Direct observation of Cu^I/Cu^III redox steps relevant to Ullmann-type coupling reactions

Abstract

A series of aryl–copper(III)-halide complexes have been synthesized and characterized by NMR and UV-visible spectroscopy, cyclic voltammetry and X-ray crystallography. These complexes closely resemble elusive intermediates often invoked in catalytic reactions, such as Ullmann–Goldberg cross-coupling reactions, and their preparation has enabled direct observation and preliminary characterization of aryl halide reductive elimination from Cu^III and oxidative addition to Cu^I centers. In situ spectroscopic studies (¹H NMR, UV-visible) of a Cu-catalyzed C–N coupling reaction provides definitive evidence for the involvement of an aryl-copper(III)-halide intermediate in the catalytic mechanism. These results provide the first direct observation of the Cu^I/Cu^III redox steps relevant to Ullmann-type coupling reactions.

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Introduction

Ullmann and Goldberg cross-coupling reactions of aryl halides for carbon–carbon and carbon–heteroatom bond formation were discovered more than 100 years ago,¹ and were among the earliest uses of catalysis in organic chemical synthesis. These classic copper-catalyzed methods have experienced a renaissance in recent years.² The recent advances, particularly in carbon–heteroatom coupling, have widespread utility in organic synthesis and medicinal chemistry, and they address important limitations of related palladium-catalyzed methods, associated with substrate scope, functional group compatibility and catalyst cost and toxicity.³ The reactions typically use a copper(I) catalyst in combination with an auxiliary ligand and a Brønsted base, and a variety of nitrogen-, oxygen-, sulfur- and carbon-based nucleophiles serve as effective coupling partners.⁴ A number of different mechanisms have been postulated for these reactions, but the most widely invoked is a Cu^I/Cu^III catalytic cycle initiated by oxidative addition of a haloarene to Cu^I to form an aryl–Cu^III-X intermediate.^2a,5–7 Despite the prominence of this mechanistic proposal, observation of aryl halide oxidative addition (or reductive elimination) at copper lacks any direct precedent. Here we report the synthesis and full characterization of a series of aryl–Cu^III-X (X = Cl, Br, I) complexes. These species undergo an acid-triggered C–X reductive elimination reaction to afford aryl-X products. The reverse reaction, aryl-X oxidative addition to Cu^I to regenerate aryl–Cu^III-X, proceeds rapidly in the absence of an acid source. The latter reaction is shown to be compatible with catalytic C–N coupling when the aryl-X reagent is combined with a nitrogen nucleophile in the presence of catalytic quantities of Cu^I. In situ spectroscopic studies (¹H NMR, UV-visible) provide experimental evidence for the involvement of an aryl-copper(III)-halide intermediate in the catalytic mechanism. These results represent the first direct observation of the Cu^I/Cu^III redox steps relevant to Ullmann-type coupling reactions.

Results and discussion

Synthesis and characterization of aryl–Cu^III-X complexes

The synthesis of aryl–Cu^III-X (X = Cl, Br) species was achieved by a modification of a previously reported aromatic C–H activation reaction mediated by Cu^II salts.⁸ By using CuCl₂ or CuBr₂ as the Cu^II source, the triazamacrocyclic ligands H₂Me33m (L₁) and H33m (L₂) react via disproportionation of Cu^II to afford 0.5 equiv of Cu^IX and the protonated ligand, and 0.5 equiv of aryl–Cu^III-X species 1_X and 2_X (X = Cl, Br; Fig. 1a). The corresponding [aryl–Cu^III-I]I compounds 1_I and 2_I were obtained by anion exchange from [aryl–Cu^III](ClO₄)₂ with KI. All aryl–Cu^III-X species are stable and have been fully characterized spectroscopically and crystallographically. The crystal structures of compounds 1_X and 2_X show that each copper center is pentacoordinate with a square-pyramidal geometry, in which the halide anion is coordinated in the axial position and the aryl moiety and three amine N atoms are coplanar with the copper center (see selected crystal structures in Fig. 1b). The short Cu–C bond distances (1.90(1) Å) are very similar to those in previously reported [aryl–Cu^III]²⁺ compounds with the same ligands.⁸ This observation, together with the charge balance and diamagnetic behaviour of the complexes, suggest the metal center is best described as Cu^III in all cases.

Fig. 1 (a) Synthesis of [aryl–Cu^III-X]X complexes. Their X-ray structures are depicted in (b) 1_Cl, (c) 1_Br, (d) 1_I and (e) 2_Cl. The ellipsoid representation is at 50% probability. The hydrogen atoms and respective second halide counteranion are omitted for clarity. Selected bond lengths [Å] for 1_Cl: Cu(1)–C(1) 1.908(3), Cu(1)–Cl(1) 2.455(2), Cu(1)–N(1) 1.972(3), Cu(1)–N(2) 2.037(3), Cu(1)–N(3) 1.971(3); for 1_Br: Cu(1)–C(1) 1.914(3), Cu(1)–Br(1) 2.600(1), Cu(1)–N(1) 1.974(3), Cu(1)–N(2) 2.034(2), Cu(1)–N(3) 1.974(2); for 1_I: Cu(1)–C(1) 1.905(3), Cu(1)–I(1) 2.900(1), Cu(1)–N(1) 1.972(2), Cu(1)–N(2) 2.017(2), Cu(1)–N(3) 1.968(2); for 2_Cl: Cu(1)–C(1) 1.898(3), Cu(1)–Cl(1) 2.468(1), Cu(1)–N(1) 1.986(5), Cu(1)–N(2) 1.999(3), Cu(1)–N(3) 1.974(4).

Electronic spectra for [aryl–Cu^III-X]X species exhibit halide-to-metal charge transfer bands in the 360–640 nm range, and the energies of these bands vary systematically with the identity of the halide. The aryl–Cu^III-Cl compounds (1_Cl, 2_Cl) show two bands centred at 369 and 521 nm, the aryl–Cu^III-Br compounds (1_Br, 2_Br) at 399 and 550 nm, and the aryl–Cu^III-I compounds (1_I, 2_I) at 422 and 635 nm. The red-shift observed in the bands upon changing from Cl⁻ to Br⁻ to I⁻ is in agreement with the ligand-field strength of the halide ligands (Cl⁻ > Br⁻ > I⁻), indicating that the bands correspond to ligand-to-metal charge transfer (LMCT) electronic transitions.

The diamagnetic character of all aryl–Cu^III-X species permitted their characterization by NMR spectroscopy. Diagnostic ¹H NMR peaks are evident in the 4–5 ppm range corresponding to the benzylic protons, and the ¹³C NMR spectrum exhibits a distinctive low field resonance for the C_ipso–Cu^III at about 180 ppm.⁸ Indeed, NOESY (Nuclear Overhauser Effect Spectroscopy) and HMBC (Heteronuclear Multiple Bond Correlation) experiments reveal that the rigid structure found in the solid state is retained in solution (see ESI†).

Cyclic voltammetry (CV) measurements of the aryl–Cu^III-X species show chemically reversible 1e⁻ processes associated with the Cu^III/Cu^II redox couple. The Cu^III/Cu^IIE_1/2 values for these complexes follow the trend E_1/2^Cl < E_1/2^Br < E_1/2^I, and the compounds bearing L₂, with a secondary amine trans to the aryl ligand, exhibit E_1/2 values 40–70 mV lower than the corresponding complexes bearing L₁, with a tertiary amine in the trans position (see ESI†). Overall, the redox potentials for Cu^III/Cu^II are substantially lower (up to 250 mV) than those measured previously for the corresponding perchlorate or triflate salts,⁸ indicating that halide coordination stabilizes the Cu^III oxidation state.

Aryl-X reductive elimination

The isolation of complexes 1_X and 2_X (X = Cl, Br, I) provides an unprecedented opportunity to study the reactivity of aryl–Cu^III-halide species related to those believed to be key intermediates in Ullmann–Goldberg cross-coupling reactions. Initial studies revealed that these complexes are remarkably stable in solution, even upon warming acetonitrile solutions at 70 °C for days (monitored by ¹H NMR spectroscopy). Addition of one equivalent of Proton Sponge® as a Brønsted base did not affect the stability of the aryl–Cu^III-halide compounds. On the contrary, the addition of a Brønsted acid (CF₃SO₃H, 1.5–10 equiv) at room temperature triggered quantitative aryl-X reductive elimination to form the halide-substituted triazamacrocycles, obtained as the protonated derivatives [L-X-H]⁺ (X = Cl, Br, I), and [Cu^I(CH₃CN)₄]⁺ (Fig. 2a).

Fig. 2 (a) Acid-triggered quantitative aryl-X reductive elimination from aryl–Cu^III-X at room temperature (counteranions omitted for clarity). (b) UV-vis monitoring of reductive elimination of complex [L₁C–Cu^III-Br]Br (1_Br) upon addition of 1.5 equiv. of acid ([1_Br] = 0.5 mM, [CF₃SO₃H] = 0.75 mM, CH₃CN, 288 K). Inset shows decay profile at 420 nm (circles = experimental data, solid line = first-order theoretical fit). (c) Electrochemical (vs. SSCE, [complex] = 1 mM, scan rate = 0.2 V s⁻¹, TBAPF₆ 0.1 M, CH₃CN, 263 K) and kinetic data associated with aryl halide reductive elimination from aryl–Cu^III-X species ([complex] = 0.5 mM, [CF₃SO₃H] = 0.75 mM, CH₃CN, 253–283 K for 1_Cl, 278–298 K for 1_Br and 2_Cl). (d) Proposed interaction of triflic acid with 1_Br through weak axial coordination of the triflate anion to the Cu^III center with concomitant protonation of the central amine.

The reactions of 1_Cl, 1_Br and 2_Cl were investigated in more detail by UV-visible spectroscopy. The kinetic profiles of the decay of the aryl–Cu^III-X LMCT bands exhibited first-order behaviour, with rates following the trend: 1_Cl > 2_Cl > 1_Br (Fig. 2b–c). Activation parameters obtained from Eyring analyses (Fig. 2c) reveal that the reductive elimination reactions exhibit a relatively large enthalpy of activation (21.5–23.2 kcal mol⁻¹), consistent with significant Cu–X bond cleavage in the transition state. The reactions of 2_Br, 1_I and 2_I were much slower, and systematic kinetic studies of these complexes were not performed. The aryl–Cu^III-I compound 1_I undergoes reductive elimination to afford (L₁-I–H)⁺ in slightly lower yields (85%). The reaction of 2_I requires extended reaction time (days), is complicated by side-reactions and (L₂-I–H)⁺ is not observed. The faster rate of C–Cl reductive elimination from 1_Cl relative to 2_Cl is consistent with the higher reduction potential of 1_Cl relative to 2_Cl. In contrast, 1_Br exhibits the slowest reductive elimination rate of the three complexes, despite having the highest reduction potential (Fig. 2c). The latter observation is amplified by the even-slower qualitative rates of C–I reductive elimination from 1_I and 2_I, which have the highest reduction potentials of the six aryl–Cu^III-X compounds (E_1/2 = −230 and −290 mV, respectively). Thus, the C–X reductive elimination rates do not correlate with the reduction potentials of the aryl–Cu^III-X species across the halide series. Rather, these observations suggest that the trends in the rates of C–X reductive elimination are controlled by the relative carbon–halogen bond strengths: C–Cl > C–Br > C–I. A different trend has been observed for aryl carbon–halogen reductive elimination from Pd^II complexes, for which the relative rates k_C–Br > k_C–I > k_C–Cl were measured.⁹

The mechanistic origin of the H⁺-triggered aryl-X reductive elimination event is not fully understood; however, electrochemical data indicate that CF₃SO₃H destabilizes the aryl–Cu^III-X species. Cyclic voltammetry studies of 1_Cl, 1_Br and 2_Cl in acetonitrile reveal that the Cu^III/Cu^II reduction potential increases by 70–170 mV when CF₃SO₃H is present in solution (see ESI†). In addition, electronic absorption spectra of acidified solutions of these complexes show a 5 nm, 9 nm and 8 nm red-shift in the UV-visible bands, respectively, consistent with formation of new species. Our current hypothesis is that CF₃SO₃H protonates the central amine of the macrocyclic ligand, thereby destabilizing the Cu^III oxidation state and facilitating C–X bond formation (Fig. 2d). The strong trans effect of the aryl ligand, as visualized in the larger Cu^III–N(2) bond distances of all compounds, also is in agreement with a preferential protonation to the central amine. Preliminary experimental support for this hypothesis is available from ¹H NMR spectroscopic studies of 1_Br. Triflic acid (1.5 equiv) was added to a solution of 1_Br in CD₃CN at −30 °C. No aryl-Br reductive elimination was observed under these conditions; however, resonances corresponding to the N–CH₃ group and the C–H protons of the adjacent methylene group undergo a noticeable upfield shift, while the other resonances remain essentially unchanged (see ESI†). We suspect that weak axial coordination of the triflate anion to the Cu^III center, approaching from the face opposite to the halide, facilitates the protonation of the central amine (Fig. 2d).

Reversible oxidative addition of aryl halides to Cu^I

The protonated aryl halides obtained from the reductive elimination reaction depicted in Fig. 2a are stable in the presence of Cu^I. Upon purification, however, the neutral aryl halide derivatives L₁-X and L₂-X (X = Cl, Br) react very rapidly with [Cu^I(CH₃CN)₄]⁺ in acetonitrile to afford the corresponding oxidative addition products 1_X and 2_X (X = Cl and Br) in quantitative yields based on ¹H NMR and UV-visible spectroscopic analysis (Fig. 3). The reactions are complete in less than 5 s, even at −40 °C in CH₃CN. In situ interconversion between the two redox states, Cu^I/L-X-H⁺ and aryl–Cu^III-X, was demonstrated via sequential addition of triflic acid and Proton Sponge® (as a non-coordinating base) to an acetonitrile solution of 1_Br. Repeated cycles were possible without significant decomposition of 1_Br (Fig. 3b). The electrochemical data described above together with the present results reveal that triflic acid destabilizes the aryl–Cu^III-X species and also stabilizes the Cu^I/aryl-X state. This unprecedented interconversion between Cu^I/aryl-X and aryl–Cu^III-X will provide the basis for future studies to gain fundamental mechanistic insights into these important processes.

Fig. 3 (a) Reversible reductive elimination/oxidative addition induced by the presence of acid or base. (b) Monitoring of 1_Br by UV-visible spectroscopy at 400 nm upon successive acid and base additions (initial conditions: [1_Br] = 0.3 mM, addition of 2 equiv. of triflic acid and Proton Sponge® in the respective additions, CH₃CN, 297 K).

Reversible aryl halide oxidative addition to Cu^I is directly relevant to catalytic transformations. For example, Cohen and coworkers have provided kinetic evidence that the Ullmann coupling of o-bromonitrobenzene proceeds via reversible oxidative addition of aryl bromide to Cu^I in the first step of the mechanism.¹⁰ Copper(I) salts are also known to catalyze halogen exchange reactions with aryl halide substrates. In a noteworthy example reported recently by Buchwald and coworkers, CuI catalyzes the conversion of aryl bromides into aryl iodides in the presence of NaI.¹¹

Catalytic C–N bond formation

The reactions of [Cu^I(CH₃CN)₄]⁺ with L₁-X and L₂-X (X = Cl, Br) provide the first observations of aryl-halide oxidative additions to Cu^I to form well-defined aryl–Cu^III species. In order to probe the relevance of these observations to Ullmann–Goldberg cross-coupling reactions, we combined L₁-Br and pyridone, as a nitrogen nucleophile, in acetonitrile with 3.3 mol % of [Cu^I(CH₃CN)₄]PF₆ (Fig. 4a). The solution turned from colourless to pale red immediately upon adding Cu^I, and the colour persisted for approximately 60–70 min before fading. In situ analysis of the catalytic reaction mixture by ¹H NMR spectroscopy (CD₃CN, 288 K) revealed nearly quantitative conversion of L₁-Br and pyridone into the HBr adduct of the C–N cross-coupling product, 3·HBr (Fig. 4b). A steady-state concentration of aryl–Cu^III-Br complex 1_Br was also evident in the ¹H NMR spectra. Integration of the resonances associated with 1_Br indicates that the aryl–Cu^III species accounts for essentially all of the Cu present in solution during the first 60–70 min of the reaction, and it disappears only after consumption of L₁-Br (Fig. 4b). The presence of an aryl–Cu^III species under catalytic conditions is supported further by UV-visible spectroscopic data (Fig. 4c): charge-transfer bands associated with 1_Br persist during the first 60–70 min of the reaction and then begin to decay as the reaction depletes the substrates. Observation of an aryl–Cu^III species under catalytic conditions is consistent with the rapid formation of 1_Br, as described above, and implicates the involvement of the aryl–Cu^III species in the turnover-limiting step of this catalytic reaction.¹²

Fig. 4 (a) Copper-catalyzed catalytic C–N bond forming reaction for the conversion of L₁-Br and pyridone into 3·HBr at room temperature. (b) ¹H NMR spectroscopic analysis of the Cu-catalyzed amination reaction: the catalytic resting state, aryl–Cu^III-Br (1_Br) is evident in the spectra obtained prior to t ∼ 120 min (for clarity only selected regions of the NMR spectrum are shown; full spectra are available in the ESI.† Conditions: [L₁-Br] = 9 mM, [pyridone] = 10 mM, [Cu^I(CH₃CN)₄PF₆] = 0.3 mM, CD₃CN, 288 K). (c) Analysis of the catalytic reaction by UV-visible spectroscopy and the time-dependent progression of the absorbance at 542 nm (inset). Immediately upon mixing, the charge-transfer bands associated with 1_Br are observed, and these features persist until most of the reaction is complete (same experimental conditions as in (b)).

Relationship to Ullmann-type coupling reactions

The relationship between the results described here and traditional Ullmann and Goldberg coupling reactions warrants further discussion. Many features of the mechanism of Ullmann–Goldberg reactions remain poorly understood. Recent studies by the groups of Buchwald and Hartwig provide valuable insights into the identity and comparative reactivity of Cu^I species that exist under the catalytic reaction conditions.^6,7 No aryl–Cu^III species were observed in these studies, however, presumably because C–N coupling from the aryl–Cu^III intermediate is much more rapid than aryl halide oxidative addition to Cu^I. The ability to observe the Cu^I/Cu^III redox steps in the present study can be attributed to the influence of the macrocyclic substrate on the relative stability and reactivity of the Cu^I and Cu^III species. The preorganized nature of the macrocyclic ligand is expected to lower the activation barrier for aryl–X oxidative addition to Cu^I and stabilize the high-valent aryl–Cu^III species. Such factors combine to invert the relative rates of two key redox steps with respect to previously studied Ullmann–Goldberg-type coupling reactions, and, for the first time, an aryl–Cu^III intermediate has been observed under catalytic reaction conditions.

The aforementioned studies by Buchwald and Hartwig have provided evidence that, in reactions with bidentate nitrogen ligands, amide substrates react with Cu^I to form Cu^I-amidate intermediates prior to oxidative addition of the aryl halide. An alternative mechanistic possibility, as discussed in a recent review by Monnier and Taillefer,^2c involves oxidative addition of the aryl halide, followed by reaction of the nucleophile with the aryl–Cu^III intermediate. The results of the present study, together with previous observations of stoichiometric C–N coupling reactions,¹² conform to the latter mechanism. It seems reasonable to expect that the mechanism of Ullmann–Goldberg-type coupling reactions will vary, depending on the identity of the substrates, ancillary ligand and/or the reaction conditions. Reactions involving nucleophiles that coordinate less readily to copper, or catalysts that feature higher-coordinate (e.g., tri- or tetradentate) ancillary ligands may disfavor pre-coordination of the nucleophile to Cu^I. In such cases, the reaction may proceed via a mechanism in which reaction of the aryl halide with Cu^I precedes that of the nucleophile. These issues will be important to address in future studies of Ullmann-type coupling reactions.

Conclusions

In summary, a series of aryl–Cu^III-halide species have been isolated and fully characterized, and these complexes have been shown to undergo H⁺-triggered reductive elimination of aryl halides.¹³ Investigation of the reactivity of the resulting aryl halides with Cu^I has led to two key results: (1) the first observation of aryl halide oxidative addition to Cu^I resulting in formation of an aryl–Cu^III-X species and (2) the first experimental evidence consistent with the involvement of an aryl–Cu^III intermediate in a catalytic C–N cross-coupling reaction. These observations provide cogent support to the oft-invoked, but heretofore unobserved, redox steps in Ullmann–Goldberg cross-coupling reactions. The two-electron redox reactivity of the Cu^I/Cu^III pair is thought be involved in a wide range of synthetically important reactions mediated by copper.^8,14 Further mechanistic insights into critical catalytic reaction steps such as the ones described here can provide a foundation for major advances in the application of non-precious-metal catalysts to chemical synthesis.

Acknowledgements

We acknowledge financial support from the MICINN of Spain (CTQ2009–08464/BQU to M.C., CTQ2009-08328 to T.P.) and the US DOE (DE-FG02-05ER15690 to S.S.S.). AC thanks MICINN for a PhD grant. MC thanks ICREA-Academia. We also thank STR's from UdG for NMR, ESI-MS and XRD technical support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Full experimental details for the synthesis, spectroscopic, and crystallographic characterization of 1_X and 2_X. Synthesis of reductive elimination L₁-X and L₂-X products. NMR and UV-vis monitoring of catalytic coupling of L₁-Br with pyridone. Crystal data for 1_Cl, 1_Br, 1_I, 2_Cl and 2_I. CCDC reference numbers 735508–735512. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0sc00245c

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