Decoding the Mechanism of Intramolecular Cu-Directed Hydroxylation of sp3 C-H Bonds

Abstract

The use of copper in directed C-H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O₂ promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu₂O₂ intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCu^II(OOR) intermediate undergoes homolytic O-O cleavage to generate reactive RO^• species, which are responsible for key C-H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.

Figure 1

(A) Directed hydroxylation of C−H bonds mediated by Cu and the approach used in this work.^, (B) Substrate-containing ligands used in this work. (C) Oxidative conditions developed by Schönecker (left) and Baran (middle) and improvements described in this work.

Figure 2

(A) Synthesis of substrate-containing copper complexes. (B) X-ray diffraction analysis of the Cu complexes (displacement ellipsoid plots, 50% probability). For clarity, some anions, disorder, lattice solvent molecules, and H atoms are not depicted. ^aReaction conditions: 1.0 equiv of Cu salt was used unless otherwise stated (acetone/Et₂O); ^b0.5 equiv of Cu salt was used. See the SI for further details.

Figure 3

(A) Oxidation of the S1 substrate described in previous reports.^, (B) Results obtained in the oxidation of the different S1-derived copper complexes (hydroxylation product S1−OH in blue) under different conditions. ^athe following reaction conditions were used unless otherwise stated: [S1] = 4.0 mM in anhydrous acetone. See the SI for further details.

Figure 4

(A) Oxidation of the steroid-containing substrates described in previous reports.^, (B) Results obtained in the oxidation of the different steroid-derived copper complexes (hydroxylation product C−OH in blue) under different conditions. ^athe following reaction conditions were used unless otherwise stated: [Cu complex] = 4.0 mM in dry acetone. See the SI for further details.

Figure 5

(A) Previous mechanistic proposal^, (Cu₂O₂ intermediacy) for the oxidation of the substrate-containing ligands used in this work. (B) Cu/O₂-derived species proposed to carry out the hydroxylation of C−H bonds in natural systems and model complexes.

Figure 6

Mechanistic scenario proposed in this work [mononuclear LCu^II(OOH) intermediacy] on the basis of the new mechanistic evidence (in gray).

Figure 7

(A) Mechanism of H₂O₂ formation derived from the reaction of the Cu^I complexes with O₂. (B) Quantification of the electrons provided by acetone (oxidation of acetone to hydroxyacetone and acetic acid). See the SI for details.

Figure 8

Oxidation of S1−Cu^I with O₂ or H₂O₂ at 0 °C. S1−Cu^I/O₂: (A) UV−vis spectral changes; (B) variation of the absorbance at selected wavelengths (left) and evolution of the reaction yield (S1−OH); (C) kinetic analysis. S1−Cu^I/H₂O₂: (D) UV−vis spectral changes; (E) variation of the absorbance at selected wavelengths (left) and evolution of the reaction yield (S1−OH); (F) kinetic analysis. It is noted that the evolution of the reaction yield was carried out at 0 °C ([S1−Cu^I]₀ = 4 mM); the first quantification was done at t = 10 s. See text and the SI for details.

Figure 9

Oxidation of S2−Cu^I with O₂ or H₂O₂ at −40 °C. S2−Cu^I/O₂: (A) UV−vis spectral changes; (B) variation of the absorbance at selected wavelengths (left) and evolution of the reaction yield (S2−OH); (C) kinetic analysis. S2−Cu^I/H₂O₂: (D) UV−vis spectral changes; (E) variation of the absorbance at selected wavelengths (left) and evolution of the reaction yield (S2−OH); (F) kinetic analysis. It is noted that the evolution of the reaction yield was carried out at −40 °C ([S2−Cu^I]₀ = 4 mM); the first quantification was done at t = 10 s. See text and the SI for details.

Figure 10

(A) Oxidation of S1−Cu^I with tBuOOH at 0 °C followed by UV−vis (inset, evolution of the absorbance and reaction yields). (B) Oxidation of S1−Cu^I with CumOOH at 0 °C followed by UV−vis (inset, evolution of the absorbance and reaction yields). See the SI for further details on kinetic analysis and the product quantification procedure.

Figure 11

(A) Analysis of the LCu^II(OOCum) decay products (CumOH vs acetophenone) as a mechanistic tool to determine the O−O cleavage mechanism (homo- vs heterolytic). (B) Products obtained in the decay of [(S1)Cu^II(OOCum)]⁺ and [(S2)Cu^II-(OOCum)]⁺ at different temperatures.

Figure 12

(A) Proposed O−O cleavage mechanism (homolytic) and fate of the RO^• species formed (intra- vs intermolecular decay). (B) Reaction yields measured after half-life decay of the putative LCu^II(OOR) species for S1 (left) and S2 (right).

Figure 13

(A) Intermolecular oxidation experiments (substrates: cyclohexane and 1,2-cis-DMCH) carried out to quantify the free RO^• species released after decay of the different LCu^II(OOR) species (intramolecular products in blue). (B) Inter- vs intramolecular reaction. See the SI for further details.

Figure 14

Radical trapping experiment. (A) Fate of various radical species. (B) Reaction of S1−Cu^I and S2−Cu^I with different oxidants at 20 °C (O₂, H₂O₂, tBuOOH, and CumOOH) in the presence of radical trap reagents CCl₄ and CCl₃Br (¹H NMR yields, see the SI for details).

Figure 15

New oxidation protocol (Cu^II/H₂O₂) for the directed oxidation of various substrates and comparison of its performance to the previous methodology.^–, See the SI for further details.