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. 2023 Sep 8;381(6662):1072-1079.
doi: 10.1126/science.adg9232. Epub 2023 Sep 7.

Oxidative addition of an alkyl halide to form a stable Cu(III) product

Yongrui Luo #  1 , Yuli Li #  1 , Jian Wu  1 , Xiao-Song Xue  1 , John F Hartwig  2 , Qilong Shen  1
Affiliations

Oxidative addition of an alkyl halide to form a stable Cu(III) product

Yongrui Luo et al. Science. .

Abstract

The step that cleaves the carbon-halogen bond in copper-catalyzed cross-coupling reactions remains ill defined because of the multiple redox manifolds available to copper and the instability of the high-valent copper product formed. We report the oxidative addition of α-haloacetonitrile to ionic and neutral copper(I) complexes to form previously elusive but here fully characterized copper(III) complexes. The stability of these complexes stems from the strong Cu-CF3 bond and the high barrier for C(CF3)-C(CH2CN) bond-forming reductive elimination. The mechanistic studies we performed suggest that oxidative addition to ionic and neutral copper(I) complexes proceeds by means of two different pathways: an SN2-type substitution to the ionic complex and a halogen-atom transfer to the neutral complex. We observed a pronounced ligand acceleration of the oxidative addition, which correlates with that observed in the copper-catalyzed couplings of azoles, amines, or alkynes with alkyl electrophiles.

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Figures

Fig. 1.
Fig. 1.. Mechanism of Cu-mediated cross-coupling.
(A) General mechanism for Cu-catalyzed cross-coupling reaction. (B) Strategy that inverted the barrier for oxidative addition (OA) and reductive elimination (RE) in the catalytic cycle for Cu-catalyzed cross-coupling. (C) State-of-the-art observations of oxidative addition of alkyl halide to Cu(I) species. M, metal or quasi-metal; X, halogen; Y, dummy ligand; TM, transmetalation.
Fig. 2.
Fig. 2.. Oxidative addition of alkyl halides to Cu(I) complexes.
(A) Oxidative addition of XCH(R)CN with ionic Cu(I) complex [Ph4P]+ [Cu(CF3)2]− (1a). (B) Oxidative addition of XCH(R)CN with [(bpy)Cu(CF3)] (1b). (C) ORTEP (Oak Ridge Thermal Ellipsoid Plot) diagrams of [Ph4P]+ [Cu(CF3)3(CH2CN)]− (3a) (countercation Ph4P+ is omitted for clarity) and trans-[(bpy)Cu(CF3)2(CH2CN)] (trans-4). Ellipsoids are shown at the 50% level. (D) Reaction progress for ionic Cu(I) complex [Ph4P]+ [Cu(CF3)2]− (1a) with BrCH2CN (2-Br) at 298 K (blue) or neutral Cu(I) complex [(bpy)Cu(CF3)] (1b) with BrCH2CN (2-Br) at 298 K (red). (E) Solvent effect on the reactions of BrCH2CN with [Ph4P]+ [Cu(CF3)2]− (1a) (blue) or [(bpy)Cu(CF3)] (1b) (red). DCM, dichloromethane; MeCN, acetonitrile (methyl cyanide).
Fig. 3.
Fig. 3.. Kinetic analysis.
Kinetic data were fit to the expression of [1a]t=[1a]0e−kobs+c for (A) and [4]t=A−Be−kobs for (B), in which t is time and kobs are the apparent (observed) rate constants (pages S12 and S35 to S38 provide details about derivation of expression of corrected rate constant kcorr from kobs). (A) Kinetic profiles of oxidative addition of XCH(R)CN (where X is Cl, Br, or I; and R is H or Me) with ionic Cu(I) complex [Ph4P]+[Cu(CF3)2]− (1a) at 298 K. (B) Kinetic profiles of oxidative addition of XCH2CN (where X is Cl or Br) with [(bpy)Cu(CF3)] (1b) at 243 K. (C) Eyring analysis of the temperature dependence of the rate constants of oxidative addition of BrCH2CN with [Ph4P]+[Cu(CF3)2]− (1a) (blue), oxidative addition of BrCH2CN with [(bpy)Cu(CF3)] (1b) (green), and oxidative addition of ClCH2CN with [(bpy)Cu(CF3)] (1b) (red). (D) Effect of added free bipyridine on oxidative addition of ClCH2CN with [(bpy)Cu(CF3)] (1b) at 268 K.
Fig. 4.
Fig. 4.. Five proposed pathways for the oxidative addition of haloacetonitriles to ionic or neutral Cu(I) complexes and free energies of each species computed with DFT.
The calculated activation free energies for the oxidative addition of BrCH2CN(2-Br) to the ionic Cu(I) complex [Ph4P]+ [Cu(CF3)2]− (1a) in DMSO are given in blue, and those for oxidative addition of ClCH2CN (2-Cl) to the neutral [(bpy)Cu(CF3)] (1b) in DMF are given in red. The energies are in kilocalories per mole and indicate the relative free energies calculated at the PBE0-D3(BJ)/Def2-TZVP(SMD, solvent)//PBE0-D3(BJ)/Def2-SVP(SMD,solvent) level. SMD, solvation model density.
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