Mechanistic Characterization of (Xantphos)Ni(I)-Mediated Alkyl Bromide Activation: Oxidative Addition, Electron Transfer, or Halogen-Atom Abstraction

Article abstract of DOI:10.1021/jacs.8b13499

Ni(I)-mediated single-electron oxidative activation of alkyl halides has been extensively proposed as a key step in Ni-catalyzed cross-coupling reactions to generate radical intermediates. There are four mechanisms through which this step could take place: oxidative addition, outer-sphere electron transfer, inner-sphere electron transfer, and concerted halogen-atom abstraction. Despite considerable computational studies, there is no experimental study to evaluate all four pathways for Ni(I)-mediated alkyl radical formation. Herein, we report the isolation of a series of (Xantphos)Ni(I)-Ar complexes that selectively activate alkyl halides over aryl halides to eject radicals and form Ni(II) complexes. This observation allows the application of kinetic studies on the steric, electronic, and solvent effects, in combination with DFT calculations, to systematically assess the four possible pathways. Our data reveal that (Xantphos)Ni(I)-mediated alkyl halide activation proceeds via a concerted halogen-atom abstraction mechanism. This result corroborates previous DFT studies on (terpy)Ni(I)- and (py)Ni(I)-mediated alkyl radical formation, and contrasts with the outer-sphere electron transfer pathway observed for (PPh₃)₄Ni(0)-mediated aryl halide activation. This study of a model system provides insight into the overall mechanism of Ni-catalyzed cross-coupling reactions and offers a basis for differentiating electrophiles in cross-electrophile coupling reactions.

Full text of DOI:10.1021/jacs.8b13499

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Article
Mechanistic Characterization of (Xantphos)Ni(I)-
Mediated Alkyl Bromide Activation: Oxidative Addition,
Electron Transfer, or Halogen-Atom-Abstraction
Justin B. Diccianni, Joseph Katigbak, Chunhua Hu, and Tianning Diao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13499 • Publication Date (Web): 06 Jan 2019
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Mechanistic Characterization of (Xantphos)Ni(I)-
Mediated Alkyl Bromide Activation: Oxidative
Addition, Electron Transfer, or Halogen-Atom-
Abstraction
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Justin B. Diccianni, Joseph Katigbak, Chunhua Hu, and Tianning Diao*
Department of Chemistry, New York University, 100 Washington Square East
New York, NY 10003
E-Mail: diao@nyu.edu
ABSTRACT
Ni(I)-mediated single-electron oxidative activation of alkyl halides has been extensively proposed
as a key step in Ni-catalyzed cross-coupling reactions to generate radical intermediates. There are
four mechanisms through which this step could take place: oxidative addition, outer-sphere
electron transfer, inner-sphere electron transfer, and concerted halogen-atom-abstraction. Despite
considerable computational studies, there is no experimental study to evaluate all four pathways
for Ni(I)-mediated alkyl radical formation. Herein, we report the isolation of a series of
(Xantphos)Ni(I)–Ar complexes that selectively activate alkyl halides over aryl halides to eject
radicals and form Ni(II) complexes. This observation allows the application of kinetic studies on
the steric, electronic, and solvent effects, in combination with DFT calculations, to systematically
assess the four possible pathways. Our data reveal that (Xantphos)Ni(I)-mediated alkyl halide
activation proceeds via a concerted halogen-atom-abstraction mechanism. This result corroborates
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with previous DFT studies on (terpy)Ni(I) and (py)Ni(I)-mediated alkyl radical formation, and
contrasts with the outer-sphere electron transfer pathway observed for (PPh3)4Ni(0)-mediated aryl
halide activation. This case study provides insight into the overall mechanism of Ni-catalyzed
cross-coupling reactions and offer a basis for differentiating electrophiles in cross-electrophile
coupling reactions.
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INTRODUCTION
Recent advances in Ni-catalyzed cross-coupling reactions have found important synthetic
applications.1 Historical2 and contemporary3 mechanistic studies provide evidence for single-
electron transfer pathways in the presence of Ni(I) and Ni(III) intermediates.4 In the catalytic
cycles of Ni-catalyzed cross-coupling and cross-electrophile coupling reactions, alkyl halides are
proposed to be activated by Ni(I)-halide or Ni(I)-carbyl intermediates via single-electron oxidative
activation to form radicals (Scheme 1).3 Capture of the radical by a Ni(II) intermediate gives rise
to a Ni(III) species, which undergo reductive elimination to generate the product. The single-
electron oxidative activation step and the formation of radical intermediates with Ni(I) catalysts
has created opportunities for stereoconvergent coupling of alkyl halides,1h,5 and the combination
of Ni catalysis with photoredox catalysis has given access to new reactivity.6 In addition,
electrophile activation is critical to the chemoselectivity and scope of cross-electrophile coupling
reactions, when both aryl and alkyl halides are present and competing for activation.1h Therefore,
it is crucial to understand the mechanistic details of single-electron oxidative activation of
electrophiles mediated by Ni(I) complexes.
Scheme 1. Possible Mechanisms of Ni-Catalyzed Cross-coupling with Ni(I)-Mediated Radical
Formation as Key Steps
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X
Ni catalyst
R3
R3–M
+
R1 R2
R1 R2
R1 and R2: aryl, alkenyl, and alkyl
M: BR2, Zn, Mg, Si, Zr, etc.
“Transmetalation after oxidative addition”
X
R3
[NiI] X
R1 R2
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R1 R2
R1
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R1 R2
[NiII]
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[NiIII]
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“Transmetalation before oxidative addition”
R3
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How are electrophiles activated by Ni(I) species and how are radicals generated? Several
different pathways are possible for Ni(I)-mediated radical formation from aryl and alkyl halides
(Scheme 2). Ni(I) complexes have been shown to undergo two-electron oxidative addition with
MeI to form Ni(III),7 from which a radical could be ejected to generate Ni(II) (Pathway 1).8 Single
electron transfer pathways, either outer-sphere (Pathway 2) or inner-sphere, via an encounter
complex (Pathway 3), have been invoked in a number of mechanistic proposals,2,3c and proceed
through electron transfer from Ni(I) to the alkyl/aryl halides to form radical anions, followed by
subsequent homolytic C–X bond cleavage to eject a radical.2,3 Many of these proposals are
primarily based on the study of Ni(0)(PEt3)4-mediated aryl halide oxidative addition by Kochi and
coworkers, who concluded that aryl radicals are formed via outer-sphere electron transfer as the
rate-determining step.9,10 A macrocyclic Ni(I) complex, relevant to cofactor F430 of methanogenic
bacteria, has been proposed to activate alkyl halides via electron-transfer.11 Finally, recent DFT
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calculations on a number of Ni(0)12 and Ni(I)13 systems propose the concerted halogen-atom-
abstraction pathway (Pathway 4). In particular, this pathway was found to be operational in
(terpy)Ni–Me,13a (PNP)Ni(CO),13b (pybox)NiMe,13c and (py)NiPh3h mediated alkyl halide
activation. Although the halogen-atom-abstraction pathway prevails in recent DFT studies, there
is limited experimental support. Moreover, despite the observation of stoichiometric radical
formation with several well-defined Ni(I) complexes,3e,14 there is no systematic experimental study
to evaluate all four pathways for Ni(I)-mediated alkyl radical formation.
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Scheme 2. Possible Pathways for Ni-Mediated Radical Formation from Alkyl Halides
In light of the prevalent proposals of Ni(I)-mediated single-electron activation of electrophiles
to form radicals in catalytic studies,2,3 we herein, report the synthesis and isolation of (tBu-
Xantphos)Ni(I)-aryl complexes that enabled a detailed study on the mechanism of Ni(I)-mediated
alkyl halide activation to form radicals. Although the vast majority of Ni-catalyzed cross-coupling
reactions utilize nitrogen-based ligands, the catalytic reactivity of the Ni/Xantphos system shown
here and the analogy of the transition states between (Xantphos)Ni-Ar and (terpy)NiMe13a suggest
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that this work could provide insight into the electrophile activation step in cross-electrophile
coupling reactions.
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RESULTS
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Synthesis and Characterization of (tBu-Xantphos)Ni(I) Complexes. The synthesis and
isolation of well-defined Ni(I)-carbyl complexes is a significant synthetic challenge due to the
radical, and often unstable, nature of Ni(I) complexes.15 Previous examples use tridentate ligands
to stabilize the Ni(I) oxidation state,3e, 14a whereas only a couple of Ni(I)-carbyl molecules have
been reported with bidentate ligands.16 We reasoned that the large bite-angle of Xantphos would
help stabilize Ni(I) complexes. After assessing the effect of substituents on Xantphos, we found
that tBu-Xantphos stabilizes Ni complexes better than Ph- and iPr-Xantphos, possibly due to the
greater steric protection. Our synthesis started with the preparation of (tBu-Xantphos)NiBr2 1 by
coordination of tBu-Xantphos to Ni(DME)Br2 (Scheme 3). Reduction of 1 with KC8 or NaBHEt3
afforded (tBu-Xantphos)Ni(N2) 2. The X-ray crystal structure of 2 shows that N2 is bridging
between two Ni centers, and the N≡N distance is 1.144(3) Å: only slightly elongated from that of
free N2 (1.098 Å) (Figure 1A). The use of Cp2Co as the reductant gave (tBu-Xantphos)NiBr 3 in
96% yield, which could be further reduced to 2 by KC8. The X-ray structure of 3 shows a distorted
tetrahedral geometry and a relatively long distance between the O-atom of tBu-Xantphos and Ni
(2.434 Å), indicating a secondary O-Ni interaction (Figure 1B). Phenylation of 3 with
phenyllithium at -35 ºC generated (tBu-Xantphos)NiPh 4 in 55% yield. X-ray crystallography
established a secondary interaction between the O-atom of tBu-Xantphos and Ni (2.518 Å) and a
distorted tetrahedral geometry (Figure 1C). Broken-symmetry DFT calculations using the ORCA
package revealed that the unpaired electron density is concentrated on Ni with a small portion
delocalized to the Ar group (Figure 2).17 Arylation of 3 with a variety of aryllithium reagents gave
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a series of (tBu-Xantphos)NiAr complexes 5-11. The analogous paramagnetic 1H NMR spectra of
5-11, compared to that of 4, suggest that these compounds have similar electronic structures.
Scheme 3. Syntheses of (tBu-Xantphos)Ni Complexes
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(A)
(B)
(C)
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Figure 1. X-ray structures of 2 (A), 3 (B), and 4 (C) at 50% probability thermal ellipsoids.
Hydrogen atoms are omitted and t-Bu groups are truncated for clarity. Selected bond lengths (Å)
for 2: N(1)≡N(2) = 1.144(3), Ni(1)··· O(1) = 2.518. Selected bond length (Å) for 3: Ni(1)··· O(1)
= 2.434. Selected bond lengths (Å) for 4: Ni(1)–C(1) = 1.9795(14), Ni(1)··· O(1) = 2.518.
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Figure 2. Spin-density plot of 4.
Ni(0) and Ni(I)-Mediated Alkyl and Aryl Halide Activation. The isolation of the well-
defined (tBu-Xantphos)Ni(N2), 2, and (tBu-Xantphos)Ni–Ar complexes, 4-11, allowed us to carry
out a study on their reactivity towards activating alkyl and aryl halides. In C6D6, addition of one
equivalent of bromobenzene or chlorobenzene to 2 led to the immediate formation of the
corresponding (tBu-Xantphos)Ni–bromide 3 or chloride 13, respectively, with concomitant
formation of biphenyl in high yields (Scheme 4). When (bromomethyl)cyclopropane 12 was added
to 2, the reaction rapidly formed (tBu-Xantphos) 3 and 1,7-octadiene in 91% yield.
Scheme 4. Ni(0) Complex 2-Mediated Activation of Alkyl and Aryl halides
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Subsequently, we examined the reactivity of the Ni(I) complexes. (tBu-Xantphos)Ni–Br 3 does
not react with PhBr, PhI, or 12. Next we probed the reactivity of (tBu-Xantphos)Ni–o-Tol, 6,
towards aryl and alkyl halides (Scheme 5). When one equivalent of bromobenzene was introduced
into a solution of 6 in C6D6, no reaction took place after 48 hours. Heating the reaction resulted in
decomposition of 6. Addition of CH3I to 6, in contrast, led to the formation of the corresponding
Ni(II) iodide 14 and ethane. Activation of 12 also took place when treated with 6 to form Ni(II)
bromide 15 and 1,7-octadiene in high yields. While the iodide of complex 14 is dissociated from
the Ni center to give a square planar geometry, as determined by X-ray crystallography (Figure
S20), the bromide from complex 15 is bound to Ni to give a distorted trigonal bipyramidal
geometry. When 15 was dissolved in a polar solvent, such as acetone, the bromide dissociated
from the Ni center to generate the square planar ionic complex. The reaction rate of 6 with 12 is
substantially slower than that of 2 with 12. In-situ NMR spectroscopy allowed us to monitor the
reaction time-course (Figure 3), as the paramagnetic resonances of 6 could be readily integrated
(Figure S37). The time-course fits into a second-order kinetic model using COPASI software to
give a second-order rate constant (k) of 0.011 M-1s-1.18 When five equivalents of TEMPO were
included in the reaction of 6 with 12, the reaction generated a mixture of 16 and 17 as the organic
products.
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Scheme 5. Ni(I) Complex 6-Mediated Activation of Alkyl and Aryl halides
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Figure 3. Kinetic profile of (tBu-Xantphos)Ni-o-Tol 6-mediated ring-opening dimerization of
cyclopropylmethy bromide 12. Reaction conditions: [6]0 = 10 mM, [12]0 = 12 mM, C6D6 = 0.65
mL, 25 ºC. Internal standard = mesitylene.
Steric Effects on Ni(I)-Mediated Alkyl Bromide Activation. The clean kinetic profile of
(tBu-Xantphos)Ni-o-Tol 6-mediated alkyl bromide activation and the formation of the resulting
(tBu-Xantphos)Ni(II)(o-Tol)(Br) 15 as a well-defined molecule provided us a special opportunity
to elucidate the mechanism of this single-electron oxidative activation process. We initiated our
study by investigating the steric and electronic effects of Ni(I) complexes and alkyl bromides on
the reaction kinetics. We first compared the activation rates of 12 with a series of increasingly
bulky aryl ligands on Ni(I) (Table 1). The reaction of (tBu-Xantphos)NiPh 4 with 12 proceeded to
form 1,7-octadiene with a second-order rate of 0.033 M-1s-1 at 25 ºC. Compared to that of 4, the
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rate of (tBu-Xantphos)Ni-o-Tol 6-mediated activation of 12 decreased threefold and no reaction
was observed over 12 h with (tBu-Xantphos)Ni-2,6-dimethylphenyl 5.
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Table 1. Steric Effect of the Ar Group on Ni(I)Ar-Mediated Activation of 12a
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aReaction conditions: [Ni(I)]0 = 10 mM, [12]0 = 20 mM, C6D6 = 0.65 mL. Internal standard =
mesitylene.
Our examination of the effect of the alkyl halide was carried out using (tBu-Xantphos)Ni(I)
complex 8 as the model molecule (Table 2). Reaction of 8 with 1-bromopropane proceeded with
a second-order rate constant of 1.4 x 10-3 M-1s-1 at 25 ºC. The reaction with secondary alkyl
bromide, 2-bromopropane, was about 4 times faster. The more hindered 4-bromoheptane led to a
slightly decreased rate relative to that of 2-bromopropane.
Table 2. Steric Effect of Alkyl Bromides on Ni(I)-Mediated Activationa
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aReaction conditions: [8]0 = 10 mM, [R–Br]0 = 20 mM, C6D6 = 0.65 mL. Internal standard =
mesitylene.
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Electronic Effect on Ni(I)-Mediated Alkyl Bromide Activation. The electronic effect of the
Ni(I) complexes on the rate of alkyl bromide activation was investigated with a series of para-
substituted (tBu-Xantphos)NiAr complexes, 6-11 (Table 3). The electronic effect of each Ni(I)
complex was parameterized by the electrochemical potentials of the oxidation and reduction in
THF solutions. The cyclic voltammetry (CV) of 6 showed quasi-reversible oxidation and reduction
waves at -2.70 V (vs. Fc/Fc+) and -1.51 V (vs. Fc/Fc+) with a scan rate of 250 mV/s, which are
assigned to Ni(0)/Ni(I) and Ni(I)/Ni(II) transitions, respectively (Figure 4). With a scan rate of 25
mV/s, the quasi-reversible Ni(0)/Ni(I) transition became irreversible. We attribute this
phenomenon to a reversible electron transfer event followed by an irreversible chemical reaction
(ErCi).19 The irreversible chemical reaction rate varies as the electronic nature of the Ni(I) complex
changes (cf. Figures S23-S28). The time-courses of the (tBu-Xantphos)NiAr, 6-11, mediated
single-electron oxidative activations of 12 were monitored by in-situ NMR spectroscopy, and fit
into a second-order kinetic model (Figures S1-S7). The E1/2 values for the Ni(I)/Ni(II) transition
and the second-order rate constants, k, for each (tBu-Xantphos)NiAr complexes are summarized
in Table 3.
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Table 3. Electronic Effect on Ni(I)-Mediated Alkyl Bromide Activation
E1/2(NiI/II)
k x 103
X
p
(V vs. Fc+/Fc) (M-1s-1)
NMe2 7
OMe 8
Me 9
-0.83
-0.27
-0.17
-1.60
-1.54
-1.59
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H 6
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Figure 4. Cyclic Voltammetry of 6 in THF. [6] = 1 mM, [Bu4NPF6] = 0.4 M. (A) scan rate = 250
mV/s; (B) scan rate = 25 mV/s. Internal standard = ferrocene.
The second-order rate constants, k, for the oxidative addition and dimerization of 12 with
various (tBu-Xantphos)NiAr complexes show a linear-free-energy relationship with the Hammett
parameters to give a slope () of -0.72 (Figure 5). The G‡ of each reaction was calculated with k
using the Eyring equation. The G0 of each reaction was estimated with the E1/2(Ni(I)/Ni(II)) and
the Nernst equation. The G‡ varied linearly as a function of G0, with R2 of 0.86 and a slope of
0.22 (Figure 6).
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Figure 5. Hammett correlation of the reaction rates of 12 dimerization mediated by complexes 6-
11.
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Figure 6. Correlation of the activation energy G‡ (kJ/mol) versus G0 (kJ/mol).
Solvent Effect. The effect of solvent on the rate of 8-mediated activation of isopropyl bromide
was investigated with four solvents (Table 4). Monitoring the reactions in pentane-d12, benzene-
d6, DME-d12 (dimethoxyethane), and acetone-d6 revealed similar rates despite the different
dielectric constants of the solvents. The reduced rates in polar solvents could be attributed to their
coordination to Ni, hindering the approach of the alkyl bromides. The rate in THF-d6 decreased
dramatically, and a black precipitate was formed from the reaction. We attribute this outlier to a
side-pathway triggered by the coordination of THF to 8. Our attempts to examine the reaction in
other polar solvents, including CH2Cl2, were complicated by the decomposition of complex 8 in
halogenated solvents.
Table 4. Solvent Effect of 8-Mediated Isopropyl Bromide Activation
Dielectric
constant
Solvent
k x 103 (M-1s-1) Yield
Pentane-d12
1.8
5.3
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95
1,2-DME-d10
THF-d6
Acetone-d6
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DFT Calculations. Computational studies were performed and compared with the
experimental data. We evaluated the four possible pathways (Scheme 2) for the single-electron
oxidative activation of EtBr by (tBu-Xantphos)Ni(Ph) 4, using spin-unrestricted formalism of DFT
calculations with the B3LYP functional and the LANL2DZ basis/pseudopotential for the nickel
centers and 6-31G(d) for the main-group elements, phosphorus, and bromine. The Gibbs free
energy change (ΔG) of -15.6 kcal/mol suggests that the single-electron oxidative activation is
exergonic. Optimization for the oxidative addition pathway converged to an SN2-type mechanism
with an activation energy of 17.0 kcal/mol (Figure S57). The outer-sphere electron transfer
mechanism was modeled using the Marcus-Hush theory, and resulted in a high barrier of 82.8
kcal/mol, suggesting an unfavorable pathway. Evaluation of the inner-sphere electron transfer
pathway failed to locate a stable encounter intermediate between 4 and EtBr. Calculations for the
halogen-abstraction pathway converged to a concerted transition state 18 with an activation energy
of 9.91 kcal/mol (Figure 7A). The geometry of the Ni center in 18 is distorted to a square pyramidal
geometry with the phenyl group lifted as the bromide approaches Ni, giving a nearly linear
geometry for the C(Ph)-Ni-Br-CH2CH3 atoms with a Ni---Br---Et angle of 169º. The spin density
plot of 18 shows that the unpaired electron density is distributed on Ni and CH2CH3 (Figure 7B).
Within the context of the halogen-abstraction mechanism, we examined the steric effect of the
electrophile on the rate of single-electron oxidative activation. When iPrBr was used instead of
EtBr, the ΔG of the reaction decreased to -16.3 kcal/mol, while the activation energy decreased to
8.53 kcal/mol. Finally, in order to unravel the lack of reactivity of Ni(I) with aryl halides, we
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calculated the ΔG for phenyl radical generation from PhBr with (tBu-Xantphos)Ni(Ph) 4. The ΔG
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of 1.15 kcal/mol suggests that the activation of sp2 electrophiles is slightly uphill.
(A)
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(B)
Figure 7. (A) Reaction coordinate for single-electron oxidative activation of EtBr by 4 via
concerted halogen-abstraction. Relative Gibbs free energy values were calculated with DFT
B3LYP/LANL2DZ/6-31G(d). (B) Spin-density plot of transition state 18.
Catalytic Reactivity. While the majority of Ni-catalyzed cross-coupling reactions utilize
nitrogen-based ligands, phosphine ligands, such as Xantphos, are competent in a number of cross-
coupling reactions.20 We explored the catalytic relevance of Xantphos ligands to the cross-
coupling of alkyl halides. Kumada coupling of benzyl bromide 19 with PhMgBr benefited from
the use of a Ph-Xantphos ligand to afford the cross-coupling product 20 in 60% yield, whereas the
reaction without a ligand gave 20 in 24% yield (Scheme 6A). Use of the bulkier tBu-Xantphos
afforded 21 in 30% yield, suggesting activation of 19, but unsuccessful cross-coupling.
Unactivated neopentyl iodide underwent cross-coupling with PhMgBr to give 23 in 83% yield,
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whereas the reaction with no ligand afforded 23 in 5% yield. Cross-electrophile coupling of 19
with PhI proceeded to generate the desired cross-coupling product 20 in 20% yield with
considerable homo-coupling by-products (Scheme 6C). These observations clearly reveal a strong
ligand effect on the reactivity and selectivity of the reaction.
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Scheme 6. (Xantphos)Ni-Catalyzed Cross-Coupling Reactions
DISCUSSION
The Ni(0) complex (tBu-Xantphos)Ni(N2) 2 undergoes facile single-electron oxidative
activation of aryl and alkyl bromides to form (tBu-Xantphos)NiBr 3 (Scheme 4). This observation
is reminiscent of previous studies on (PEt3)4Ni(0).9 In contrast, Ni(I) complex (tBu-Xantphos)Ni–
o-Tol 6 selectively activates alkyl halides, but is inactive towards aryl halides (Scheme 5). We
attribute the lack of reactivity with aryl bromides to the instability of aryl radicals, which results
in a positive G for the reaction, as determined by DFT calculations. This selective activation of
alkyl bromides activation over aryl bromides has important implications in controlling selectivity
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in cross-electrophile coupling reactions, when both sp2 and sp3 electrophiles are present.1h The
reaction of (tBu-Xantphos)Ni–o-Tol 6 with radical clock 12 forms 1,7-octadiene, indicating a
radical-mediated ring opening that precedes the dimerization of the homoallylic radical (Scheme
5). Such radical dimerizations have been extensively observed in catalytic reactions proceeding
through radical intermediates.21 This assignment is supported by the trapping experiment of the
cyclopropylmethyl radical with TEMPO to form 16 and 17. The ratio of 16 to 17 is dependent on
the relative rates of cyclopropylmethyl radical ring-opening and trapping by TEMPO.22
Four different mechanisms were postulated for the activation of alkyl halides by Ni(I)
complexes (Scheme 2), and the results described above provide evidence to distinguish among
these possibilities. The slower rate with primary alkyl bromides relative to secondary alkyl
bromides (Table 2) rules out the oxidative addition pathway (Scheme 2, Pathway 1). This
interpretation is consistent with DFT calculations, which show an activation energy of 17.0
kcal/mol for the SN2 type oxidative addition: substantially higher than that of the halogen
abstraction pathway (9.91 kcal/mol). The faster rate of secondary bromide activation, relative to
primary bromide activation, is reproduced by DFT calculations on the halogen-atom-abstraction
pathway, and can be attributed to the formation of a more stable secondary radical which has a
higher driving force compared to the formation of a primary radical.
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The steric effect of aryl groups on Ni and the slope of the linear correlation of G‡ with G0,
according to Marcus theory, provides evidence against an outer-sphere electron transfer pathway
(Scheme 2, Pathway 2). Increased steric hindrance of the Ni complexes significantly reduced the
reaction rate (Table 1), whereas outer-sphere electron transfer rates are unlikely to be subject to
steric effects.23 According to Marcus theory,24 the activation barrier (G‡) of electron transfer
would exhibit a linear-free-energy relationship with G0 and a slope of 0.5 (eq 1).25 The observed
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slope of 0.22 for the correlation of G‡ to G0 significantly deviates from 0.5 (Figure 6), which is
inconsistent with the outer-sphere electron transfer pathway. Corroborating this analysis, DFT
calculations on the outer-sphere electron transfer pathway returned a very high activation energy
of 82.8 kcal/mol.
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G‡ = 0.5G0 + constant
(1)
The difference between the inner-sphere electron transfer (Scheme 2, Pathway 3) and the
concerted halogen-atom-abstraction pathways (Scheme 2, Pathway 4) mainly rests on whether a
caged ionic pair is formed as an intermediate. Polar solvents are expected to accelerate the rates of
reactions going through an ionic intermediate.9 In this Ni(I)-mediated single-electron oxidative
activation, DME and acetone gave slightly slower rates than those in pentane and benzene (Table
4). We attribute the reduced rates with polar solvents to their coordination to Ni, which hinders the
approach of the alkyl bromides. This solvent effect is inconsistent with the inner-sphere electron
transfer pathway.
Halogen-atom-abstraction is fully supported by experimental and computational data. The high
susceptibility of the rate to the steric effect of the Ni complex (Table 1) indicates association of Ni
with the alkyl bromide in the rate-determining step. Such a steric effect is corroborated by the
faster rate for 2-bromopropane relative to 4-bromoheptane (Table 2). The encounter of the Ni(I)
with the alkyl bromide could be viewed as nucleophilic donation of electron density from Ni(I) to
the * orbital of the C–Br bond.26 TS 18 is stabilized by delocalizing electrons among three atoms,
Ni, Br, and CH2CH3, and forming a three-center-three-electron bond (eq 2). The nearly linear
geometry of 18, with a Ni---Br---Et angle of 169º, is reminiscent of TS 24 identified for
(terpy)NiMe-mediated activation of iodopropane.13a In contrast, halogen-abstraction by (py)Ni(Ph)
was calculated to have a bent TS 25.3h The activation barriers for 24 and 25 were determined to be
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18 and 7.3 kcal/mol, respectively. The barrier of 9.91 kcal/mol for 18 is in between of the two
systems. The trans-geometry of the aryl group on Ni to the incoming bromide in TS 18 is expected
to enhance the electronic effect on the rate. The Hammett correlation of the rates with para-
substituted Ni-aryl complexes indicates a build-up of partial positive charge on Ni in transition
state (TS) 18. A similar electronic effect has been proposed for 24.13a The slope of -0.72 is similar
to previous reactions going through a concerted mechanism.27 The Marcus dependence of G‡ as
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a function of G0 shows an unusually shallow slope of 0.22. A comparable slope has been reported
in a C–H oxidation reaction, going through concerted PCET (proton-coupled-electron-transfer).28
While the origin of the moderate slope is unclear in either system, studies to explain it are
underway.
(2)
SUMMARY
We prepared a series of (tBu-Xantphos)Ni(I)–Ar complexes that selectively activate alkyl
halides over aryl halides via single-electron oxidative activation to eject alkyl radicals. Kinetic
studies on the steric, electronic, and solvent effects, in combination with DFT calculations, reveal
that the single-electron oxidative activation of alkyl halides proceeds via a concerted halogen-
atom-abstraction mechanism, in contrast with the previous proposal of outer-sphere electron
transfer for Ni(0)-mediated aryl halide activation9 and consistent with recent DFT calculations on
Ni(I) systems.13 Corroborated by the stoichiometric study, Xantphos is shown to promote catalytic
cross-coupling of unactivated alkyl halides. The selective reactivity of (Xantphos)Ni(I) toward
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alkyl halides, relative to aryl halides, and the elucidation of the mechanism, as a case study, provide
insight into the mechanism of Ni-catalyzed cross-coupling reactions. However, whether the
mechanism could be generalized remains to be seen, and the insight obtained here should be
cautiously applied to other systems.
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ASSOCIATED CONTENT
Supporting Information
All experimental procedures, additional figures, details of DFT calculations, NMR spectra, and
crystallographic data (PDF, CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
diao@nyu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation under award number DMR-1420073
and ACS-Petroleum Research Foundation (56568-DNI3). J.D. is supported by the Margaret and
Herman Sokol Fellowship and the Ted Keusseff Fellowship. T.D. is a recipient of the Alfred P.
Sloan Research Fellowship (FG-2018-10354).
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