together with elongation of the C1−C2 bond (from 1.21 to 1.27 Å) suggest that the phenylacetylene moiety in 11 is activated. The complex 11 goes through hydrogen abstraction transition state TS(11-12), leading to HCO3− anion and the copper(I) acetylide [PhC CCu] (12) . This process requires an activation energy of 15.9 kcal/mol. The formation of complex 12 is exergonic by 0.7 kcal/mol relative to 7, suggesting a thermodynamically balanced process. For modeling the formation of copper acetylide, the interaction of acetylenic hydrogen with the oxygen atoms attached to the Cu atom in 7 was calculated and complexes 13 (path II) and 14 (path III) were located, respectively (Scheme 3). 13 and 14 are almost isoenergetic (relative energies of −20.7 vs − 20.2 kcal/mol) and their (PhCC)H···O contacts are 1.80 and 1.84 Å, respectively. Starting with 13, the abstraction of proton of terminal alkyne occurs via the six-membered-ring transition state TS(13-15) (Figure 2) to give the I−-coordinated copper(I) acetylide 15, [PhCCCu]I−. This exergonic (ΔG = −14.4 kcal/mol) step is

Figure 2. Optimized transition state structures (distances in Å) indicated in Scheme 3. C


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Organometallics

Cu−I bond length almost remains unchanged. Due to the steric hindrance, the I−Pd−C(Ph) angle decreases from 179.2° in 4 to 120.7° in TS(4-19). In addition, the Pd−I bond length increases from 2.82 and 3.42 Å, suggesting that the I− ion is leaving from the Pd center. TS(4-19) leads to the intermediate trans-[(PPh3)2Pd(Ph)(CCPh)(CuI)] (19). The species 19 can be viewed as a complex of CuI with trans-[(PPh3)2Pd(Ph)(CCPh)], as the Cu−I bond length in 19 (2.50 Å) is comparable to that in the free CuI molecule (2.44 Å). In view of the energy barrier of 13.6 kcal/mol and the exergonic character (Figure 3), this associative substitution (replacement of I− ligand in 4 by 15) is feasible. The released I− ion could react with Cs2CO3 to generate CsCO3− and CsI, and the subsequent complexation of CsCO3− with CuI could result in complex 7 (Scheme 3). Previous studies indicated that CuI is capable of coordinating with various ancillary ligands, and the resulting mononuclear Cu complex was also used in theoretical calculations.41−44 In view of this point, the existence of CsCO3−-ligated CuI species such as 7 could be reasonable. The cis complex 5 has also been considered for the transmetalation step. However, many attempts failed to locate the corresponding transition state. All attempts resulted in the separation of the reactants (5 and 15). This could be attributed to the steric hindrance between the PPh3 ligands and anionic complex [PhCCCu]I−. This suggests that such a pathway might be unfeasible. Reductive Elimination. The newly formed 19 could undergo reductive elimination. Two possibilities were considered for this stage: viz., with and without dissociation of CuI. As shown in Figure 4, the almost isoenergetic isomerization of 19 gives the cis analogue 20. In the reductive elimination transition state TS(20-21), the C−Pd−C angle is reduced by 27.7° (from 83.3° in 20 to 55.6° in TS(20-21)) and the distance between carbon atoms, which are bound to the Pd atom, is 1.94 Å. The formation of a Csp2−Csp bond (reductive elimination) via TS(20-21) requires a free energy barrier of 12.2 kcal/mol to regenerate Pd(PPh3)2 (1) and to give complex 21 with a diphenylacetylene moiety as the final product. In 21, CuI coordinates to the CC triple bond of the diphenylacetylene. With the interaction of CsCO3− anion, the subsequent dissociation of CuI from diphenylacetylene could occur to yield CsCO3−·CuI (7). This step is exergonic by 20.0 kcal/mol. With the interaction of CsCO3− anion, CuI could dissociate from 19 and result in the formation of 22, which is exergonic by 10.2 kcal/mol. Like the CuI dissociation pathway, the isomerization of 22 gives 23 and further results in Pd(PPh3)2 and final product via transition state TS(23-1). It is noted that such cis−trans isomerizations (19 to 20 and 22 to 23) could be also kinetically feasible with respect to the similar isomerization with an energy barrier of less than 10 kcal/mol.29 As shown in Figure 4, although the two pathways have the same relative energy barriers (12.0 and 12.2 kcal/mol), the stationary points involved in the CuI-dissociation pathway are significantly lower in energy than those in the pathway without dissociation of CuI. Therefore, the dissociation of CuI could occur prior to reductive elimination. [PhCCCu]I− vs [PhCCCu]. As indicated in a previous experimental study,10 the transfer of the alkynyl group of neutral copper acetylide to the Pd center was feasible. Recently, Burk et al.27 calculated the transmetalation reaction between [(PH3)PdBrPh] and neutral [PhCCCu] without consideration of the Cu cycle. Their results suggest that the transmetalation step is initiated by the dissociation of the

As shown in Scheme 3, it is obvious that the stationary points involved in path I are significantly higher in energy and the overall barrier (ΔG⧧ = 22.5 kcal/mol) is also higher in comparison with the other pathways (see also Figure S1 in the Supporting Information). In addition, the formation of 12 (path I) as the transmetalation species is energetically unfavorable in comparison with 15 derived from paths II−IV. This result suggests that the anionic complex [PhCCCu]I− is more easily generated than the neutral complex [PhCCCu] (12). Therefore, the neutral copper(I) phenylacetylide is unlikely to be involved in a copper-cocatalyzed Sonogashira cross-coupling reaction. The overall barrier for path III is lower than that for path II by 1.4 kcal/mol. Therefore, the formation of the [PhCCCu]I− species is more likely to occur through path III. The Cs2CO3-mediated formation of 15 was also calculated.38 However, it has been found to have a higher energy barrier in comparison with path III (ΔG⧧ = 8.7 vs 13.0 kcal/mol; see Scheme 3 and Figure S2 in the Supporting Information). Transmetalation. Two possibilities (with and without phosphine ligand dissociation) were considered in the transmetalation step.21,39,40 The dissociation of I− ion from the Pd center of oxidative addition product 4 (Figure 1) to form cationic [PhPd(PPh3)2]+ is highly endergonic (ΔG = +13.2 kcal/mol, ΔH = +24.1 kcal/mol). The dissociation of one phosphine ligand in 4 results in the complex [(PPh3)PdIPh] (3; Figure 1). This process is also endergonic (ΔG = +15.8 kcal/mol, ΔH = +31.2 kcal/mol). These results suggest that the dissociation of iodide or phosphine ligand is energetically unfavorable, and the dissociative substitution mechanism is unlikely to work for the current system. This situation led us to investigate possible associative substitution mechanisms, where 15 replaces the I− ion or a PPh3 ligand. First, the replacement of PPh3 ligand by anionic 15 was considered. However, many attempts to locate a coordination complex or transition state were fruitless. Then, we turned to the replacement of I− ligand by 15. The approach of 15 to the Pd center of 4 leads to the corresponding transition state TS(4-19) (Figure 3). The computed Gibbs free energy barrier is 15.2 kcal/mol. As shown in Figure 3, in TS(419), the distances between Pd and the two C atoms of the C C triple bond are 2.80 and 3.35 Å, respectively. The angle C C−Cu decreases from 180.0° in 15 to 157.1° in TS(4-19). The

Figure 3. Gibbs free energy profile of transmetalation (energies in kcal/mol and distances in Å). For clarity, the phenyl groups of the phosphine ligand in the 3D structure of TS(4-19) are omitted. D


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Figure 4. Gibbs free energy profiles for the reductive elimination reactions (energies in kcal/mol and distances in Å). For clarity, the phenyl groups of the phosphine ligand in the 3D structure of TS(20-21) and TS(23-1) are omitted.

Sonogashira cross-coupling of substituted oxazoles and thiazoles with terminal alkynes, a copper(I) source screen indicated the reactivity trend CuI > CuBr > CuCl.47 However, CuCl showed better performance in the Pd-catalyzed coupling reaction of propiolic acid with aryl iodides.46 Modified Mechanism. On the basis of the aforementioned calculation results, the mechanism of the copper-cocatalyzed Sonogashira reaction could be modified. As shown in Figure 5,

neutral ligand and the transfer of acetylide from Cu(I) to Pd(II) was almost barrierless.29 The rate of the transmetalation reaction depends on the dissociation process of the phosphine ligand in their study. However, this is contrast to the experimental results that the transmetalation step was established as the rate-limiting step and the reaction rate correlated with the substituents of alkynes.45 Therefore, the mechanism working for the reaction of copper acetylide with the Pd complex under base-free conditions might be different from that for the actual process of Sonogashira coupling. If the neutral copper acetylide is the actual intermediate, the CuX1 derived from ArX1 substrate (X = I, Br, Cl) will be formed during the transmetalation and reductive elimination step. In other words, the halide of the regenerated CuX1 is from substrate ArX1 rather than from the original copper compound CuX2 (CuI in the current case). In addition, the copper salt as an additive has no effect on the reaction rate. This is in disagreement with the experimental observation that the reactivity depends on the copper source used.46−48 As discussed above, in the current study, the energy barrier of oxidative addition is 9.7 kcal/mol, and it is 12.2 kcal/mol for the reductive elimination process. These values are lower than the energy barrier for the transmetalation step (13.6 kcal/mol, Figure 3). Therefore, on the basis of the current results, it is speculated that the transmetalation step is the rate-limiting step of the whole reaction. This is well consistent with a quantitative kinetic investigation indicating that the transmetalation in the Sonogashira coupling reaction is the rate-limiting step (ΔG⧧ = 13.6 kcal/mol, at 25 °C).45 The calculated energy barriers of the transmetalation step are 14.3 and 15.2 kcal/mol for the cases of [PhCCCu]Cl− and [PhCCCu]Br−), which are higher than that for the [PhC CCu]I− case by 0.7 and 1.6 kcal/mol, respectively. In addition to the electronic factor of halides, the steric hindrance may also account for the reactivity, as suggested by the optimized transition structures (Figure S3 in the Supporting Information). Experimentally, the effect of halides of copper(I) salt varies with the reaction conditions adopted. For examples, in the

Figure 5. Modified mechanism of copper-cocatalyzed Sonogashira cross-coupling reaction.

the palladium catalytic cycle (Pd cycle) starts with oxidative addition of R1−X1 to the Pd(0) center. The resulting Pd(II) species subsequently undergoes transmetalation via a connection with the copper-cocatalytic cycle (Cu cycle). Then, reductive elimination could occur to regenerate the Pd catalyst and coupling product. In the Cu cycle, the anion-coordinated (such as I−-coordinated) copper(I) acetylide has been proposed, for the first time, to be the active species in the Cu cycle. The transmetalation step produces a CuX2coordinated [R1Pd(CCR2)(CuX2)(PPh3)2] species, which is capable of reductive elimination after trans/cis isomerization. The rate of the Sonogashira reaction was experimentally found to be affected by the nature of the substituent and halide of an E


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aryl halide as well as the halide of the copper(I) salt.45−48 The modified mechanism could reflect all of these factors. Consequently, the anion-coordinated species is the most likely actual active species in the copper-cocatalyzed Sonogashira coupling reaction.

*E-mail for Y.L.: [email protected]. ORCID

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AUTHOR INFORMATION

Corresponding Author

Yi Luo: 0000-0001-6390-8639

CONCLUSION In summary, the thorough reaction mechanism for the coppercocatalyzed Sonogashira reaction between iodobenzene and phenylacetylene has been computationally investigated. The theoretical results suggest that the diphosphine pathway is favored in the oxidative addition step. Interestingly, it has been found that the I−-coordinated copper(I) acetylide rather than the generally accepted neutral copper acetylide is more likely to be the actual active species. This is because the formation of anionic I−-coordinated copper(I) acetylide is more favorable than the neutral copper acetylide both kinetically and thermodynamically, and the proposed anionic mechanism could account for the effect of copper salt on the coppercocatalyzed Sonogashira cross-coupling reaction; however, the conventional neutral mechanism is incapable of accounting for that. The current result may cause a reconsideration of the mechanism for copper-cocatalyzed Sonogashira cross-coupling reactions. The results reported here are expected to provide a theoretical basis for designing new Sonogashira coupling reactions, providing the desired arylacetylenes and conjugated enynes through tailoring of the cocatalyst structure.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by the NSFC (No. 21429201). The authors also thank the Fundamental Research Funds for the Central Universities (DUT2016TB08) and the Network and Information Center of the Dalian University of Technology for part of computational resources.

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REFERENCES

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All calculations were performed with the Gaussian 09 program.49 The DFT method of B3LYP50,51 was used for geometry optimizations and subsequent frequency calculations. The LanL2DZ basis set together with associated effective core potential (ECP) was used for Pd, Cu, I, and Cs atoms, and the remaining atoms were treated with the basis set 6-31+G*. Such a combination of the basis sets is denoted as BSI. Frequency calculations were performed to identify the geometrically optimized stationary points as minima (zero imaginary frequency) or transition states (TS, one imaginary frequency) and to obtain the thermodynamic data. Subsequent intrinsic reaction coordinate (IRC) analysis was carried out to identify the transition state connecting two relevant minima. The single-point calculations were performed at the level of M0652/BSII on the basis of the B3LYP-optimized geometry. In the BSII, the larger basis sets were used: viz., the SDD basis set together with associated ECP for Pd, Cu, I, and Cs atoms and the 6311+G(d,p) for the remaining atoms. In these single-point calculations, the solvation effect was considered with the SMD solvation model.53 The N,N-dimethylformamide (DMF, ε = 37.2) generally used in such reactions was employed as a solvent in the SMD calculations. For some important species, the optimized structures in solution are very similar to the case of optimization in the gas phase (Figure S4 in the Supporting Information). The energy profile was described by the Gibbs free energy in solution, which was obtained from the M06/BSII(SMD)//B3LYP/BSI calculation, including the free energy correction from gas-phase calculations at 298.15 K and 1 atm. S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.7b00010. Figures S1−S5, as described in the text (PDF) Optimized Cartesian coordinates with the self-consistent field (SCF) energies and the imaginary frequencies of transition states (XYZ) F


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Organometallics (29) Sikk, L.; Tammiku-Taul, J.; Burk, P.; Kotschy, A. J. Mol. Model. 2012, 18, 3025−3033. (30) Mak, A. M.; Lim, Y. H.; Jong, H.; Yang, Y.; Johannes, C. W.; Robins, E. G.; Sullivan, M. B. Organometallics 2016, 35, 1036−1045. (31) Liu, C.; Luo, Y.; Zhang, W.; Qu, J.; Lu, X. Organometallics 2014, 33, 2984−2989. (32) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−321. (33) Sperger, T.; Sanhueza, I. A.; Schoenebeck, F. Acc. Chem. Res. 2016, 49, 1311−1319. (34) Guest, D.; Menezes da Silva, V. H.; de Lima Batista, A. P.; Roe, S. M.; Braga, A. A. C.; Navarro, O. Organometallics 2015, 34, 2463− 2470. (35) García-Domínguez, P.; Nevado, C. J. Am. Chem. Soc. 2016, 138, 3266−3269. (36) Lam, K. C.; Marder, T. B.; Lin, Z. Organometallics 2007, 26, 758−760. (37) Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954−959. (38) Our previous study indicated that the dissociation of Cs2CO3 to CsCO3− and Cs+ in DMF solution has been computed to be exergonic by ca. 1 kcal/mol, suggesting an ionization equilibrium. In addition, the reasonability of taking CsCO3− anion as a base in solution was also suggested previously.31 Actually, Cs2CO3 could react with the I− ion (formed in the transmetalation step, see Figure 3) to generate CsCO3− and CsI, and the subsequent complexation of CsCO3− with CuI could result in complex 7 (Scheme 3). The whole process (Cs2CO3 + I− + CuI → CsCO3−·CuI (7) + CsI) is quite exothermic (ΔH = − 29.6 kcal/mol, ΔG = − 23.2 kcal/mol). The optimized structures of DMFsolvated species indicated that the effect of the DMF molecule is insignificant for the formation of species 7 (see Figure S5 in the Supporting Information). CuI should have the neutral form in the reaction process, since the CuI-coordinated Sonogashira coupling products were obtained in a previous experimental study.10 Thus, during the catalytic cycle, I−-coordinated copper(I) acetylide (15) could be formed through the reaction of phenylacetylene with CsCO3− and CuI (see Scheme 3), although the participation of neutral Cs2CO3 at the initial stage of forming 15 could not be excluded (see Figure S2 in the Supporting Information). Actually, the CsCO3− anion as a base was also previously reported. For examples, see: Yu, H.-Z.; Jiang, Y.-Y.; Fu, Y.; Liu, L. J. Am. Chem. Soc. 2010, 132, 18078−18091. Zhang, Q.; Yu, H.-Z.; Fu, Y. Organometallics 2013, 32, 4165−4173. (39) Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978− 8985. (40) Sosa Carrizo, E. D.; Fernández, I.; Martín, S. E. Organometallics 2015, 34, 159−166. (41) Beaupérin, M.; Fayad, E.; Amardeil, R.; Cattey, H.; Richard, P.; Brandès, S.; Meunier, P.; Hierso, J.-C. Organometallics 2008, 27, 1506−1513. (42) Papazoglou, I.; Cox, P. J.; Papadopoulos, A. G.; Sigalas, M. P.; Aslanidis, P. Dalton Trans. 2013, 42, 2755−2764. (43) Fromm, A.; van Wüllen, C.; Hackenberger, D.; Gooßen, L. J. J. Am. Chem. Soc. 2014, 136, 10007−10023. (44) Liu, L.; Wu, Y.; Wang, Z.; Zhu, J.; Zhao, Y. J. Org. Chem. 2014, 79, 6816−6822. (45) He, C.; Ke, J.; Xu, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 1527−1530. (46) Kim, W.; Park, K.; Park, A.; Choe, J.; Lee, S. Org. Lett. 2013, 15, 1654−1657. (47) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485−2488. (48) Hung, Y.-T.; Chen, M.-T.; Huang, M.-H.; Kao, T.-Y.; Liu, Y.- S.; Liang, L.-C. Inorg. Chem. Front. 2014, 1, 405−413. (49) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; heeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;

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Mechanistic Insights into the Copper-Cocatalyzed Sonogashira Cross

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