Potassium phenolate is a potassium salt of phenol. Potassium phenolate is a key component in the synthesis of polycarbonate, epoxy resin, bakelite, nylon, detergents, etc. Transition metal-catalyzed cross-coupling reactions of aryl halide electrophiles and heteroatom nucleophiles are widely used in the construction of drug molecules, agrochemicals, and functional materials.
Although copper catalysts were first used in this coupling reaction more than a century ago, chemists know little about the mechanism of copper-catalyzed coupling reactions because copper complexes are usually paramagnetic and difficult to measure using spectroscopic methods, and the ligand exchange process is usually faster than the elementary steps of the catalytic cycle, so most copper catalysts are determined by trial and error. The Ullmann coupling reaction catalyzed by oxalamide ligand-complexed Cu(II) complexes proceeds through the coordinated oxidative addition of aryl halides to Cu(II) to form a high-valent copper species. Potassium phenolate and others were used to participate in the study, and computational studies showed that this high-valent species can be stabilized by the free radical characteristics on the oxalamide ligand. This mechanism is distinct from those involving Cu(I) and Cu(III) intermediates that have been used in other Ullmann-type coupling reactions. In addition, the stability of Cu(II) not only allows the reaction to proceed in air, but also has high turnover numbers, e.g., >1000 for the coupling of phenolates with aryl chloride electrophiles.
1-Bromo-4-fluorobenzene (1) and potassium phenolate (2) reacted in the presence of CuI as catalyst, H2-BPPO (4) as ligand, and DMSO as solvent at 100 °C for 16 h to form the coupling product 3 in 98% yield. Since studies on monoanionic ligands have shown that the coupling of phenols is carried out through the oxidative addition of aromatic halides to Cu(I)-phenolate complexes (13), the researchers synthesized Cu(I) complex 5 containing a dianionic oxamide ligand from K,H-BPPO (6) and trimethyl copper (I). X-ray diffraction showed that 5 was a dimeric structure in which two dianionic oxamides bridged two copper atoms. If potassium 3-tert-butylphenolate was added to the DMSO solution of 5, a phenoxy-copper complex (8) was formed, and the 1H NMR spectrum of 5 showed a chemical shift shifted to the downfield, which means that phenolate can bind to the complex rapidly and reversibly.
In addition, a small amount of aromatic ether was formed when 1-bromo-4-fluorobenzene (1) was reacted with a mixture of 5 and potassium phenolate at room temperature, but the 1H NMR signal of Cu(I) complex 5 disappeared, which means that the Cu(I) complex was oxidized to a new paramagnetic Cu(II) complex. Electron paramagnetic resonance (EPR) spectroscopy confirmed this process. Heating the reaction mixture at 100 °C for 20 min can form diaryl ether 3 with a yield of 75%, and fluorobenzene (11, yield: 18%) is also generated. Secondly, the researchers also synthesized Cu(I) complex 12 with a monoanionic oxalamide ligand. NMR spectroscopy and mass spectrometry confirmed the existence of 12, but it was in equilibrium with two cuprates 14 and 15. Adding 1-bromo-4-fluorobenzene (1) to the equilibrium mixture caused the 1H NMR signal of the ligand to disappear, which may be due to the oxidation of Cu(I) to Cu(II); while the 19F NMR spectrum showed that 1 consumed 0.2 equiv and formed 0.1 equiv of fluorobenzene (11). If the reaction mixture was heated at 100 °C for 23 h, 0.3 equiv of fluorobenzene (11) and 0.2 equiv of diphenyl ether 16 were formed. These results indicate that the Cu(I) species is not an intermediate in the catalytic process.
To investigate the Cu(II) complexes in the catalytic reaction, the researchers heated aryl halide 1, phenolate 2, copper iodide, and oxalamide 4 in DMSO at 100 °C for 20 min. The EPR spectrum of the reaction mixture corresponded to a Cu(II) species. In addition, the Cu(II)-dioxalamide complex 17, which was bonded by four nitrogen atoms, was the most plausible structure matching the EPR data of the catalytic reaction. It was independently synthesized from CuBr2, ligand, and base and was fully characterized, including single crystal X-ray diffraction. In particular, the EPR spectrum matched the EPR spectrum of the catalytic reaction.
Since Cu(II) complexes can initiate reactions catalyzed by Cu(I)/Cu(III) pairs, the researchers further investigated whether Cu(II) complex 17 was the true catalyst or a precatalyst that was reduced to Cu(I). The results showed that the reaction was zero-order with potassium 4-chlorophenolate (19), suggesting that the phenolate either existed in a resting state or entered the catalytic cycle after the turnover-limiting step. In contrast, the reaction showed first-order association for both aryl halide 1 and the catalyst, suggesting that it binds prior to the transition state of the catalytic process.
To evaluate whether the copper-phenolate complex reacts with the aryl halide, kinetic studies were performed, which showed no effect of the phenolate charge on the reaction rate, indicating that the phenolate does not bind to the copper in the turnover-limiting step and excluding a σ-bond metathesis mechanism. Second, to determine whether arene coordination or C-X bond cleavage occurs in the rate-determining reaction between Cu(II) and aryl halide, a free radical oxidative addition mechanism was excluded. Overall, all results were consistent with a concerted redox mechanism.
Finally, density functional theory (DFT) calculations were performed to evaluate the mechanism of C-X bond cleavage by the reaction of Cu(II) species with aryl halide. These energies are consistent with the conclusion drawn from experimental studies that the Cu(II) species cleaves the C-X bond in the rate-determining step and suggest that this bond cleavage can occur via oxidative addition.
