Catalyzed Oxidative Cross-Coupling Reaction between Arenes and

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Mechanistic Study on Cu(II)-Catalyzed Oxidative Cross-Coupling Reaction between Arenes and Boronic Acids under Aerobic Conditions Qian Zhang, Yang Liu, Ting Wang, Xinhao Zhang, Chao Long, Yun-Dong Wu, and Mei-Xiang Wang J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018

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Journal of the American Chemical Society

Mechanistic Study on Cu(II)-Catalyzed Oxidative Cross-Coupling Reaction between Arenes and Boronic Acids under Aerobic Conditions Qian Zhang,†,§ Yang Liu,†,§ Ting Wang,‡,§ Xinhao Zhang,*,‡ Chao Long,† Yun-Dong Wu,‡ Mei-Xiang Wang*,† †

MOE Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China ‡ Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China Supporting Information Placeholder ABSTRACT: Substantial attention has been given to modern organocopper chemistry in recent years because of the need of sustainability since copper salts are naturally abundant, cheap and less-toxic in comparison to precious metals. Copper salts also exhibit versatility in catalyzing and mediating carbon-carbon and carbon-heteroatom bond forming reactions. Despite the wide applications of copper salts in catalysis, reaction mechanisms have remained elusive. Using azacalix[1]arene[3]pyridine, an arene-embedded macrocycle, and its isolated and structurally well-defined ArCu(II) and ArCu(III) compounds as molecular tools, we now report an indepth experimental and computational study on the mechanism of Cu(II)-catalyzed oxidative cross-coupling reaction between arenes and boronic acids with air as the oxidant. Stoichiometric reaction of organocopper compounds with p-tolylboronic acid validated arylcopper(II) rather than arylcopper(III) as a reactive organometallic intermediate. XPS, EPR, 1NMR, HRMS and UV-vis spectroscopic evidences along with the isolation and quantification of all products and copper speciation, combined with computational analysis of the electronic structure and energetics of the transient intermediates suggested a reaction sequence involving electrophilic metalation of arene by Cu(II), transmetalation of arylboronate to ArCu(II), the redox reaction between the resulting ArCu(II)Ar’ and ArCu(II) to form respectively ArCu(III)Ar’ and ArCu(I), and finally reductive elimination of ArCu(III)Ar’. Under aerobic catalytic conditions, all Cu(I) ions released from reductive elimination of ArCu(III)Ar’ and from protolysis of ArCu(I) were oxidized by oxygen to regenerate Cu(II) species that enters into the next catalytic cycle. The unraveled reactivity of arylcopper(II) compounds and the catalytic cycle would enrich our knowledge of modern organocopper chemistry and provide useful information in the design of copper catalyzed reactions.

of copper(I)-mediated or -catalyzed carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation reactions and thus are hard to access.7 Recently, several structurally well-defined organocopper(III) complexes were successfully isolated.7-18 The detailed studies on their structures and reactivity have immensely promoted our mechanistic understanding of copper-involved organic reactions. In stark contrast, the Cu(II)-carbon bond is very rare and there are only a few sporadically reported organocopper(II) compounds.16,18-23 Latos-Grażyński16,19 and Furuta20,21 reported for example (1H-pyrrol-3-yl)copper(II)19-21 and furan-3-ylcopper(II)16 complexes derived from corresponding N- and O-confused porphyrins, while Kinoshita22 showed the synthesis of alkylcopper(II) compounds using tris(2-pyridylthio)methane. The extended porphyrinoid-systems16,19-21 and a tripodal ligand22 are believed to stabilize the Cu(II)-C(sp2) and Cu(II)-C(sp3) structures, respectively. Very recently, we have successfully synthesized the first arylcopper(II) compounds from electrophilic aromatic metalation of azacalix[1]arene[3]pyridines with copper(II) salts.23 Owing to the

INTRODUCTION Copper is one of the most widely used transition metal elements in chemical synthesis. While organocuprates are widely recognized organometallic reagents, copper salts catalyze various functional group transformations and cross coupling reactions.1 Substantial attention has been given to modern organocopper chemistry in recent years because of the need of sustainability since copper salts are naturally abundant, cheap and lesstoxic in comparison to precious metals.2 Moreover, as the surrogate of noble metal catalysts, copper salts have been shown to exhibit remarkable versatility in catalyzing or mediating various chemical bond forming reactions.1-3 Although the known oxidation states of copper range from 0 to 4+, the common one in isolable organocopper compounds is dominated by the 1+ oxidation state. Therefore, synthesis and reactivity studies of organocopper(I) compounds attract great attention in spite of their acknowledged structural complexity and variability.4-6 On the other hand, organocopper(III) compounds are often regarded as transient intermediates in the transformation process

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unique structural features of macrocyclic heteracalixaromatics,24 all arylcopper(II) compounds are stable under atmospheric conditions, permitting full and unambiguous characterization by means of various methods including X-ray crystallography, electron paramagnetic resonance (EPR) and X-ray photoelectron spectroscopy (XPS). They can be oxidized by Oxone or by a free Cu(II) ion to produce arylcopper(III) compounds23 which can interact with different nucleophilic reagents and undergo a reductive elimination to construct diverse C-C25 and CX bonds.17,26-29 In a seminal work in 2006 Yu30 communicated the Cu-catalyzed and mediated regioselective C-H functionalization reactions of (pyridin-2-yl)arenes to form C-X bonds (X = heteroatoms and CN). Since then a plethora studies on directing-groupassisted arene C-H bond transformations have been reported using a copper salt as a catalyst and a mediator.31,32 Despite significant developments in synthetic methodology, the mechanism for the copper-catalyzed and mediated arene C-H bond activation remains elusive. In this regard, a number of hypotheses comprising various oxidation states of copper and organocopper species have been proposed.33-36 Reactions proceeding through plausible Cu(III)/Cu(I)31,32,36 and Cu(II)/Cu(0)37-39 catalytic cycles, and the Cu(II)/Cu(I)36,40 catalytic cycle through a single-electron transfer (SET) pathway have been invoked to rationalize the reported Cu(II)-catalyzed functionalizations of arene C-H bonds. By means of the systematic synthesis and reactivity studies of organocopper(III) compounds using macrocyclic substrates, we,23-29 Stahl31,41 and Ribas42 have provided sufficient experimental evidences that a Cu(I)/Cu(III) catalytic cycle operates in the C-H bond functionalization reactions with a number of “anionic” carbon and heteroatom nucleophiles. The aryl-Cu(III) intermediates are formed through two distinct pathways: either an electrophilic metalation of arene followed by the oxidation of the resulting aryl-Cu(II) species with free copper(II) ion23 or a proton-coupled electron transfer (PCET) reaction.43 Oxidative addition of haloarenes25a or an aryl triflates44 to Cu(I) also gives rise to arylcopper(III) complexes. The boron reagents are widely used in carbon-carbon bond forming reactions due to their high thermal stability, functional group compatibility and the convenience of handling. The Cu(II)-mediated direct cross-coupling of boron reagents with arene was pioneered by Itami45 who reported in 2008 the arylation of 1,3,5-trimethoxybenzene, an electron-rich arene, with arylboronic acids under acidic conditions (Figure 1). A Cu(OAc)2-catalyzed coupling reaction of arene C-H bond with ArBpins was achieved by Dai and Yu46 in 2014 (Figure 1). The reaction of arenes bearing a bidentate amide-oxazoline direction group, which uses Ag2O (1.5 equiv) as an oxidant and an excess amount of Na2CO3 (2 equiv) and KOAc (2 equiv) as bases, leads to the formation of biaryl bonds in moderate yields.46 Later on, a Cu(OAc)2-mediated ortho-arylation of N-(quinolin8-yl)benzamides with arylboronic acids was reported by Tan. 47 Noticeably, both research groups postulated the formation of a similar bidentate ligand-bonded arylcopper(II) intermediate and its conversion to arylcopper(III) intermediate by oxidation of a free copper(II) ion. The transmetalation of the aryl group from boron reagent to arylcopper(III) was hypothesized as a key step prior to reductive elimination.46,47

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Figure 1. Previous examples of Cu(II)-mediated (top) and Cu(II)-catalyzed (bottom) arene C-H bond arylation with boron reagents.

Figure 2. Cu(II)-catalyzed arene C-H arylation of azacalix[1]arene[3]pyridine 1 with arylboronic acids using air as an oxidant. We have discovered very recently, that under atmospheric conditions macrocyclic azacalix[1]arene[3]pyridines underwent highly efficient Cu(ClO4)2.6H2O-catalyzed direct oxidative arene C-H bond coupling reactions with aryl, alkenyl and alkyl boronic acids to form Caryl-Caryl, Caryl-Calkenyl and Caryl-Calkyl bonds, respectively.48 The reaction in Figure 2 would provide us with a unique and ideal model to study the mechanism of Cu(II)-catalyzed cross-coupling reaction between arenes and boronic acids as azacalix[1]arene[3]pyridine 1 forms isolable and structurally well-defined arylcopper(II) and arylcopper(III) compounds.23 Being reactive species, the high valent organocoppercompounds would facilitate determination of organometallic intermediates in the reaction. We report herein an in-depth experimental and computational investigation on the reaction mechanism of copper catalysis. All experimental evidences combined with computational analysis of the electronic structure and energetics of the transient intermediates support an unprecedented mechanism that features sequential electrophilic metalation of arene by Cu(II), transmetalation of arylboroate to ArCu(II), the redox reaction between the resulting ArCu(II)Ar’ and ArCu(II) to form respectively ArCu(III)Ar’ and ArCu(I) followed by reductive elimination from ArCu(III)Ar’. All Cu(I) ions released both from reductive elimination of ArCu(III)Ar’ and from protolysis of ArCu(I) are oxidized by oxygen under aerobic catalytic conditions to regenerate Cu(II) species that enters into the next catalytic cycle. Results and Discussion It has been shown23 that azacalix[1]arene[3]pyridine 1 reacts efficiently with Cu(ClO4)2.6H2O to form -bonded high valent ArCu(II) (2) and ArCu(III) (3) products under ambient atmospheric conditions. ArCu(II) compound 2 is resulted directly


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from electrophilic aromatic metalation while ArCu(III) complex 3 is generated from oxidation of 2 by free copper(II) ion. To identify the reactive organometallic species in copper catalysis (Figure 2), we commenced our study with the examination of stoichiometric reactions of 2 and 3 with p-tolylboronic acid 4 (Figure 3). Under the catalytic reaction conditions (air, 80 oC in DMSO), ArCu(II) compound 2 underwent efficient reaction with p-tolylboronic acid 4 to produce a cross-coupling product 5 exclusively in 96% yield in 0.5 h. Quantitative conversion was also observed at ambient temperature in DMSO and in DMF in 4 h and 1 h, respectively. After completion of Caryl-Caryl bond forming reaction, the characteristic red color of ArCu(II) compound 2 changed into blue-green of Cu(II) ion (Figure 4a). The color of reaction mixture changed into yellow when the reaction was conducted under nitrogen (Figure 4b), and these results will be discussed further below. The reaction took place as well in hot acetonitrile (80 oC) albeit the efficiency appeared lower. Surprisingly, when ArCu(III) compound 3 was treated with 4 under the identical conditions as for reaction between 2 and 4, formation of cross-coupled product 5 was not observed at all (Figure 3). The dark color of high valent organocopper(III) reactant 3 remained (Figure 4c) despite its partial protolysis to give a small amount of parent azacalix[1]arene[3]pyridine 1 due to the treatment with acidic 4 (see Supporting Information). It was also noteworthy that the presence of TEMPO (2,2,6,6tetramethylpiperidine-N-oxyl) did not inhibit the reaction between 2 and 4, with product 5 being obtained in 96% yield. It indicated the reaction was not radical in nature.

Figure 4. The change of the color of the reaction mixture of the reactions of p-tolylboronic acid 4 with arylcopper(II) compound 2 under air (a) and under nitrogen (b), and with arylcopper(III) compound 3 under air (c).The reaction was conducted at 30 oC with the concentration of reactant 2 in DMF being 0.25 mmol/mL. The clear-cut distinction between the reactivity of boronic acid with organocopper(II) and organocopper(III) compounds was not expected. Our previous studies have shown that azacalix[1]arene[3]pyridine-derived arylcopper(III) complexes exhibit remarkable reactivity towards diverse nucleophiles ranging from halides, acetates, aryloxy and alkoxy, nitrate and amides, thiocynate and cyanide to alkyl and alkynyl lithium reagents.17,25-29 Analogous cross-coupling reaction property has also been observed by Stahl and Ribas31,37,40-43 for a similar macrocyclic arylcopper(III) species which is derived from a m-phenylene-embedded azacrown ether.15 It should be addressed that the outcomes of the stoichiometric reactions of high valent arylcopper compounds with arylboronic acid was very important in comprehending the mechanism of catalysis. In stark contrast to the reaction of common anionic nucleophiles, in which nucleophiles bond to the metal site of ArCu(III) intermediate and then undergo reductive elimination, boronic acids don’t react with ArCu(III) compound. Apparently, it is the ArCu(II) rather than ArCu(III) that act as the key reactive organometallic intermediate in Cu(II)-catalyzed cross-coupling reaction between arenes and boronic acids.

Figure 3. Reactions of p-tolylboronic acid 4 with arylcopper(II) compound 2 and arylcopper(III) compound 3 under an oxygen atmosphere.

Figure 5. A plausible ArCu(II)/Cu(0) catalytic cycle.



Although it is much less popular than the Cu(III)/Cu(I) catalytic cycles suggested for many copper-catalyzed cross-coupling reactions, a Cu(II)/Cu(0) catalytic pathway has been proposed in the literature,37-39 albeit without direct evidence. The experimental evidence for the involvement of ArCu(II) species as the reactive intermediate raised the possibility of a ArCu(II)/Cu(0) mechanism in operation. In other words, the reaction would proceed through consecutive transmetalation of ptolylboronic acid 4 to ArCu(II) 2 and reductive elimination from ArCu(II)Ar’, hereafter referred to as species A, to afford biaryl product 5. The Cu(0) species generated would be oxidized by molecular oxygen into Cu(II) which enters into the next catalytic cycle (Figure 5). Due to most likely the instability of ArCu(II)Ar’ A and the rapid oxidation of atomic Cu(0) species under atmosphere, their isolation and detection would be difficult. We then thought stoichiometric reaction between ArCu(II) 2 and boronic acid 4 under an anaerobic condition would probably permit the detection of Cu(0) since the oxidation step was blocked. Moreover, the reaction course can be monitored by means of electron paramagnetic resonance (EPR) spectroscopy. The information acquired would shed light on the mechanism. In our previous study,23 we have successfully observed the EPR signals of ArCu(II) 2 in a mixture of ethanol and DMF at 77 K. According to such measurement conditions, we performed the reaction at 30 oC under the protection of nitrogen and recorded the EPR spectra of the DMF/EtOH solution of reaction mixture at 77 K at different time intervals (0.05, 1, 12, 24, 36 and 144 h) under nitrogen. As shown in Figure 6, the EPR spectra clearly indicated the gradual decrease of organocopper(II) 2 as the reaction progressed. Accordantly, no signals of inorganic Cu(II) species were detected in reaction mixture even after 144 h.

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color of the reaction mixture changing from red into yellow rather than blue-green (vide supra, Figure 4b). To trace the fate of copper in reactant ArCu(II) 2, reaction was carried out under the strictly oxygen-free condition. Intriguingly, after reaction in a glove box was finished in 12 h and the mixture was left for a few days, we observed the existence of nano-sized metal particles by transmission electron microscope (TEM) images. The compositions of those metal particles were explicitly assigned as metallic copper based on energy dispersive spectroscopy (EDS) (Figures S1-S3). High-resolution TEM found the lattice fringe spacings of the particle as 0.21 nm corresponding to the {111} planes of copper49 (Figure 7a). Occasionally, we also observed copper mirror on the surface of a stirring bar used for the reaction along with the firebrick-colored powder on the wall of reaction vial (Figure 7b). The metallic nature of copper powder and mirror samples was further substantiated by XRD (Figure 7c). The 2 peaks (43.3°, 50.5°and 74.2°) of the copper powder and of copper mirror-covered teflon plate that was cut down from the stirring bar agreed quite well with the reported values of the metallic copper.49 Though the EPR results and the formation of metallic copper diverted us to consider a Cu(II)/Cu(0) catalytic cycle, the low chemical yield of 5 along with the isolation of azacalix[1]arene[3]pyridine 1 from the reaction of 2 and 4 under nitrogen (Figure 4b) casted however serious doubts on the proposal. If the mechanism depicted in Figure 5 worked, the stoichiometric reaction of 2 with 4 would not be affected by the reaction atmosphere, viz. the chemical yield of product 5 would be virtually same irrespective of the presence or absence of oxygen. However, we discovered that the reaction at room temperature in DMF under oxygen-free conditions produced 5 never exceeding 50% yield in 12 h (50%) and 24 h (48%) (Figure 8) whereas a quantitative yield was obtained from the reaction in a vial exposure to an air atmosphere. In addition to crosscoupling product 5, the parent macrocyclic compound 1 was also isolated in 48% yield after 12 h and 24 h (Figure 8). Comparable results were obtained when reaction was carried out at 80 oC. It was obvious that the ArCu(II)/Cu(0) pathway outlined in Figure 5 did not explain both the atmosphere dependence of the reaction and the formation of an equal amount of 5 and 1 from the oxygen-free reaction between 2 and 4.

Figure 6. EPR spectra of arylcopper(II) 2 and of the reaction mixture of 2 and 4 at 30 oC in 0.05, 1, 12, 24, 36 and 144 h under nitrogen. (X-band, EtOH / DMF = 4 / 1, 104 K). EPR experimental conditions: microwave frequency, ν = 9.0355 GHz; microwave power, 0.998 mW; modulation amplitude, 600; modulation frequency, 100 kHz; g⊥ = 2.06, g∥ = 2.10.

Figure 7. TEM images (inset) of copper nanoparticles obtained from reaction solution, and high resolution TEM image of an individual Cu nanoparticle taken from the region marked by a box in inset (a). Copper mirror on the teflon surface of a stirring bar and copper powder on the wall of reaction vial (b). XRD

The devoid of free Cu(II) ion in reaction as substantiated by EPR measurement was in agreement with the observation of the


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100

patterns of copper powder precipitated from reaction and of copper mirror on stirring bar after reaction (c).

90 80

[Cu(I)] / [2]o (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


70 60 50 40 30 20

10

Figure 8. Reaction of 2 with 4 under oxygen-free conditions.

0 0

Before proposing an alternative mechanism, we set to understand the origin of parent macrocycle 1 by monitoring the reaction under nitrogen atmosphere using 1H NMR spectroscopy and high resolution mass spectrometry. Evidenced clearly by the proton signals that were also verified by those of the authentic samples (Figures S4-S6), compound 1 was generated concomitant with the formation of 5! From the same reaction mixture, a high resolution mass spectrum (ESI-MS) of a sample taken in a 20 h time interval showed only two intense ion peaks corresponding to [1+Cu]+ (m/z, 486.1459) and [5+Cu]+ (m/z, 576.1928) along with weak ion peaks of [1+H]+ (m/z, 424.2240) and [5+H]+(m/z, 514.2709). Only extremely weak peaks attributable to [2-ClO4]+ (m/z, 485.1377) and [3-(ClO4)2]2+ (m/z, 242.5689) were traced (Figures S7-S10). The detection of almost sole Cu(I) ion, which was associated with macrocycles 1 and 5, conflicted entirely with the mechanism involving copper in +2 and 0 oxidation states.

5

10

time / h

15

20

25

Figure 9. A plot of [Cu(I)]/[2]0 against reaction time. The discovery of the formation of nearly a quantitative amount of Cu(I) ion form the reaction between 2 and 4 under inert atmosphere (Figure 8) led us to suspect whether metallic copper was formed directly from reductive elimination of putative intermediate ArCu(II)Ar’ A in Figure 5 as we discussed (vide supra). It is well known that the Cu(I) ion is unstable in aqueous solution and undergoes spontaneous disproportionation reaction to give Cu(II) and metallic copper.51 Our reaction conditions which contain boronic acid and water would be favorable to the disproportionation reaction. Precedent that Cu(I) species disproportionate in copper-catalyzed organic reaction has been reported.52 To answer the question if metallic copper as we observed before (Figure 7) is derived from Cu(I), we then left the reaction mixture in question under oxygen-free conditions for an extended period of time. The fine copper powders were found indeed to precipitate from the solution in a few days, indicating the conversion of initially formed Cu(I) into Cu(0). Such a disproportionation reaction process was further proved by a control experiment. For example, keeping Cu(CH3CN)4PF6 in an otherwise identical reaction media but without ArCu(II) 2 for several days resulted in the formation of metallic copper powders. These results excluded convincingly the possible Cu(II)/Cu(0) catalytic cycle depicted in Figure 5. On the basis of all aforementioned experimental evidences, a most plausible reaction mechanism was proposed. As delineated in Figure 10, reaction of arene 1 with a copper(II) salt produces ArCu(II) complex 2.This metalation step has been explicitly elucidated previously.23 Transmetalation of the aryl of boronic acid 4 to copper center of 2 gives ArCu(II)Ar’ intermediate A, a step analogous to that in Chan-Evans-Lam reaction unveiled recently by Stahl.52,53 The intermediate A undergoes redox reaction with 2 to form diarylcopper(III) B and arylcopper(I) C intermediates, respectively. Reductive elimination of diarylcopper(III) B affords the cross-coupling product 5 and Cu(I). As well-documented in literature,54 the arylcuprate compound C is highly hygroscopic and its protolysis upon the interaction with water and boronic acid furnishes the formation of the starting material 1 with the release of Cu(I) ion. The Cu(I) ion is complexed by both macrocyclic ligands 1 and 5 to exist as Cu(I)L (L = 1 and 5). Under acidic conditions, the Cu(I) resulted from both reductive elimination of B and protolysis of C is oxidized by molecular oxygen to form Cu(II) which enters into the next catalytic cycle.

Considering the importance the fate of copper of organocopper species in elucidating the mechanism, we focused on the formation of Cu(I) ion from the reaction depicted in Figure 8. To quantify Cu(I) generated with the progress of reaction, aliquots removed from reaction mixture at different time intervals were quenched immediately with a solution of 2,9-dimethyl1,10-phenanthroline, a powerful and specific complexation reagent for Cu(I) ion.50 The concentration of Cu(I) of each sample was then measured right away by means of a UV-visible spectrophotometric method50 (Figures S11-S14, Table S1). A plot of the conversion of reactant Ar(Cu(II) 2 to Cu(I), [Cu(I)]/[2]0, against reaction time was obtained (Figure 9). Significantly, more than 90% of starting organocopper(II) compound 2 was transformed into Cu(I) species within 5 h. Complete conversion was observed after 10 h, coinciding with the formation or isolation of ca. 50% of product 5 and of product 1 (Figure 8).



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p-tolylboronic acid 4 under oxygen-free conditions as demonstrated in Figure 8 led us to exclude the pathway of oxidation of diarylcopper(II) by Cu(II) ion. In a further control experiment,55 reaction of ArCu(II) 2 with boronic acid 4 in the presence of one equivalent of Cu(ClO4)2.6H2O under N2 afforded products 5 and 1 in 48% yield and 50% yield, respectively (see Supporting Information). The outcome of this control experiment indicated clearly that free Cu(II) ion does not oxidize diarylcopper(II) intermediate A, since if the oxidation of diarylcopper(II) A by Cu(II) ion worked, the reaction would yield a quantitative amount of product 5 without the formation of parent macrocycle 1. Moreover, there is necessity to explain the observation of extremely weak peaks of ArCu(III) compound 3 from the HRMS analysis of reaction mixture of 2 and 4 under aerobic conditions (vide supra). Initially, we thought it was most probably due to the hydrolysis of ArCu(II) 2 in the presence of boronic acid to release Cu(II) ion which in turn oxidized ArCu(II) 2 into ArCu(III) 3. However, from control experiments (cf. experiments 5.7 – 5.9 in Supporting Information) to understand the stability of ArCu(II) 2 under the catalytic reaction conditions, we found free Cu(II) ion does not appreciably convert ArCu(II) 2 into ArCu(III) 3. Instead, ArCu(II) 2 showed a very low tendency to undergo disproportionation reaction to form a very small amount of ArCu(III) 3 in DMF. The presence of a boronic acid such as 2,4,6-trifluorophenylboronic acid, an inert reactant toward cross-coupling reaction with ArCu(II), appeared slightly favorable for disproportionation of 2.

Figure 10. Mechanism (blue) for Cu(II)-catalyzed arene C-H bond arylation with boronic acids under aerobic conditions. The mechanism, which are consistent with all experimental results obtained so far, also raises some other interesting issues that are worthy of discussion. First, at a glance of the mechanism, ArCu(II) and Cu(I) should also act as catalysts as Cu(II). As illustrated in Figures 11(a) and 11(b), either ArCu(II) 2 or Cu(CH3CN)4PF6 catalyzed as efficiently as Cu(ClO4)2.6H2O the cross-coupling reaction between 1 and boronic acid 4 under aerobic condition. Second, since the oxidation of Cu(I) to Cu(II) plays an essential role, the absence of oxygen should stop the catalytic turnover. This has been exemplified indeed by the recovery of almost all reactant 1 (95%) from the same Cu(I)-catalyzed reaction under nitrogen protection (Figure 11(c)). In addition, the redox reaction between diarylcopper(II) intermediate A and ArCu(II) 2 to form diarylcopper(III) intermediate B and ArCu(I) C followed by respective reductive elimination of B and protolysis of C best explain the outcome of the anaerobic reaction of ArCu(II) 2 with boronic acid 4 in Figure 8, which afforded 5 and 1 each in nearly 50% yield along with almost quantitative Cu(I). This key proposal was further supported by converting all in situ generated arene 1 into final product 5 simply by running the reaction under an oxygen atmosphere after under nitrogen. As shown in Figure 11(d), replacement of nitrogen with oxygen led to the improvement of chemical yield of 5 from ca. 50% to 97% owing to the oxidation of Cu(I) into Cu(II) which enabled catalysis. Furthermore, it is very important to address that the fact that products 5 and 1 were always yielded in a 1:1 ratio from the stoichiometric reaction of 2 with

Figure 11. Catalytic reactions between 1 and 4 and stoichiometric reactions between 2 and 4 under nitrogen and oxygen conditions. So far, the missing link in the mechanism proposed Figure 10 is the direct observation of the two reactive diarylcopper intermediates A and B. However, these two transient species were neither isolable nor detectable owing most likely to their instability and low concentration. Therefore, computational study was conducted to probe the different reactivity of ArCu(II) 2 and ArCu(III) 3 toward boronic acid 4 and provide insight about the electronic structures.56 Since the Cu(II)/Cu(0) catalytic cycle in Figure 5 was excluded, the aryl-aryl coupling is most probably occur via reductive elimination from the diaryl copper(III) intermediate B. Concurring with the documented results of the reactions of high-valent organocopper(III) complexs,17,18,25-29,40-44,57 the reductive elimination from diarylcopper(III) complex B was calculated to be almost barrierless


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(Figure S15 in the Supporting Information). Therefore, the central question was focused on the intriguing step of transmetallation of a boronic acid to organocopper species.

Several factors of transmetalation processes, including the oxidation states of copper, coordination sites and spin states, were considered (Figures S16 and S17). The most favorable pathway for 2 and 3 are presented in Figure 12 and the corresponding geometries and spin density were listed in Table 1. Firstly, ArCu(II)ClO4 2 and ArCu(III)(ClO4)2 3 both dissociate ClO4anions, leading to the formation of the cationic Cu(II) intermediate INT2A and Cu(III) intermediate sINT2B, respectively. In the subsequent transmetalation step, direct transfer of the phenyl group from phenylboronic acid was found energetically prohibited (Figure S18 in Supporting Information). The anionic phenylboronate, which is in equilibrium with boronic acid 4 in the presence of water,58 acts as a much more reactive species.59,60 Transmetalation of the phenyl of [PhB(OH)3]- to copper center via TS1A and tTS1B (triplate state) generates the phenyl transferred complexes A and B, respectively.59,60 The triplet tTS1B is found to be the most stable one among all the considered models of transmetallation with ArCu(III) species (see Figures S16 and S17, and discussion below). The barrier of the transmetalation tTS1B is 2.5 kcal/mol (14.0 kcal/mol) higher than that of TS1A in free energy (electronic energy), consistent with experimentally observed difference in reactivity between ArCu(II) 2 and ArCu(III) 3 (Figure 3). Table 1. Bond distances and spin density of critical complexes. INT2A

sINT2B

TS1A

tTS1B

Cu-C1

1.926

1.902

1.933

1.942

Cu-N1

2.059

1.920

2.451

2.340

Cu-N2

2.045

1.963

3.351

3.354

Cu-N3

2.059

1.920

Bond distance (Å)

3.188

3.229

Cu-C2

2.141

2.170

Cu-O1

1.979

1.977

B-C2

2.050

2.050

B-O1

1.469

1.475

Spin density

Figure 12. Potential energy surfaces of transmetalation of arylborate to (a) ArCu(II) 2 and to (b) ArCu(III) 3 and distortioninteraction analysis for the TS1A and tTS1B. Relative free energies (electronic energies) are in kcal/mol. Majority of the H atoms are hidden for simplicity. The superscript s and t in Figure 12b refer to the singlet and triplet state, respectively.

Cu

0.491

-

0.393

0.407

C1

0.282

-

0.222

0.240

C2

-

-

0.172

0.191

Macrocycle

-

-

-

1.088

To have a deep insight into the transmetalation reactivity of ArCu(II) 2 and ArCu(III) 3 toward arylboronate, we employed the distortion-interaction model, which was proposed by Morokuma,61-65 Bickelhaupt,66-68 and Houk,69-72 and has been widely used to illustrate the energy difference of the transition states in bimolecular reactions. As given in Figure S19, the activation energy (ΔE‡) is decomposed into distortion energy (ΔE‡dist), which includes the distortion energies of substrate and arylcopper complex relative to their optimized ground-states (ΔE‡dist = ΔE‡dist_sub + ΔE‡dist_Cu), and interaction energy (ΔE‡int). As highlighted in red in Figure 12, the barrier difference is mainly contributed from the ΔE‡dist_Cu, since ΔE‡dist_sub and ΔE‡int

Previously, high-valent organoccopper complexes were usually hypothesized to be generated in situ. It was difficult to compare the reactivity between arylcopper(II) and arylcopper(III) species because their relative stabilities cannot be estimate accurately when both Cu(III) and Cu(II) co-exist in the same reaction system. In the current study, isolation of both ArCu(II) 2 and ArCu(III) 3 provide a great opportunity to compare their reactivity under the same reaction condition experimentally and computationally. In theory, compounds 2 and 3 can be regard as the reference zero-point on their own potential energy surface.



Page 8 of 10

AUTHOR INFORMATION

are not sensitive to the change of ArCu(II) and ArCu(III) species. We then examined the electronic structures to seek the origin of distortion energy. Both of two intermediates INT2A and sINT2B adopt a C2 symmetry square-planar structure. Copper center is coordinated with C1 and three N atoms from pyridines in the macrocycle. Due to the higher oxidation state and charge state, Cu-N distances are shorter in sINT2B. In order to achieve transmetalation, the macrocycle has to flip away with dissociation of Cu-N2 and Cu-N3 coordination to accommodate the incoming boronate. The distortion from sINT2B to tTS1B is indeed more significant. Interestingly, the geometrical parameters of TS1A and tTS1B are quite similar around the transmetalation region (Table 1), suggesting that these two Cu centers may have the same electronic configuration. The spin density shown in Table 1 indicates that the spin remains in Cu(II) center in TS1A whereas one of the spin delocalizes into the macrocycle in tTS1B with the copper center being actually a Cu(II) as well. This finding implies that transmetalation takes place at the Cu(II) complex no matter what initial oxidation state the Cu is. ArCu(III) complex 3 needs to endure a more significant distortion and spin delocalization process prior to the transmetalation, which increase the reaction barrier.

Corresponding Author *E-Mail: [email protected] *E-mail: [email protected]. §These

authors contributed equally.

ACKNOWLEDGMENT We are grateful to the National Natural Science Foundation of China (21572111, 21421064, 91427301, 21132005), Shenzhen STIC (JCYJ20170412150507046, JCYJ20170412150343516) and Tsinghua University for financial support.

REFERENCES 1. The Chemistry of Organocopper Compounds, Eds. Rappoport, Z.; Marek, I. John Wiley & Sons Ltd. Chichester, West Sussex, 2009. 2. Van Koten, G.; Pérez, P. J.; Liebeskind, L. S. Organometallics 2012, 31, 7631-7633. 3. For recent review articles and research examples, see: (a) Allen, S. E.; Walvood, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234-5458 (b) McCann, S. D.; Stahl, S. S. Acc. Chem. Res. 2015, 48, 1756-1766. (c) Li, J.; Chen, G.; Tan, Z. Adv. Synth. Catal. 2016, 358, 1174-1194. (d) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Science 2016, 353, 1014-1018. (e) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2016, 138, 15547-15550. (f) Zultanski, S. L.; Zhao, J.; Stahl, S. S. J. Am. Chem. Soc. 2016, 138, 6416-6419. (g) Wu, Q.; Luo, Y.; Lei, A. You, J. J. Am. Chem. Soc. 2016, 138, 2885-2888. (h) Xia, S.; Gan, L.; Wang, K.; Li, Z.; Ma, D. J. Am. Chem. Soc. 2016, 138, 13493-13496. (i) Fan, M.; Zhou, W.; Jiang, Y.; Ma, D. Angew. Chem. Int. Ed. 2016, 55, 6211-6215. 4. Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339-2372. 5. Van Koten, G. Organometallics 2012, 31, 7634-7646. 6. Geng, W.; Wei, J.; Zhang, W.-X.; Xi, Z. J. Am. Chem. Soc. 2014, 136, 610-613. 7. Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc., Chem. Commun.1989, 1633-1634. 8. Naumann, D.; Roy, T.; Tebbe, K.-F.; Crump, W. Angew. Chem. Int. Ed. Engl. 1993, 32, 1482-1483. 9. Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor, B. J. J. Am. Chem. Soc. 2007, 129, 7208-7209. 10. Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Dorton, D. C.; Murphy, M.; Ogle, C. A. Chem. Commun. 2008, 1176-1177. 11. Hannigan, S. F.;Lum, J. S.; Bacon, J. W.; Moore, C.; Golen, J. A.; Rheingold, A. L.; Doerrer, L. H. Organometallics 2003, 32, 34293436. 12. Romine, A. M.; Nebra, N.; Konovalov, A. I.; Martin, E.; BenetBuchholz, J.; Grushin, V. V. Angew. Chem. Int. Ed. 2015, 54, 27452749. 13. Santo, R.; Miyamoto, R.; Tanaka, R.; Nishioka, T.; Sato, K.; Toyota, K.; Obata, M.; Yano, S.; Kinoshita, I.; Ichimura, A.; Takui, T. Angew. Chem. Int. Ed. 2006, 45, 7611-7614. 14. Furuta, H.; Maeda, H.; Osuka, A. J. Am. Chem. Soc. 2000, 122, 803-807. 15. Ribas, X.; Jackon, D. A.; Donnadieu, B.; Mahia, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet A.; Stack, T. D. P. Angew. Chem. Int. Ed. 2002, 41, 2991-2994. 16. Pawlicki, M.; Kanska, I.; Latos-Grażyński, L. Inorg. Chem. 2007, 46, 6575-6584. 17. Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899-2900. 18. Liu, L.; Zhu, M.; Yu, H.-T.; Zhang, W.-X.; Xi, Z. J. Am. Chem. Soc. 2017, 139, 13688-13691. 19. Chmielewski, P. J.; Latos-Grażyński, L.; Schmidt, I. Inorg. Chem. 2000, 39, 5475-5482.

CONCLUSION The mechanism of the Cu(II)-catalyzed oxidative cross-coupling between arene C-H bonds and boronic acids was systematically studied by means of various experiments and theoretical calculations using a model reaction of macrocyclic azacalix[1]arene[3]pyridine with p-tolylboronic acid. Substantiated by experimental evidences, the Cu(II) catalytic reaction proceeds most likely through a sequence of electrophilic metalation of arene by Cu(II), transmetalation of aryl of boronic acid to ArCu(II), the redox reaction between the resulting ArCu(II)Ar’ and ArCu(II) to form respectively ArCu(III)Ar’ and ArCu, and reductive elimination of ArCu(III)Ar’. Protolysis of ArCu(I) species and oxidation of Cu(I) by molecular oxygen afford ArH and Cu(II), respectively, which enter into the next catalytic cycle. Computational analysis of the electronic structure and energetics of the transient intermediates shows the transmetalation of arylboronate to ArCu(II) complex is the most energetically favorable pathway. ArCu(III) complex does not undergo cross coupling reaction with boronic acids because of a larger energy barrier due to significant distortion and spin delocalization of macrocyclic ArCu(III) required for the process. The catalytic cycle revealed by this study would enrich our knowledge of modern organocopper chemistry and provide useful information in the design of copper catalyzed reactions. It is also worth addressing again that heteracalixaromatics, in their capacity of forming structurally well-defined organometallic intermediates that are not accessible by other means, are powerful and valuable molecular tools in the study of fundamentals of transition metal catalysis.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Detailed experimental procedures (PDF).


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