Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates

Abstract

A series of experimental studies, along with DFT calculations, are reported that provide a detailed view into the mechanism of Ullmann coupling of phenols with aryl halides in the presence of catalysts generated from Cu(I) and bidentate, anionic ligands. These studies encompass catalysts containing anionic ligands formed by deprotonation of 8-hydroxyquinoline, 2-pyridylmethyl tert-butyl ketone, and 2,2,6,6-tetramethylheptane-3,5-dione. Three-coordinate, heteroleptic species [Cu(LX)OAr]^- were shown by experiment and DFT calculations to be the most stable complexes in catalytic systems containing 8-hydroxyquinoline or 2-pyridylmethyl tert-butyl ketone and to be generated reversibly in the system containing 2,2,6,6-tetramethylheptane-3,5-dione. These heteroleptic complexes were characterized by a combination of ¹⁹F NMR, ¹H NMR, and UV-vis spectroscopy, as well as ESI-MS. The heteroleptic complexes generated in situ react with iodoarenes to form biaryl ethers in high yields without evidence for an aryl radical intermediate. Measurements of ¹³C/¹²C isotope effects showed that oxidative addition of the iodoarene occurs irreversibly. This information, in combination with the kinetic data, shows that oxidative addition occurs to the [Cu(LX)OAr]^- complexes and is turnover-limiting. A Hammett analysis of the effect of phenoxide electronic properties on the rate of the reaction of [Cu(LX)OAr]^- with iodotoluene also is consistent with oxidative addition of the iodoarene to an anionic phenoxide complex. Calculations by DFT suggest that this oxidative addition is followed by dissociation of I^- and reductive elimination of the biaryl ether from the resulting neutral Cu(III) complex.

Figure 1

(a) Superimposed ¹⁹F NMR spectra of 4-fluorophenol, bis(4-fluorophenoxide)cuprate (1b), and potassium 4-fluorophenoxide at −100 °C in THF. (b) ¹⁹F NMR spectrum of cuprate 1b and KLX2 at room temperature. (c) ¹⁹F NMR spectrum of cuprate 1b and KLX2 at −100 °C. (d) ¹⁹F NMR spectrum of cuprate 1b and HLX2 at room temperature. (e) ¹⁹F NMR spectrum of cuprate 1b and HLX2 at −100 °C. (f) Proposed structure of K[Cu(LX2)OAr] and equilibria to generate the new species observed at −135.5 ppm. All ¹⁹F NMR spectra were obtained in THF and are referenced to fluorobenzene at −113.2 ppm.

Figure 2

(a) Superimposed ¹⁹F NMR spectrum of 4-fluorophenol, bis(4-fluorophenoxide)cuprate (1b), and potassium 4-fluorophenoxide at −100 °C in THF. (b) ¹⁹F NMR spectrum of cuprate 1b and KLX3 at room temperature. (c) ¹⁹F NMR spectrum of cuprate 1b and KLX3 at −100 °C. (d) ¹⁹F NMR spectrum of cuprate 1b and HLX3 at room temperature. (e) ¹⁹F NMR spectrum of cuprate 1b and KLX3 at −100 °C. (f) Proposed structure of K[Cu(LX3)OAr] and equilibria to generate the new species observed at −135.1 ppm. All spectra were obtained in THF and are referenced to fluorobenzene at −113.2 ppm.

Figure 3

(a) Superimposed ¹⁹F NMR spectra of 4-fluorophenol, bis(4-fluorophenoxide)cuprate (1b), and potassium 4-fluorophenoxide at −100 °C in THF. (b) ¹⁹F NMR spectrum of cuprate 1b and KLX1 at room temperature. (c) ¹⁹F NMR spectrum of cuprate 1b and KLX1 at −100 °C. (d) ¹⁹F NMR spectrum of cuprate 1b and HLX1 at room temperature. (e) ¹⁹F NMR spectrum of cuprate 1b and HLX1 at −100 °C. (f) Proposed structure of K[Cu(LX1)OAr] and equilibria to generate the new species observed at −134.7 ppm. All spectra were obtained in THF and are referenced to fluorobenzene at −113.2 ppm.

Figure 4

(a) Plot of the formation of the product 2 from the reaction of p-iodotoluene (0.20 M) with K[Cu(LX1)OPh] generated in situ from the reaction of KLX1 (0.010 M) with KCu(OPh)₂ (1a) (0.010 M) in DMSO-d₆ at 30 °C. (b) Plot of k_obs versus [p-iodotoluene] for the reaction of p-iodotoluene (0.10–0.80 M) with K[Cu(LX1)OPh] generated in situ from the reaction of KLX1 (0.010 M) with KCu(OPh)₂ (1a) (0.010 M) in DMSO-d₆ at 30 °C. (c) Plot of the added [KOPh] (0.00–0.080 M) vs the initial rate for the formation of the product 2 from the reaction of p-iodotoluene (0.10 M) with K[Cu(LX1)OPh] generated in situ from the reaction of KLX1 (0.010 M) with KCu(OPh)₂ (1a) (0.010 M) in DMSO-d₆ at 50°C.

Figure 5

(a) Plot of the rise of the biaryl ether product 2 from the reactions of p-iodotoluene (0.10 M) with 0.010 M (blue diamonds) or 0.005 M (red circles) of KCu(OPh)₂ (1a) in the presence of KLX3 (0.080 M) in DMSO-d₆ at 50 °C. (b) Plot of the [p-iodotoluene] vs the initial rate for the rise of the biaryl ether product 4 from the reaction of p-iodotoluene (0.10–0.40 M) with KCu(OPh)₂ (1a, 0.01 M) in the presence of KLX3 (0.02 M) in DMSO-d₆ at 50 °C. (c) Plot of the concentration of the ligand KLX3 ([L], 0.02–0.08 M) vs the initial rate for the rise of the biaryl ether product 2 from the reaction of p-iodotoluene (0.10 M) with KCu(OPh)₂ (1a, 0.01 M) in DMSO-d₆ at 50 °C. (d) Plot of the added [KOPh] (0.010–0.080 M) vs the reciprocal of the initial rate (1/rate) for the rise of the biaryl ether product 4 from the reaction of p-iodotoluene (0.20 M) with KCu(OPh)₂ (1a, 0.01 M) in the presence of KLX3 (0.02 M) in DMSO-d₆ at 50 °C.

Figure 6

Reaction of 1a (10 mM) with 4-iodotoluene (100 mM) in the presence of KLX3 (80 mM) in the absence (black) or presence of CuI (10 mM, red line) in DMSO at 30 °C.

Figure 7

(a) Plot of the rise of the product 2 from the reaction of p-iodotoluene (0.10 M) with K[Cu(LX3)OPh] generated in situ from the reaction of K[Cu(LX3)₂] (0.010 M) with KCu(OPh)₂ (1a) (0.010 M) in DMSO-d₆ at 90 °C. (b) Plot of k_obs versus [p-iodotoluene] for the reaction of p-iodotoluene (0.10–0.60 M) with in situ generated complex K[Cu(LX3)OPh] from the reaction of K[Cu(LX3)₂] (0.010 M) with KCu(OPh)₂ (1a) (0.010 M) in DMSO-d₆ at 90 °C.

Figure 8

Hammett plot for the reactions of 1a–d (0.05 M) with 2-fluoro-4-iodotoluene (0.5 M) in the presence of KLX2 (0.05 M). The values of k_obs were obtained fitting the function C_t = C₀(1 − e^−k_obst) + C_res to the experimental values of the concentration of the corresponding product.

Figure 9

Computed reaction pathways for Ullmann etherification of aryl iodides in the presence of anionic ligands LX (the numbers correspond to computed values of ΔG/kcal·mol⁻¹). ^a All attempts to optimize the geometry of this structure were unsuccesful. ^b LX-INT-3b is 2.5 kcal/mol downhill to LX-TS-1b in gas phase.

Scheme 1

Ullmann Coupling Reactions Catalyzed by Ligated Copper Complexes

Scheme 2

Mechanism of Ullmann Coupling Reactions Catalyzed by Complexes of Netural Bidentate Ancillary Ligands

Scheme 3

Possible Catalytic Cycles Proposed for Couplings of Aryl Halides with Various Nucleophiles Catalyzed By Cu^I Coordinated to Anionic Ligands

Scheme 4

A Series of Reaction Pathways for CuI-Catalyzed Coupling Reactions in the Presence of Anionic Ancillary Ligands

Scheme 5

Model Systems Studied in This Work

Scheme 6

Synthesis of Potassium Cuprates K[Cu(OAr)₂] and K[Cu(LX)₂]

Scheme 7

Reactions of 1a with 4-Iodotoluene in the Absence and the Presence of Complexes K[Cu(LX1)₂] and K[Cu(LX3)₂]^{a a}Yields are reported relative to the number of OPh groups in the starting material.

Scheme 8. Reactions of 1a with 4-Iodotoluene in the Presence of Anionic Ligands KLX^a

^aYields are reported relative to the number of OPh groups in the starting material.

Scheme 9

Reactions of 1a with 3 in the Presence of the Ligands KLX

Scheme 10

Catalytic Reactions of KOPh with 3 in the Presence of CuI and the Ligands KLX

Scheme 11. Reaction for Which ¹³C/¹²C Isotope Effects (IE) Were Measured^a

^aThe carbon for which the IE was determined is marked with *.

Scheme 12

Proposed Catalytic Cycle for the Ullmann Biaryl Ether Formation Catalyzed by Cu^I in the Presence of Anionic Ligands LX

Chart 1. ESI-MS Analysis of Solutions Containing Mixtures of 1b and Ligands LX^a

^aThe calculated masses are shown without highlighting, and the observed masses are shown in bold. All masses are given for the corresponding anions.