Theoretical Study on Copper-Catalyzed S-Arylation of Thiophenols

Aug 23, 2013 - Subsequently, reactivity studies of these copper species with aryl halides were performed in the context of several commonly proposed ...
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Theoretical Study on Copper-Catalyzed S‑Arylation of Thiophenols with Aryl Halides: Evidence Supporting the LCu(I)-SPh Active Catalyst and Halogen Atom Transfer Mechanism Song-Lin Zhang* and Hui-Jun Fan The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, China S Supporting Information *

ABSTRACT: A systematic theoretical study on reaction mechanisms for copper-catalyzed Ullmann S-arylation reactions of thiophenols with aryl halides is reported herein. The equilibriums and consequent relative concentrations of possible copper species in the reaction solution were carefully evaluated to determine the most probable active catalytic forms. Subsequently, reactivity studies of these copper species with aryl halides were performed in the context of several commonly proposed mechanisms for copper(I)-catalyzed Ullmann reactions, such as oxidative addition/reductive elimination, σ-bond metathesis, single electron transfer (SET), and halogen atom transfer (HAT) mechanisms. On the basis of these intensive studies, we propose for the f irst time that the active copper catalyst should be neutral (L)Cu(I)-SAr species (L denotes a neutral ancillary ligand; SAr denotes a thiophenolato type ligand) in nonpolar or less polar solvent and anionic Cu(SAr)2 species in highly polar solvent. These two kinds of species are in equilibrium with each other. For both copper species, the HAT mechanism is the most favored among all the possible mechanisms examined. Under the HAT mechanism, a critical halogen atom transfer from aryl halide to Cu(I) center occurs and accordingly involves the formation of intermediate Cu(II)(SAr)(X) (X denotes a halide ligand) species as well as an aryl radical. Subsequent direct and rapid attack of the aryl radical to the thiophenolato ligand in Cu(II)(SAr)(X) delivers the coupling product. Aryl halide substrate effect studies reveal that various kinds of aryl halides follow the reactivity trend of ArI > ArBr > ArCl under this HAT mechanism. This trend prediction is in good agreement with experimental observations that aryl iodides are generally more reactive than aryl bromides and chlorides for such Ullmann S-arylation reactions and thus lends further support for this HAT mechanism. Given the mechanistic proposals for Ullmann N- and O-arylation reactions, Ullmann S-arylation reactions should probably follow an analogous mechanism to that of O-arylation reactions, which is in distinct contrast with the oxidative addition mechanism proposed for N-arylation reactions. This highlights once again that the reaction mechanism of such copper(I)-catalyzed Ullmann reactions is dependent on the nature of the nucleophiles employed. Nucleophiles with reactive centers from different groups in the periodic table may possibly be involved in different mechanisms, and vice versa. These insights should therefore be valuable for the understanding of the mechanism of Ullmann S-arylation reactions and further development of orthogonal or selective Ullmann reactions involving multifunctional nucleophiles. reactions,5,11 mechanistic studies concerning the identity of active catalytic species and relevant intermediates in the catalytic cycle and their reactivity patterns remain less developed.12 Nevertheless, consensus has generally been reached that the active catalyst involved in the catalytic cycle should be a Cu(I) species.13 Copper precursors with other oxidation states such as 0 and +2 have been shown to be converted to active Cu(I) species via ready redox process with the electrophiles (aryl halides) or nucleophiles (such as amines or alcohols), respectively.14,15 However, for different Ullmanntype reaction systems, various reaction mechanisms have been supported by pieces of evidence, which complicated the

1. INTRODUCTION In recent years, Ullmann-type reactions1−3 have grown into a versatile tool for access to C−X (X = C, N, O, S, etc.) bonds, which are prevalent in pharmaceuticals, natural products, materials, and biology.4 These reactions forge C−X bonds by employing copper(I)-catalyzed cross-coupling of aryl halides with various kinds of carbon- or heteroatom-based nucleophiles. Mild and functional group-tolerant Ullmann-type protocols have been achieved recently with the employment of ancillary bidentate ligands as the key to success.5 These ancillary ligands are primarily N- and/or O-based bidentate ligands, such as phenanthrolines,6 1,2-diamines,7 amino acids,8 1,3-dicarbonyl compounds,9 bis-pyridylimines,10 and others. Despite the great effort devoted to reaction condition optimization and substrate scope expansion for Ullmann-type © 2013 American Chemical Society

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et al.25 Cheng et al. reported an ESI-MS study that characterized several Cu-thiolate intermediates during the Ullmann S-arylation reaction developed by Venkataraman et al.26 However, the mechanism is still vague and elusive. Up to now, Ullmann S-arylation has generally escaped detailed computational study. There is no analogous theoretical study clarifying the reactivity of possible copper species and the probable catalytic cycle, as have been done for Ullmann N- and O-arylation reactions.27 Furthermore, from the proposed mechanisms for Ullmann N- and O-arylation reactions, it is implied that different kinds of nucleophiles may possibly be involved in different mechanisms.23,24 For these reasons, it deserves our continuous effort to elucidate the mechanism for Ullmann coupling of S-nucleophiles. Herein, we report our systematic DFT study on the mechanism of copper(I)catalyzed coupling of aryl iodides with thiophenols. Systematic evaluation of relative concentrations of possible copper species in reaction solution and reactivity studies of some key copper complexes under several possible reaction mechanisms have been presented. A probable detailed catalytic cycle has been presented that is consistent with the experimental observations. In addition, the role of the nature of the nucleophiles, the polarity of the solvent, the aryl halide substrate effect, the relationship to mechanisms for other Ullmann coupling reactions, and consequent mechanistic implications are discussed. Notably, this study represents the first systematic computational study elucidating the detailed mechanism for Ullmann S-arylation reactions.

understanding of Ullmann-type reactions. Among the mechanisms proposed, two have often been argued for different reaction systems: oxidative addition16−18 and radical mechanisms.19 Very recently, considerable effort has been devoted to elucidating the mechanism of Ullmann N-arylation reactions between aryl halides and N-nucleophiles, including the preparation and characterization of proposed key copper intermediates, reactivity and kinetic studies of these intermediates with aryl halides, and theoretical analysis of possible reaction pathways.16−18 As a result, Cu(I)(amidate) intermediates coordinated by an ancillary ligand have been accepted to be the active catalysts in these copper(I)-catalyzed Narylation reactions. Activation of aryl halides by such (L)Cu(I)(amidate) intermediates constitutes the rate-determining step of the catalytic cycle. However, analogous studies on Oarylation and S-arylation reactions have received much less attention.20−23 It is not until very recently that Hartwig et al. were able to isolate related Cu(I)-phenoxide complexes in the presence of diamines or phenanthrolines and study their reactivity with aryl halides.20 On the basis of a series of evidence including kinetic studies and radical clock experiments, the oxidative addition mechanism has been proposed by Hartwig for the Ullmann coupling of phenols with aryl halides, which is analogous to the mechanism of N-arylation reactions.21,22 However, a significant report by Buchwald and Houk et al. clearly demonstrated that the iodine atom transfer mechanism is much more favorable for Ullmann O-arylation of alcohols with aryl iodides.23 Later, studies of our own also confirmed that for Ullmann O-arylation of phenols with aryl bromides a similar bromine atom transfer mechanism is the most favored among several commonly proposed mechanisms.24 As to the S-arylation mechanism, there is one experimental study concerning the preparation and reactivity studies of a few Cu(I)-thiophenolato complexes reported by Weng and Hartwig

Scheme 1. Equilibriums of Possible Copper Species in Toluene Solution

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2. METHOD

generally determined by the aryl halides used, but are independent of the precatalyst used. Calculation results show that the conversion of complex A to B in the presence of thiophenol and NaOt-Bu is exothermic by 20.6 kcal/mol (Scheme 1). Therefore, complex B is thermodynamically more favorable. Complex C is coordination-saturated, which must dissociate one molecule of 1,10phenanthroline ligand before reacting with aryl halides, thus generating complex E. This dissociation process needs 34.0 kcal/mol in free energy, demonstrating that complex C is unlikely to be the active copper species initiating the catalytic reaction. This conclusion is in agreement with experimental observations by Hartwig and co-workers.20 The formation of complex F from complex B has been shown to be endothermic by 14.6 kcal/mol in toluene solvent. Summarizing all these results, complex B should be the most abundant species in toluene solvent. However, both experimental and computational studies have shown that the disproportionation equilibrium between neutral complexes of type B and ionic complexes C and D should be largely influenced by the polarity of the solvent.20,24 Therefore, solvent effects (toluene, THF, and DMSO) with different dielectric constants have been considered for this disproportionation process. The results are shown in Table 1. As can been

28

All calculations were performed with Gaussian 03. The B3LYP method was used.29 This method has been demonstrated to be a reliable method for dealing with the mechanisms for Cu(I)-catalyzed Ullmann reactions and other copper-mediated reactions by many previous theoretical studies.16−18,22−24,30 Geometry optimizations were conducted with a combined basis set in which copper and iodine atoms were described by the LANL2DZ basis set and an effective core potential was implemented;31 6-311+G(d, p), a triple-ζ all-electron basis set, was employed for sulfur atoms with a third polarizable valence orbital, and the 6-31G* basis set was used for the other atoms. Frequency analysis was conducted at the same level of theory for geometry optimization, aiming to verify whether the stationary points obtained are real minima or saddle points and to get the thermodynamic energy corrections. For each saddle point, the intrinsic reaction coordinate analysis32 was carried out to confirm that it connected the desired reactant and product on the potential energy surface. Natural population analysis was performed also at the same level of theory.33 Single-point energy calculations were performed on the stationary points by using a larger basis set, i.e., SDD34 for Cu and I and 6-311+G(d, p) for the other elements. The solvent effect was calculated in toluene solvent (ε = 2.379) unless otherwise noted by using the self-consistent reaction field method35 with the CPCM solvation model36 and UAHF radii. For each stationary point, its energy was calculated by using single-point energy corrected by Gibbs free energy correction and solvation energy throughout the study.37

3. RESULTS AND DISCUSSIONS 3.1. Model Reaction and Possible Copper Complexes. The reaction between iodobenzene 1 and thiophenol 2 was chosen as the model reaction (eq 1). The ancillary ligand was modeled by 1,10-phenanthroline (phen). This model reaction was devised on the basis of the reaction protocol originally reported by Venkataraman et al.,11a which remains a relatively well studied system to date.25,26 Equilibriums between different copper complexes in the reaction solution have been envisaged as shown in Scheme 1. Thus, complexes A, B, D, and E are possible starting species that would activate phenyl iodide to form the final coupling product. Complex A is phen-ligated cuprous iodide, which may be formed directly once the precatalyst CuI is added into the reaction solution in the presence of a phen ancillary ligand due to the large binding enthalpy of phen with CuI (41.7 kcal/mol). Complex B is a phen-ligated copper(I)-thiophenolato intermediate, which is formed by reaction of complex A with thiophenol in the presence of base. Disproportionation of two equivalents of complex B would generate bis-ligated cationic complex C and anionic complex D with multiple thiophenolato ligands. This disproportionation phenomenon has been observed for a long time for analogous Cu(I)-phenoxide complexes.38 Additionally, the aggregation of two equivalents of complex B would form dimeric complex F, which has been isolated and characterized by X-ray crystallography by Hartwig et al.25 These copper complexes are believed to be in fast dynamic equilibriums in the reaction solution. The conversion of A to B involves an acid/base neutralization process, which is regarded to be facile naturally and is confirmed by the experimental observation of ready preparation of complexes of type B from precatalyst CuX (X represents halides) in the presence of the corresponding nucleophiles, ancillary ligand, and appropriate bases. The ready disproportionation between an analogous Cu(I)-phenoxide complex of type B and complexes of type C and D has long been observed.38 Additionally, it has been shown that the reaction kinetics of these Ullmann reactions are

Table 1. Solvent Polarity Effect on Disproportionation Processa

solvent ΔG(sol)

toluene (ε = 2.379)

THF (ε = 7.580)

DMSO (ε = 46.70)

+18.2

+3.8

−2.5

a

All values in the table are changes of Gibbs free energies in kcal/mol. Symbol ε denotes the dielectric constant of the solvent.

seen, in the more polar solvent THF, an increase of only 3.8 kcal/mol in free energy is required to achieve this disproportionation process. Moreover, in highly polar DMSO solvent, the energy change of this disproportionation process is even exothermic by 2.5 kcal/mol, favoring the ionic forms instead. Therefore, there should be equilibrium between the neutral form B and the ionic forms C and D in reaction solution, the direction of which is influenced by the polarity of the solvent, with the neutral form favored in nonpolar or less polar solvents, while ionic forms are favored in highly polar solvent. From the above results, in the toluene solution we studied, complex B is likely to be the most abundant species among the possible copper complexes. This conclusion is in agreement with the general opinion that the active catalyst in these copper(I)-catalyzed Ullmann reactions should be a Cu(I)(nucleophile) species.12 However, complex D can dominate in polar solvents, such as DMSO. To provide more information for determining the reaction mechanisms for these copper(I)-catalyzed couplings of phenols with aryl halides, reactions of complexes B and D (and also other related species) with aryl iodide under several frequently proposed mechanisms, such as oxidative addition/reductive elimination,16−18 single-electron transfer,19 σ-bond metathesis, 4946

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and halogen atom transfer mechanisms,23,24 are investigated. Detailed results are shown below. 3.2. Oxidative Addition Mechanism. Oxidative addition of complex B with aryl iodide features a typical three-center two-electron transition state (Scheme 2), resulting in the

coupling product. The reductive elimination step is rather facile compared to the oxidative addition step and is largely exothermic, as shown in Figure 1. The activation barrier for oxidative addition of the anionic cuprate complex D with phenyl iodide is even higher, 41.5 kcal/ mol in toluene and 43.6 kcal/mol in DMSO (see Table S1 in the Supporting Information for more detailed information). A similar observation has been made for oxidative addition of Cuphenolato-type complexes with aryl halides.24 Other species such as complex A have an activation barrier of 37.0 kcal/mol (for more details, see Figures S1 and S2 in the Supporting Information). Complexes C and E have activation barriers larger than 34.0 kcal/mol, due to the difficult dissociation of one molecule of phen ligand from complex C. To summarize, in the context of oxidative addition mechanism, all possible copper species have too large activation barriers. Therefore, the oxidative addition mechanism seems unlikely for copper(I)-catalyzed S-arylation reactions between aryl halides and thiophenols due to kinetic inhibition, in contrast to the proposal of the oxidative addition mechanism for related Ullmann N-arylation reactions. 3.3. σ-Bond Metathesis Mechanism. As shown in Scheme 3, the σ-bond metathesis mechanism involves a

Scheme 2. Oxidative Addition of Copper Species with Iodobenzene

cleavage of the C−I bond and an increase of oxidation state of the copper center by two. The whole catalytic cycle and the critical transition state for oxidative addition of complex B with phenyl iodide are shown in Figure 1. The transition state for oxidative addition of complex B to phenyl iodide involves a typical three-membered ring structure, which is similar to that for related (diamine)Cu(I)(amidate) and (phen)Cu(I)(phenolato) complexes.16−18 However, the activation barrier for this oxidative addition step is 39.3 kcal/mol, which is much larger than those for amide and phenol arylation reactions (28.7 and 34.2 kcal/mol, respectively).18,24 This is possibly due to the π* orbitals of the phen ligand and 3d vacant orbitals of the S atom that decrease the electron density of the 3dπ orbitals of copper center and thus results in a higher activation barrier for oxidative addition. Oxidative addition would generate a high-lying intermediate, PDb, with an energy level of 31.6 kcal/mol. From this intermediate, reductive elimination occurs to deliver the final

Scheme 3. σ-Bond Metathesis Transition States for Complexes B and Da

a

All values in parentheses are Gibbs free energies in kcal/mol.

Figure 1. Oxidative addition of complex B with phenyl iodide. All values in parentheses are Gibbs free energies in kcal/mol. 4947

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reaction with phenyl iodide. Therefore, the SET mechanism seems unlikely for this copper(I)-catalyzed S-arylation reaction. 3.5. Halogen Atom Transfer (HAT) Mechanism. In recent theoretical studies, the halogen atom transfer mechanism has been proposed for analogous Ullmann O-arylation reactions of aryl halides with O-nucleophiles, such as alcohols and phenols.23,24 This HAT mechanism involves the critical halogen atom transfer from aryl iodide to Cu(I) center, leading to the formation of a Cu(II)(SPh)(I) intermediate and a phenyl radical (Scheme 5). Although the Ph−I bond is quite strong, the cleavage of this bond is compensated by the formation of a Cu−I bond. The resulting phenyl radical can either directly attack the thiophenolato sulfur atom to form the coupling product or recombine with the generated LCu(II)(SPh)(I) intermediate to form the same Cu(III) intermediate PDb from oxidative addition of phenyl iodide to LCu(I)-SPh. Unfortunately, the transition state for this HAT process could not be located despite great effort. Additionally, a smooth potential energy surface scan on the Ph−I bond fixed from 2.2 to 3.6 Å with a step size of 0.1 Å shows a consistent increase in energy during the HAT process, without an apparent maximum point, indicating that there is no apparent transition state for this HAT process (see Figure S3 in the Supporting Information for more details). Therefore, the activation energy needed should be very close to the energy change of this process.41 Calculation results show that the energy change for this HAT process is 32.2 kcal/mol. The magnitude of this value is quite reasonable in view of the fact that these copper(I)-catalyzed Sarylation reactions need to be conducted at 110 °C for hours. Given the high-lying intermediate PDb (refer to discussions in Section 3.2), the phenyl radical generated from the HAT process is more prone to directly attack the thiophenolato sulfur atom to afford the coupling product, rather than to combine with the Cu(II) center to form intermediate PDb. The direct attack of the phenyl radical with coordinated thiophenolato is exothermic by 36.5 kcal/mol and therefore is thermodynamically favorable, resulting in the formation of a complex composed of complex A and product biphenyl sulfide. Finally, the release of biphenyl sulfide would give complex A, which can be readily converted to the active complex B in the presence of thiophenol and base. Thus, a whole catalytic cycle is completed, as shown in Figure 2. Additionally, complex D was also examined under the HAT mechanism. Calculation results show that the activation barriers are 33.2 kcal/mol in toluene and 34.8 kcal/mol in DMSO. Although these values are a bit larger than that for complex B, for reactions performed in polar solvent such as DMSO, where complex D is dominant and the concentration of complex B is

concerted C−I bond cleavage/C−S bond formation process, which is in contrast to the oxidative addition/reductive elimination mechanism involving stepwise C−I bond cleavage and C−S bond formation. Calculation results show that the transition states for the σbond metathesis mechanism are much higher in free energy than the corresponding transition states for the oxidative addition mechanism. Specifically, for complex B, the transition state for σ-bond metathesis, i.e., TSmet1, is higher than the transition state TSb for the oxidative addition mechanism by 6.2 kcal/mol in free energy. Similarly, the transition state TSmet2 for complex D is 4.7 kcal/mol higher in free energy than the oxidative addition transition state in toluene. Therefore, the σbond metathesis mechanism can be excluded for these copper(I)-catalyzed S-arylation reactions. 3.4. Single Electron Transfer (SET) Mechanism. As shown in Scheme 4, the SET mechanism commences with Scheme 4. SET Mechanism for Complex B

single electron transfer from the Cu(I) center of complex B to aryl iodide, resulting in the formation of the Cu(II) radical cation and aryl iodide radical anion.39 The aryl iodide radical anion further dissociates the iodide anion to generate a free aryl radical, which reacts with the Cu(II) radical cation to afford the final coupling product. Similar SET mechanisms have already been proposed for Ullmann-type reactions.19,23,24 According to Marcus theory, the activation barrier of a SET process should be slightly larger than the energy change of the process (generally less than 15 kJ/mol).40 Therefore, in this study the free energy changes were used to estimate the lower limit of activation barriers of such SET pathways. Calculation results show that the SET process has a dramatically large energy increase of 70.1 kcal/mol for SET from complex B to phenyl iodide. Therefore, the SET mechanism is kinetically inhibited for complex B. When complex D was examined under the SET mechanism, activation barriers of 45.4 kcal/mol in toluene and 41.8 kcal/mol in DMSO were estimated for Scheme 5. HAT Mechanism for Complex B

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Figure 2. A catalytic cycle proposed for the halogen atom transfer mechanism. All values in parentheses are Gibbs free energies in kcal/mol.

reaction mechanism for Ullmann-type S-arylation reactions. Phenyl bromide and chloride were examined to represent relevant aryl bromides and chlorides. As can be seen from Table 3, for both oxidative addition and HAT mechanisms, the

very low, the complex D-initiated halogen atom transfer pathway should dominate. 3.6. Discussion. 3.6.1. Summary of Mechanisms for Ullmann S-Arylation Reactions. Activation barriers for complexes B and D in the context of different mechanisms are summarized in Table 2. Obviously, the halogen atom

Table 3. Activation Barriers for Various Kinds of Aryl Halidesa

Table 2. Summary of Activation Barriers for Different Mechanismsa

oxidative addition

copper species

oxidative addition

σ-bond metathesis

SET

HAT

B D

39.3 41.5

45.5 47.2

70.1 45.4

32.2 33.2

HAT

PhX (X =)

B

D

B

D

I Br Cl

39.3 43.2 47.8

41.5 45.5 49.8

32.2 35.3 37.5

33.2 36.6 41.4

a

a

transfer mechanism is the most favored for both complexes B and D. This conclusion is consistent with mechanistic proposals for analogous Ullmann O-arylation reactions.23,24 Under this mechanism, an initial halogen atom transfer from aryl halide to the Cu(I)-SAr intermediate generates a phenyl radical and an intermediate Cu(II)(SAr)(I). Direct combination of the phenyl radical with the thiophenolato ligand of Cu(II)(SAr)(I) affords the final coupling product. The magnitude of the activation barrier for the halogen atom transfer mechanism (32.2 kcal/ mol for complex B and 33.2 kcal/mol for complex D) is well consistent with the reaction conditions (110 °C for hours). Other possible mechanisms such as oxidative addition, SET, and σ-bond metathesis all possess extremely high activation barriers, rendering them kinetically unfavorable. 3.6.2. Various Aryl Halides’ Effect. Various aryl halides with different halides were examined under the proposed HAT mechanism in this study as well as the oxidative addition mechanism, to get insight into the halogen effect on the

aryl halides’ reactivity follows the trend ArI > ArBr > ArCl. This prediction reproduces the experimental trend observed and possibly explains the reluctance of aryl chlorides to participate in Ullmann S-arylation reactions. Noteworthy, the HAT mechanism is consistently more favorable when compared to the oxidative addition mechanism for all kinds of aryl halides and both complexes B and D. This can possibly be attributed to the less demanding requirement of energies during the redox of the copper center under the HAT mechanism (Cu from +1 to +2), compared to the more energy-intensive change of oxidation state from +1 to +3 under the oxidative addition mechanism. Complex B should be a little more reactive toward all kinds of aryl halides than complex D under both oxidative addition and HAT mechanisms. This finding highlights the importance of generating the active neutral (L)Cu(I)-SAr species for achieving mild Ullmann S-arylation reactions. Furthermore, these results also rationalize the inherent difficulty of Ullmann coupling of S-nucleophiles, as reflected by the large activation barriers.

All the values are activation free energies in kcal/mol in toluene solvent.

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All values are activation free energies in kcal/mol in toluene solvent.

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3.6.3. Importance of Solvent Polarity. As shown in Table 1, in the strongly polar solvent DMSO, the disproportionation equilibrium favors the ionic forms, and thus the active copper species should be the cuprate Cu(SAr)2 anion. The activation barriers for reaction of the Cu(SPh)2 anion with phenyl iodide under oxidative addition, σ-bond metathesis, SET, and HAT mechanisms are 41.5, 47.2, 45.4, and 33.2 kcal/mol, respectively (see Table 2). Subsequently, for complex D, the HAT mechanism is also the most favored. Therefore, the reaction mechanism for Ullmann coupling of thiophenols with aryl halides is likely to follow the mechanistic picture shown in Scheme 6, which is analogous to that for Ullmann O-arylation

be a neutral (phen)Cu(I)-SAr species in nonpolar or less polar solvent. However, in highly polar solvents, the cuprate anion form Cu(I)(SAr)2 is likely to be the active catalyst. For both the neutral form (phen)Cu(I)-SAr and the anionic form Cu(I)(SAr)2, the halogen atom transfer mechanism is favored, which involves a rate-limiting halogen atom transfer from aryl halide to the copper(I) center and the consequent participation of Cu(II) intermediates and aryl radicals. Additionally, halide effects of the electrophiles were investigated in the context of the favored halogen atom transfer as well as oxidative addition mechanism for complex (phen)Cu(I)(SAr). Calculation results reveal that the reactivity of aryl halides follows the trend ArI > ArBr > ArCl under the HAT mechanism, which is in good agreement with experimental findings. Generally speaking, Ullmann S-arylation reactions follow a similar mechanism to that of O-arylation reactions, but are distinct from that of N-arylation reactions. This implies that the mechanisms of Ullmann reactions are dependent on nucleophiles types. Nucleophiles with homologous reactive centers should follow analogous mechanisms, while nucleophiles with reactive centers from different groups in the periodic table of elements may be involved in different mechanisms. This study presents for the first time a mechanistic proposal for Ullmann S-arylation reactions and sheds new insights into the mechanisms for copper(I)-catalyzed Ullmann reactions. It should therefore stimulate more efforts directed toward the developments and applications of Ullmann-type reactions.

Scheme 6. Mechanistic Profile of Copper(I)-Catalyzed Coupling of Thiophenols with Aryl Halides

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reactions. We should emphasize that this mechanistic proposal for Ullmann S-arylation reactions has not yet been reported in the literature. 3.6.4. Relationship to Mechanisms for Ullmann N- and OArylation Reactions. Given the widely accepted oxidative addition mechanism for Ullmann N-arylation reactions16−18 and the halogen atom transfer mechanism proposed for Ullmann O-arylation reactions,23,24 it is suggested that Ullmann S-arylation reactions follow a similar mechanism to that of Oarylation reactions. Therefore, this implies that the mechanism of Ullmann reactions is dependent on the nucleophiles involved. Nucleophiles with reactive central atoms from different groups in the periodic table of elements may follow different reaction pathways, whereas nucleophiles of homologous reactive centers should react by a common mechanism. Furthermore, copper-catalyzed S-arylation is probably less kinetically competitive than O-arylation reactions, as reflected by the relative activation barriers for these reactions (28.7 kcal/ mol for PhBr in O-arylation; 35.3 kcal/mol for PhBr in Sarylation).24 This may explain the difficulty of developing mild Ullmann S-arylation reaction conditions, as compared to those for O- and N-arylation reactions. These insights are believed to be valuable for the understanding and application of coppercatalyzed orthogonal or selective reactions of substrates containing multiple nucleophilic functional groups.

ASSOCIATED CONTENT

S Supporting Information *

Additional computational results, detailed optimized geometries, free energies, and full citation of the Gaussian03 program. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant No. 21202062) and the Natural Science Foundation of Jiangsu Province (Grant No. BK2012108).

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REFERENCES

(1) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (2) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. (3) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (4) (a) Negwer, M. Organic-Chemical Drugs and Their Synonyms: An International Survey, 7th ed.; Akademie Verlag: Berlin, 1994. (b) MacDiarmid, A. G.; Epstein, A. J. In Science and Applications of Conducting Polymers; Salaneck, W. R.; Clark, D. T.; Samuelsen, E. J., Eds.; Hilger: New York, 1991. (c) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In Chemistry of Anilines; Rappoport, Z., Ed.; Wiley-Interscience: New York, 2007; Vol. 1, p 455. (5) For recent reviews on copper-catalyzed C−N, C−O, and C−S bond formation reactions, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 15, 2428. (b) Ley, S. V.; Thomas, A. W. Angew. Chem.,

4. CONCLUSIONS In this study, we have performed a detailed theoretical study on the mechanism of copper(I)-catalyzed coupling reactions of aryl halides with thiophenols in toluene (and also DMSO in some cases). Through evaluation of the equilibriums of possible copper species in the reaction solution and reactivity of these species with aryl halides in the context of several common reaction mechanisms, we propose that the active catalyst should 4950

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dx.doi.org/10.1021/om4006615 | Organometallics 2013, 32, 4944−4951