A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study

Article abstract of DOI:10.1021/jacs.9b00097

Ni-catalyzed C(sp³)-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetalation with the Grignard reagent and syn-reductive elimination produce the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic C-O bond cleavage and transmetalation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular S_N2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp³)-O bond activation.

Full text of DOI:10.1021/jacs.9b00097

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Article
A Unified Explanation for Chemoselectivity and Stereospecificity of
Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of
Benzylic Ethers: A Combined Computational and Experimental Study
pan-Pan Chen, Erika L. Lucas, Margaret A. Greene, Shuo-Qing Zhang, Emily J.
Tollefson, Lucas W Erickson, Buck L. H. Taylor, Elizabeth R. Jarvo, and Xin Hong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 Mar 2019
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Page 1 of 17
Journal of the American Chemical Society
A Unified Explanation for Chemoselectivity and Stereospecificity of
Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of
Benzylic Ethers: A Combined Computational and Experimental
Study
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Pan-Pan Chen,†, Erika L. Lucas,‡, Margaret A. Greene,‡ Shuo-Qing Zhang,† Emily J. Tollefson,‡ Lucas
W. Erickson,‡ Buck L. H. Taylor,ǁ Elizabeth R. Jarvo*,‡ and Xin Hong*,†
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†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡Department of Chemistry, University of California, Irvine, California 92697, United States
ǁ Department of Chemistry, University of Portland, Portland, Oregon, 97203, United States
ABSTRACT: Ni-catalyzed C(sp3)O bond activation provides a useful approach to synthesize enantioenriched products from readily
available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations.
To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions
with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding.
Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoin-
version of the benzylic stereogenic center. Subsequent transmetallation with the Grignard reagent and syn reductive elimination pro-
duces the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction
initiates with the same benzylic CO bond cleavage and transmetallation to form a common benzylnickel intermediate. However, the
presence of the tethered alkyl chloride allows a facile intramolecular SN2 attack by the benzylnickel moiety. This step circumvents the
competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for
the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the ben-
zylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective
transformations involving Ni-catalyzed C(sp3)−O bond activation.
Introduction
in nickel-catalyzed Kumada and XEC reactions will provide a
useful guide for future design of stereoselective transformations
involving Ni-catalyzed C(sp3)–O bond activation.10
Cross-coupling (XC) and cross-electrophile coupling (XEC)
reactions that generate new C–C bonds between sp3-hybridized
carbons are of great synthetic interest, particularly as medicinal
chemistry shifts away from flatland.1 One of our laboratories has
developed a series of such transformations employing benzylic
ethers.26 At the foundation of these projects has been the idea
that the reactions would share a key elementary step:
stereospecific oxidative addition of the C–O bond. This step
was envisioned to control the stereochemical outcome of the
reactions, and to likely be the rate-determining step of the
catalytic cycles. In this manuscript, we report our collaborative
computational and experimental studies to delineate the
mechanistic similarities and differences between Kumada and
XEC reactions of closely related benzylic ethers. This work
builds on our prior collaboration to elucidate the basis for the
ligand-controlled stereochemical switch in Suzuki coupling
reactions of benzylic esters.7
Scheme 1. Chemoselectivity and stereospecificity of Ni-
catalyzed Kumada and XEC reactions of benzylic ethers.
Computational Methods
We envisioned that the reactions in Scheme 1 would serve as
ideal test cases for comparison of XC and XEC reaction
manifolds.3a,8 These reactions employ identical catalysts and
reaction conditions as well as similar substrates, however, there
are notable differences when comparing the reaction outcomes.
Kumada reactions of benzylic ethers reliably proceed with
inversion at the benzylic center (Scheme 1a). In contrast, XECs
of closely related benzylic ethers proceed with retention at the
benzylic center (Scheme 1b) and provide only XEC products,
with no competitive Kumada cross-coupling observed. To reach
a unified explanation for substrate-dependant chemoselectivity
and stereospecificity, we undertook a combined computational
and experimental mechanistic study.9 The increased
understanding of the mechanistic underpinnings of selectivity
All density functional theory (DFT) calculations were
conducted with the Gaussian 09 software package.11 Geometry
optimizations of all the intermediates and transition states were
performed at the B3LYP12 level of theory with def2-SVP13 basis
set, including solvation energy corrections and Grimme’s D3
(BJ-damping) dispersion corrections.14 Based on the optimized
structures, vibrational frequencies were calculated at the same
level of theory to evaluate its zero-point vibrational energy
(ZPVE) and thermal corrections at 298 K. The single-point
energies were computed with B3LYP functional and def2-
TZVPP13,15 basis set, including solvation energy corrections and
Grimme’s D3 (BJ-damping) dispersion corrections. The
solvation energies were evaluated by a self-consistent reaction
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Page 2 of 17
field (SCRF) using SMD model.16 Fragment distortion and
interaction energies were calculated at the B3LYP level of
theory with def2-TZVPP basis set, including Grimme’s D3 (BJ-
damping) dispersion corrections without the inclusion of
Prior studies of nickel-catalyzed coupling reactions of allylic
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ethers have found that magnesium salts play a key role as Lewis
acid co-catalysts.22 To evaluate magnesium coordination to the
tetrahydropyrans, we examined the relative free energies of
complexes of 1 with the Mg(II) species present in the reaction
mixture (Scheme 3).24 MgI2 is present in the reaction mixture
because of the Schlenk equilibrium25 (i.e., formation of dialkyl
magnesium compounds and magnesium halide salts) and
competitive Wurtz coupling that occurs during Grignard
formation.26 Complexation of 1 with MgI2 and Grignard reagent
MgMeI are both exergonic, with the ether-MgI2 complex 3 more
favorable by 3.1 kcal/mol (7.3 kcal/mol vs. 4.2 kcal/mol,
Scheme 3). Bonding with MgI2 is stronger because of the higher
Lewis acidity as compared to MgMeI. Therefore, the ether-
MgI2 complex 3 was identified as the species which interacts
with the nickel catalyst in the Kumada coupling.
solvation
energy
corrections.
The
details
of
distortion/interaction analysis are provided in the Supporting
Information. Extensive conformational searches for the
intermediates and transition states have been conducted to
ensure that the lowest energy conformers were located. The 3D
diagrams of molecules were generated using CYLView,17 all the
hydrogens were omitted in the CYLView diagrams except for
the stereogenic centers.
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To correct the entropy change in solution, we applied an
empirical approach,18 because there is currently no widely
accepted quantum mechanics-based approach to correct
entropy in solution. For each component change in a reaction
at 298 K and 1 atm, a correction of 4.3 kcal/mol is applied to the
reaction free energy (i.e., a reaction from m- to n-components
has an additional free energy correction for (n − m) × 4.3
kcal/mol). This approach has been validated through a number
of computational and experimental studies. Yu and co-workers
have found that the entropy corrections are overestimated by
about half in several cycloaddition reactions.19 Wang and co-
workers have discovered the improved description of free
energy changes in a number of metal-catalyzed reactions using
the same empirical approach.20
Scheme 3. Free energy changes of complexation between
benzylic ether and Mg(II) species involved in Kumada coupling.
Results and Discussion
Computational study of Kumada coupling mechanism. Two
possible catalytic cycles for Ni-catalyzed Kumada coupling with
benzylic ethers are shown in Scheme 2.21,22 From the active
catalyst LnNi(0) species A, one of the proposed cycles begins
with oxidative addition cleaving the benzylic CO bond,
The free energy changes of the most favorable pathway of
Ni/BINAP-catalyzed Kumada coupling with benzylic ether 1
are shown in Figure 1.27 DFT-optimized structures of selected
intermediates and transition states are shown in Figure 2. Based
on Hartwig’s previous experimental characterization and study
of the Ni(BINAP)2 complex,28 we believe this complex could
exist as an off-cycle resting state and equilibrate with the active
monoligated nickel catalyst. Indeed, our calculations showed
that the substrate-ligand exchange of Ni(BINAP)2 (6) to form
generating the zwitterionic 3-nickel(II) species
B with
inversion at the benzylic center. Complex B undergoes
transmetallation with the Grignard reagent to deliver the
LnNi(benzyl)(methyl) intermediate C. Alternatively, the
LnNi(0) species A can form a nickelate species F with the
Grignard reagent.23 Complex F then undergoes oxidative
addition to cleave the benzylic CO bond to generate
intermediate C. From C, CC reductive elimination produces
the Kumada coupling product and subsequent product
liberation regenerates the active catalyst A.
the substrate-coordinated complex
7 is 13.4 kcal/mol
endergonic. Other studied nickel(0) complexes are all much
less stable as compared to the catalyst resting state Ni(BINAP)2
(6); see Supporting Information for details (Figure S1). Arene
complex 7 undergoes oxidative addition via TS8, via backside
attack, generating the zwitterionic 3-nickel(II) species 9 with
stereoinversion of the benzylic position. Alternative CO bond
cleavage transition states are all less favorable as compared to
TS8. For example, we also located the similar stereoinvertive
oxidative addition leading from Grignard reagent complex 5, as
well as a number of possible stereoretentive CO bond cleavage
transition states, but these transition states were all significantly
higher in energy than TS8 (Figure S2).
Scheme 2. Possible catalytic cycles of Ni-catalyzed Kumada
coupling of benzylic ethers.
Completion of the catalytic cycle requires, in broad strokes,
transmetallation and reductive elimination. Based on our
calculations, this proceeds first by coordination of Grignard
reagent 4 with benzylnickel complex 9, to provide a more stable
nickel(II) species 10. This complex (10) undergoes facile
transmetallation
via
TS11
to
generate
the
(BINAP)Ni(benzyl)(methyl) species 12. We also considered
the MeMgI addition through an outer-sphere mechanism, this
process is less favorable than the inner-sphere process via TS11
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process is less favorable as compared to TS13 (Figure S4).
(Figure S3). Subsequent syn reductive elimination via TS13
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4
generates the new C–C bond and leads to the product-
coordinated complex 14. The reductive elimination can also
occur with an 3-benzylnickel complex, but this alternative
Product liberation of complex 14 releases Kumada coupling
product and regenerates catalyst 6. IRC analysis of key
transition states were performed to verify their positions in the
free energy surface (Figure S5).
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Figure 1. DFT-computed free energy changes of Ni/BINAP-catalyzed Kumada coupling of benzylic ether 1.
Figure 2. DFT-optimized structures of selected intermediates and transition states involved in Ni-catalyzed Kumada coupling.
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Our calculations find that the alternative pathway shown in
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Scheme 2, involving a nickelate species (F), is infeasible. The
free energy changes of the competing pathways from the Ni(0)
catalyst are compared in Figure 3. The interaction between
Ni(BINAP) and the Grignard reagent is quite weak, making the
formation of complex 16 endergonic by 27.5 kcal/mol as
compared to 6. Subsequent methyl group transfer via TS17 is 7.1
kcal/mol less favorable than the irreversible oxidative addition
of the CO bond via TS8. Therefore, methyl group transfer
from the Grignard reagent to the Ni(0) complex is not
competitive with oxidative addition of the benzylic ether via
TS8. We also evaluated methyl group transfers involving the
Grignard reagent dimer or coordination of the benzylic ether,
and these processes are also not operative (Figure S6).
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Figure 4. Comparison of the CO bond cleavage between
naphthyl and phenyl substrates.
possible competing transition states that could result in
retention or inversion. The CO bond cleavage can occur in a
stereoinvertive fashion through backside attack, via transition
state TS8, or a stereoretentive fashion via the concerted cyclic
transition state TS24. TS8 is 37.3 kcal/mol more favorable than
TS24, indicating that the CO bond cleavage occurs with
exclusive stereoinversion. These findings are consistent with
prior observations that oxidative addition of allylic ethers
proceeds with inversion.6b
The origins of this stereospecificity were further elucidated
with distortion/interaction analysis (Figure 5).30,31 Each
transition state was separated into two fragments: the
Ni(BINAP) catalyst fragment and the ether-MgI2 substrate
fragment. The distortion energy (Edist) is the energy required
for the geometric change during the CO bond cleavage, and
the interaction energy (Eint) reflects the strength of the
interaction between the catalyst and substrate fragments in the
transition state (details of distortion/interaction analysis are
included in Figure S8).
Figure 3. Free energy changes of the competing pathways from
Ni(0) catalyst 6 in the Kumada coupling.
The rate-determining oxidative addition step explains the
observed reactivity differences between naphthyl and phenyl
substrates.29 The overall oxidative addition barrier of naphthyl
substrate is 7.4 kcal/mol lower than that of phenyl substrate
(TS8 vs. TS21, Figure 4). The coordination of naphthyl moiety
is stronger than that of phenyl moiety, which stablizes the pre-
oxidative addition intermediate (7 vs. 20), as well as the
subsequent oxidative addition transition states. Our further
Hammett analysis verified the oxidative addition nature of CO
bond cleavage transition state TS8. A linear correlation between
the Hammett constant and the computed CO bond cleavage
rate was observed (Figure S7), suggesting that the electron-
withdrawing substituent of arene would accelerate the CO
bond cleavage.
Comparing the two C−O bond activation transition states,
Edist-cat and Eint are the leading causes for the stereoselectivity.
The remarkable difference of Edist-cat is due to the change of
nickel coordination. In the stereoinvertive transition state TS8,
the nickel is bisligated with two phosphine coordinations of the
BINAP ligand. The stereoretentive transition state TS24
requires dissociation of one phosphine coordination to
accommodate the nickel-oxygen interaction, leading to
significant catalyst distortion. In addition, the interaction
between catalyst and substrate is weaker in TS24: Eint (TS8) is
−20.0 kcal/mol, while Eint (TS24) is 2.4 kcal/mol. Therefore,
both the catalyst distortion and catalyst-substrate interaction
contribute to the high stereospecificity of the Ni/BINAP-
mediated oxidative addition of the C–O bond, eventually
leading to the stereoinversion in the Kumada coupling.
Origins of stereospecificity of Kumada coupling. Based on the
free energy profile of the Ni/BINAP-catalyzed Kumada
coupling with benzylic ether 1 (Figure 1), oxidative addition of
the CO bond is irreversible and determines the overall
stereospecificity of the Kumada coupling. Figure 5 shows the
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Figure 5. Origins of stereospecificity of CO bond activation in the Kumada coupling. Energies are in kcal/mol.
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Experimental kinetic study of the Kumada coupling. To further
validate the computed mechanistic model of the Ni/BINAP-
catalyzed Kumada coupling with benzylic ether 1, experimental
kinetic studies were performed. Ether 25 was chosen as the
substrate for determination of the empirical rate law because the
cross-coupling reaction proceeds cleanly, without side products,
and at a rate that is convenient for kinetic analysis (eq 1).2a Our
primary interest was to determine the order of the reaction with
respect to the electrophile (25), nucleophile (MeMgI), and
catalyst.
Despite the fact that the reaction is zero order with respect to
MeMgI, we have observed discrepencies in reaction rate when
different batches of methyl Grignard reagent are employed. We
hypothesized that this discrepancy is caused by varying
quantities of magnesium iodide salts present in the Grignard
reagents.25,26 Indeed, we have observed that addition of MgI2
accelerates sluggish XC and XEC reactions.3a,8,32 These results
are consistent with the important role of the magnesium salts in
the calculations, serving as a Lewis acid to activate the substrate
for oxidative addition, as with prior proposed mechanisms for
allylic coupling reactions.22 As anticipated, Kumada coupling of
substrate 25 displays first order dependance on MgI2 (Figure
6d).
The empirical rate law generated for cross-coupling of ether
25 is below (eq 2). The reaction is first order with respect to
substrate 25, nickel catalyst, and Lewis acid MgI2. This rate law
is consistent with rate-determining oxidative addition via TS8
(Figure 1). Therefore, the empirically determined rate law and
DFT cacluations are consistent with the same mechanism.
Initial rate kinetic studies were performed under pseudo-first
order conditions monitoring formation of product 26 by gas
chromatography (Figure 6). Varying initial concentrations of
substrate 25 (Figure 6a), catalyst (Figure 6b), and Grignard re-
agent (Figure 6c), and analysis of the initial rates demonstrated
that the reaction is first order with respect to ether 25 and cata-
lyst, and zero order with respect to the Grignard reagent.
풅[ퟐퟔ]
= k[25]1[MeMgI]0[catalyst]1[MgI2]1
(2)
풅풕
0.16
0.24
0.18
0.12
0.08
0.04
0.00
0.12
y = 0.1236x + 0.0208
R² = 0.9778
y = 0.0070x + 0.0338
R² = 0.9813
0.06
0.00
0.0
0.2
0.4
0.6
0.8
1.0
0
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25
30
[catalyst]init (mM)
[25]init (mM)
0.06
0.04
0.02
0.00
0.24
0.18
0.12
0.06
0.00
y = 0.0019x + 0.0237
R² = 0.8974
y = 0.0248x + 0.0468
R² = 0.9849
0
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[MeMgI]init (mM)
[MgI2]init (mM)
Figure 6. Dependence of the initial rate (mM/min) for formation of product 26 on (a) [25]init (525 mM) with [MeMgI] = 0.50 M,
and [catalyst] = 0.1 mM in toluene; (b) [catalyst] (0.11.0 mM) with [25] = 10 mM, and [MeMgI] = 50 mM in toluene; (c) [MeMgI]
(210 mM) with [25] = 50 mM and [catalyst] = 0.5 mM in toluene; (d) added [MgI2] (0-6 mM) with [25] = 50 mM, [MeMgI] = 4
mM and [catalyst] = 0.5 mM in toluene.
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We next performed an experiment inspired by Blackmond’s Overall mechanism of Kumada coupling reaction. Based on the
same excess experiments (Figure 7).33 The reaction was
performed using several [MeMgI]init and monitored for
formation of product 25. Plotting [MeMgI] versus time (Figure
7a) and adjusting the time axis for the 10 mM and 4 mM
reactions allows for straightforward comparison of the slopes
(Figure 7b). This experiment confirmed that the reaction is
zero-order with respect to MeMgI. Importantly, we can also
conclude that the catalyst is not degrading over the course of the
reaction and that product 26 does not inhibit the reaction.
combined computational and experimental investigations, the
overall mechanism of the Kumada coupling is shown in Scheme
5. From the off-cycle resting state Ni(BINAP)2, ligand-
substrate exchange generates the on-cycle arene complex 7.
This species undergoes rate- and stereospecificity-determining
oxidative addition, which cleaves the CO bond of the benzylic
ether and irreversibly leads to the 3-benzyl nickel(II)
1
2
3
4
5
6
7
8
intermediate
9
with
stereoinversion.
Subsequent
transmetallation and reductive elimination steps are both facile
and do not alter the configuration of the benzylic stereogenic
center, producing the Kumada coupling product with inversion.
9
To further corroborate the computational and kinetic
findings that oxidative addition is the rate-determining step of
the cross-coupling reaction, we measured 13C kinetic isotope
effects using the Singleton method (Scheme 4).34 Benzylic ether
27 was designed as a suitable substrate, since the 13C spectrum
features disperse resonances, allowing for accurate integration.
The Kumada reaction was performed on a 10 mmol scale, and
the reaction was quenched when 7% of the starting material
remained. Analysis of the data indicated that C3 and C4
displayed a significant (>1.01) KIE. These results are also
consistent with rate-determining oxidative addition.
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Scheme 5. Overall mechanism of Kumada coupling.
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90
120
150
Time (min)
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1
Computational study of XEC mechanism. We next investigated
the reaction mechanism of Ni/BINAP-catalyzed XEC of 4-
chlorotetrahydropyrans (Scheme 1b). A major question at the
outset of these investigations was whether the reaction initates
with oxidative addition of the C–O or C–Cl bond. Four
proposed catalytic cycles are shown in Scheme 6; all account for
the observed stereospecific transformation of both the benzylic
ether and alkyl halide. Notably, these mechanisms bear little
similarity to the proposed mechanisms of related XEC reactions
of alkyl and aryl halides, due to the distinct substrates, reaction
conditions, and stereochemical outcomes.35,36
0
30
60
90
120
150
Time (min)
Figure 7. Same excess experiment. [MeMgI]init = 4 mM (), 8
mM (), and 10 mM (). (a) Grignard concentration over time
starting with different [MeMgI]init. (b) X-axis adjusted to over-
lay 10 and 4 mM reactions with 8 mM reaction.
Scheme 4. 13C KIE experiment and KIE numerical distribution
of Ni/BINAP-catalyzed Kumda coupling reaction.
We first consider two catalytic cycles that initiate by oxidative
addition of the benzylic ether (blue cycles). From the active
catalyst LnNi(0) A, the benzylic CO bond cleavage can occur
to generate the zwitterionic species H. Benzylnickel complex H
undergoes transmetallation with the Grignard reagent to form
LnNi(benzyl)(methyl) intermediate I. Subsequent CCl
cleavage can proceed via oxidative addition, leading to the
nickel(IV) intermediate J.37 Reductive elimination would
achieve cyclopropane formation. The resultant nickel(II)
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through formation of LnNi(alkyl)Cl species N. Subsequent
complex, L, can undergo a second transmetallation with the
1
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8
Grignard reagent to deliver LnNiMe2 species M, which
undergoes reductive elimination to provide ethane and
regenerate the active Ni(0) catalyst A. An alternative
mechanism involves direct transformation from benzylnickel
complex I to product K through an intramolecular SN2
reaction,38 in which the alkyl chloride is attacked by the
nucleophilic benzylnickel fragment39.
transmetallation with the Grignard reagent leads to
LnNi(alkyl)(methyl) intermediate O. From O, the CC bond
formation can occur via a sequential oxidative addition and
reductive elimination (O-P-Q), or an intramolecular SN2
reaction of alkyl chloride (O-Q). Nickel alkoxide complex Q
then undergoes a second transmetallation with the Grignard
reagent to release the XEC product and generate LnNiMe2 (M).
Reductive elimination from M regenerates the nickel(0) catalyst
accompanied by the release of ethane.
Alternatively, catalytic cycles can be considered wherein the
initial oxidative addition of nickel(0) catalyst occurs with the
alkylchloride moiety (red cycles). These cycles proceed
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Scheme 6. Proposed catalytic cycles of Ni-catalyzed cross-electrophile coupling of benzylic ether.
To discriminate between these mechanistic possibilities, we
began by evaluating the possible oxidative addition pathways
that could initate the catalytic cycles. We first studied the
coordination of the Lewis acidic Mg(II) species with benzylic
ether 29. Both oxygen and chlorine may coordinate to the Lewis
acidic Mg(II) species, and the free energy changes of the four
possible complexes are shown in Scheme 7. Similar to the
senario in Kumada coupling (Scheme 3), complex formation
with MgI2 is more favorable than that with MeMgI (30 vs. 32;
31 vs. 33). In addition, oxygen coordination is significantly
stronger than chlorine coordination (30 vs. 31; 32 vs. 33), which
is consistent with HSAB theory.40 Therefore, magnesium
complex 30 was employed in the catalytic cycle.
intermediate 36. This transition state is nearly identical to that
for oxidative addition in Kumada coupling (TS8, Figure 1).
Scheme 7. Free energy changes of complexation between
substrate 29 and Mg(II) species involved in XEC.
The free energy changes of the most favorable pathway of the
Ni/BINAP-catalyzed XEC with benzylic ether 29 are shown in
Figures
8 and 9. DFT-optimized structures of selected
intermediates and transition states are shown in Figure 10.
From the catalyst resting state Ni(BINAP)2 (6), the endergonic
ligand-substrate exchange delivers the (BINAP)Ni(substrate)
complex 34. Arene complex 34 then undergoes oxidative
addition by backside attack via TS35 to cleave the benzylic CO
bond with stereoinversion, generating the zwitterionic
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Figure 8. DFT-computed free energy changes of Ni/BINAP-catalyzed XEC with benzylic ether 29 (product formation).
Subsequent complexation with the Grignard reagent and
transmetallation through TS38 generates LnNi(benzyl)(methyl)
intermediate 39. From 39, coordination of the Grignard reagent
assists to promote intramolecular attack of the benzylnickel
moiety on the alkyl chloride via TS41. This intramolecular SN2
reaction produces cyclopropane product 42 and
(BINAP)Ni(Me)Cl 43, which results in inversion at both the
benzylic center and the alkyl halide.41 This key transition state
(TS41) can be visualized as an SE2 reaction, from the
perspective that a benzylmetal fragment attacks an electrophile,
resulting in inversion at the nucleophilic center. Noteably, the
arene is not coordinated to nickel during C–C bond formation
in TS41 (Figure 10), consistent with SE2 nomenclature (and not
SE’). It is also SN2-like because an alkyl halide is displaced via
backside attack, resulting in inversion at the electrophilic center.
Henceforth, we will refer to this step as an intramolecular SN2
reaction. The very low intramolecular SN2 barrier is due to the
similar geometries between the transition state TS41 and the
preceding intermediate 40 (Figure S9). The Hammond
postulate applies to this SN2 step: varying the halide leaving
group can lower the reaction barrier by making this step more
exothermic (Figure S10). We also considered the alternative
CC bond formation process without the assistance of Grignard
reagent, but this hypothetical process is less favorable (Figure
S11).
Completion of the catalytic cycle requires reduction of
(BINAP)Ni(Me)Cl 43 to regenerate the nickel(0) catalyst. The
free energy changes of the catalyst regeneration are shown in
Figure 9. From 43, transmetallation with Grignard reagent
occurs via TS44 to generate (BINAP)NiMe2 46. Subsequent
reductive elimination via TS47 produces (BINAP)Ni(ethane)
48, which then releases ethane to regenerate the active nickel(0)
catalyst for the next catalytic cycle.
Based on the free energy profile, the oxidative addition of the
C–O bond via TS35 determines the overall efficiency;
subsequent cyclopropane formation via TS41 is facile. The
stereospecificity of the XEC reaction is synergistically
controlled by two elementary steps: oxidative addition of the
benzylic ether via TS35 (which affects the benzylic stereogenic
center) and the intramolecular SN2 reaction of benzylnickel
intermediate via TS41 (which affects both stereogenic centers).
Figure 9. DFT-computed free energy changes of Ni/BINAP-
catalyzed XEC with benzylic ether 29 (catalyst regeneration).
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30
Figure 10. DFT-optimized structures of selected intermediates and transition states involved in Ni-catalyzed XEC.
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The alternative catalytic cycles involve initial CCl bond
cleavage, and the free energy changes of the competing path-
ways from the substrate-ligated catalyst, intermediate 34, are
shown in Figure 11. Oxidative addition of the benzylic CO
bond via TS35 is 18.8 kcal/mol more favorable than oxidative
addition of the CCl bond via TS50. We also located a number
of alternative transition states for oxidative addition of the CCl
bond; these transition states are less favorable than TS50 (Fig-
ure S12 and S13). Thus, irreversible benzylic CO bond activa-
tion initiates the catalytic cycle. Comparing the two competing
transition states, two factors contribute to the strong preference
towards benzylic CO bond activation. In TS35, naphthalene
coordination stabilizes the forming nickel(II) and leads to for-
mation of a stable -benzylnickel complex. Naphthalene coor-
dination in TS50 is impossible due to geometric constraints, and
the product of oxidative addition is a less stable alkylnickel com-
plex. In addition, the Lewis acidic magnesium co-catalysts favor
coordination to (and thus activation of) the benzylic ether
(Scheme 7). These factors combine to provide the remarkable
chemoselectivity of bond activation.
Figure 11. Comparison of oxidative addition of the CO and
CCl bonds.
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An alternative pathway for C–C bond formation is sequential
same chemoselectivity towards XEC product experimentally.3a
Our computations also corroborate this trend; details are in-
cluded in the Supporting Information (Figure S14).
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2
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8
oxidative addition and reductive elimination via nickel(IV)
intermediate J (blue cycle, Scheme 6). The free energy changes
of competing pathways from intermediate 39 are shown in
Figure 12. From 39, cyclization via TS41 is facile with a barrier
of 9.3 kcal/mol, while oxidative addition through TS52 is
significantly less favorable. Thus, the sequential oxidative
addition and reductive elimination involving a nickel(IV)
intermediate is not operative for this XEC reaction.
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60
Figure 13. Cross-electrophile coupling and Kumada coupling
product formation from intermediate 39.
Origins of stereospecificity of XEC. Two elementary steps, oxi-
dative addition of the benzylic CO bond and intramolecular
SN2 attack of the benzylnickel moiety on the pendant alkyl hal-
ide, control the overall stereospecificity of the XEC reaction.
The competing transition states for stereoinvertive and stere-
oretentive oxidative addition are shown in Figure 14a. CO
bond cleavage with inversion, via TS35, is more facile than that
with retention, via TS57. Notably, the calculated transitions
state for oxidative addition in the XEC reaction is almost iden-
tical to that in the Kumada coupling, consistent with the simi-
larity of the substrates (TS8, Figure 5 versus TS35, Figure 14a).
Subsequent cyclopropane formation impacts the
stereochemistry at both the benzylic and tertiary centers
(Figure 14b). Two possible transition states are shown in
Figure 14b. TS41 is the intramolecular SN2 transition state
where the benzylnickel complex approaches the back side of the
alkyl chloride. This attack inverts both stereogenic centers,
leading to the net retention at the benzylic position and
inversion at the alkyl chloride. TS58 is the competing attack of
the benzylnickel complex on the front side of the alkyl chloride,
which leads to stereoretention. TS41 is 8.4 kcal/mol more
favorable than TS58, which indicates a strong selectivity for
inversion at the alkyl chloride and is consistent with the
observed high stereospecificity of the reaction. This selectivity
is due to the intrinsic preference for back-side attack on alkyl
halides.41 Therefore, the benzylic stereogenetic center
undergoes two invertive elementary steps, oxidative addition
and intramolecular SN2 attack on the alkyl chloride, resulting in
net retention. In contrast, the tertiary alkyl stereogenic center
only undergoes one invertive step.
Figure 12. Free energy changes of the competing intramolecular
SN2 reaction and oxidative addition from intermediate 39.
Chemoselectivity between XEC and Kumada coupling. Simple
Kumada coupling of substrates such as 29 was never observed as
a competitive side reaction in XEC of these substrates. This ob-
servation was quite unexpected, since Kumada coupling does
not require formation of a strained ring, and it was anticipated
that dialkylnickel intermediates such as 39 could undergo re-
ductive elimination. To better understand the striking
chemoselectivity, we sought to compare these alternative path-
ways. The free energy changes of these competing pathways
from alkylnickel complex 39 are shown in Figure 13. Reductive
elimination transition state TS54 is 18.3 kcal/mol higher in free
energy as compared to the intramolecular SN2 transition state
TS41. These energy differences are consistent with the com-
plete selectivity for XEC over XC observed experimentally
(Scheme 1b). Therefore, facile cyclopropane formation drives
alkylnickel complex 39 towards the desired cross-electrophile
coupling, which prevents background Kumada coupling. The
chemoselectivity does not depend on the stereochemistry of the
alkyl chloride, both the cis- and trans-substrates exhibit the
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Figure 14. Stereospecificity of the CO bond cleavage(a) and intramolecular SN2 reaction(b). Free energies are in kcal/mol.
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Experimental analysis of XEC. To validate the computed reac-
tion mechanism, we measured the 13C kinetic isotope effects
(KIE) using Singleton’s method.34 We anticipated that 13C
KIE’s would distinguish whether the rate-determining step in-
volves the benzylic stereocenter, the alkyl chloride, or both.
Tetrahydropyran 29 was subjected to the cross-electrophile
coupling reaction conditions on a 4 mmol scale. The reaction
was quenched when 6% of 29 remained (Scheme 8a). NMR
analysis determined that C11 was the only carbon that had a sig-
nificant (>1.01) KIE (Scheme 8b). The presence of a KIE at
C11 and the absence of a KIE at C13 are consistent with oxida-
tive addition into the benzylic CO as the rate-determining step
for product formation.
29 should be more facile than oxidative addition of 2-
phenyltetrahydropyran 60 because of the lower aromatic
stabilization energy of the naphthyl moiety as compared to an
isolated phenyl ring (Scheme 9a).29,42 Therefore, these
substrates should react with different rates if oxidative addition
of the C–O bond is rate-determining, but similar rates if
oxidative addition of the C–Cl bond is rate-determining. When
subjected
to
a
competition
experiment,
2-
naphthyltetrahydropyran 29 underwent the ring contraction to
generate an 88% yield of cyclopropane 59, while 2-
phenyltetrahydropyran 60 was recovered in an 89% yield
without the formation of any phenylcyclopropane 61 (Scheme
9a). Similarly, allylic ether 62 should outcompete benzylic ether
29 if oxidative addition of the C–O is rate-determining (Scheme
9b). As expected, vinylcyclopropane 63 is generated in a higher
yield (71%, Scheme 9b) than naphthylcyclopropane 59 (12%,
Scheme 9b). These results are consistent with oxidative
addition into the C–O bond as the first step of the cross-
electrophile coupling reaction rather than oxidative addition
into the C–Cl bond. They are also consistent with rate-
determining oxidative addition of the C–O bond.
Scheme 8. 13C KIE experiment and KIE numerical distribution
of Ni/BINAP-catalyzed cross-electrophile coupling.
Overall mechanism of XEC. Based on the combined
computational and experimental investigations, the overall
mechanism of the XEC reaction is shown in Scheme 10. From
the off-cycle resting state Ni(BINAP)2, ligand-substrate
exchange generates the on-cycle arene complex 34. This active
species undergoes oxidative addition to cleave the benzylic
CO bond with stereoinversion, leading to benzylnickel(II)
intermediate 36. Subsequent transmetallation with the
Grignard reagent generates the benzylnickel complex 39. The
tethered alkyl chloride is then attacked by the electron-rich
benzylnickel moiety in an intramolecular SN2 reaction. This
CC bond forming step generates the cyclopropane, with
To corroborate the computational findings that the cross-
electrophile coupling reaction initiates by oxidative addition of
the benzylic ether, and not at the alkyl chloride, we designed a
series of competition experiments (Scheme 9). Oxidative
addition into the benzylic ether of 2-naphthyltetrahydropyran
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inversion of both stereogenic centers. Catalyst regeneration is
accomplished by transmetallation with an additional equivalent
of Grignard reagent and reductive elimination to form ethane.
Scheme 10. Overall mechanism of cross-electrophile coupling
reaction.
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5
Scheme 9. Competition experiments to distinguish rate-
determining oxidative addition of C–O versus C–Cl.
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Scheme 11. Unified mechanism for Kumada and cross-electrophile coupling reactions.
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Comparison between Kumada and cross-electrophile coupling
net inversion at the benzylic stereocenter. The empirical rate
law and 13C KIE’s are consistent with this proposed mechanism.
Cross-electrophile coupling initiates with the same invertive
oxidative addition of the benzylic C–O bond and transmetalla-
tion step. This is supported by DFT calculations, competition
experiments, and measured 13C KIE’s. At this point, the mecha-
nisms diverge. Due to the presence of the pendant secondary
alkyl chloride, the electron-rich benzylnickel moiety can attack
via a facile intramolecular SN2 reaction. This efficient step pro-
duces the strained cyclopropane ring with inversion at both ste-
reocenters. It also outcompetes the reductive elimination for
Kumada coupling, leading to excellent control of chemoselec-
tivity. Over the course of the mechanism, the benzylic position
reacts twice with inversion, resulting in net retention at this po-
sition, while the alkyl chloride reacts with inversion. This mech-
anism is distinct from those typically proposed for XEC reac-
tions of alkyl and aryl halides, as it does not involve alkyl radical
intermediates or odd-electron nickel complexes.
These combined computational and experimental results
provide a refined understanding of the reactions of ether elec-
trophiles with nickel(0) catalysts, including the critical role of
Lewis acidic co-catalysts. We characterize two-electron oxida-
tive addition and intramolecular SN2 reactions, providing in-
sight into the transition states that lead to stereospecific reac-
tions. We anticipate that this improved understanding will facil-
itate the design of new stereospecific catalytic reactions includ-
ing those that involve oxidative addition of C(sp3)–O bonds.
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8
reaction. Based on above mechanistic studies, a unified
mechanistic picture of Ni-catalyzed Kumada coupling and XEC
reactions is shown in Scheme 11. Starting from the
(BINAP)Ni(substrate) complex I, both Kumada coupling and
XEC reactions proceed via stereoinvertive oxidative addition of
the benzylic CO bond. This step is facilitated by MgI2, which
serves as a Lewis acid to activate the leaving group, and is rate-
determining for formation of both XC and XEC products.
Benzylnickel(II)
intermediate
II
then
undergoes
9
transmetallation with the Grignard reagent to form
(BINAP)Ni(benzyl)(methyl), IV. From IV, the mechanistic
pathways of Kumada coupling and XEC divert. Direct
C(benzyl)C(methyl) reductive elimination produces the
Kumada coupling product and regenerates the active nickel(0)
catalyst, which completes the catalytic cycle of Kumada
coupling. However, if the secondary alkyl chloride is present, as
in an XEC reaction, facile intramolecular SN2 attack occurs to
form the cyclopropane ring. Subsequent transmetallation and
reductive elimination regenerates the nickel(0) catalyst for next
catalytic cycle of the XEC reaction.
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Competition experiment between Kumada coupling and XEC
reactions. To challenge our unified mechanistic understanding
of the Kumada and cross-electrophile coupling reactions, we
performed a competition experiment (Scheme 12). Based on
the calculated free energy diagrams, both reactions share a rate-
determining oxidative addition step with a similar barrier height.
Therefore, in a competition reaction, a Kumada-type and cross-
electrophile-type substrate should be consumed with similar
rates. Indeed, subjecting a mixture of tetrahydropyrans 1 and 29
to the standard reaction conditions produced a similar amount
of ring-opened Kumada product (25%) and cyclopropane XEC
product (31%). These results corroborate our proposed
mechanisms for the Kumada and XEC reactions, and support a
similar oxidative addition event in both catalytic cycles.
ASSOCIATED CONTENT
Supporting Information.
Additional computational results. Coordinates and energies of
DFT-computed stationary points. General information for experi-
ments. Detailed results of experiments. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
Scheme 12. Competition experiment between Kumada and
cross-electrophile coupling.
*erjarvo@uci.edu
*hxchem@zju.edu.cn
ORCID
Erika L. Lucas: 0000-0003-0714-3517
Emily J. Tollefson: 0000-0002-8681-6232
Buck L. H. Taylor: 0000-0002-6586-3865
Elizabeth R. Jarvo: 0000-0002-2818-4038
Xin Hong: 0000-0003-4717-2814
Author Contributions
Conclusions.
In summary, the reaction mechanism and origins of chemose-
lectivity and stereospecificity of Ni-catalyzed Kumada and
cross-electrophile coupling reactions of benzylic ethers have
been defined using a combined computational and experi-
mental approach. Kumada coupling proceeds via a classical
cross-coupling mechanism. Rate- and stereospecificity-deter-
mining oxidative addition occurs to cleave the CO bond of the
benzylic ether and inverts the benzylic stereogenic center. Sub-
sequent transmetallation with the Grignard reagent and syn re-
ductive elimination produce the Kumada coupling product with
§
These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Natural Science Foundation of
China (21702182, 21873081, X. H.), US National Institutes of
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Health NIGMS (R01GM100212, E. R. J.) Zhejiang University, and
the Chinese “Thousand Youth Talents Plan” is gratefully acknowl-
edged. Calculations were performed on the high performance com-
puting system at Department of Chemistry, Zhejiang University.
33073310. (e) Zhou, Q.; Cobb, K. M.; Tan, T.; Watson, M. P. Stere-
ospecific Cross Couplings to Set Benzylic, All-Carbon Quaternary Ste-
reocenters in High Enantiopurity. J. Am. Chem. Soc. 2016, 138,
1205712060.
1
2
3
(6) Allylic ethers undergo facile and stereospecific cross-coupling em-
ploying nickel catalysts, see: (a) Takahashi, T. and Kanno, K. Nickel-
Catalyzed Cross-Coupling Reactions. In Modern Organonickel Chemis-
try; Tamaru, Y. Ed.; Wiley-VCH: Weinheim, 2005; p47. (b) Consiglio,
G.; Morandini, F.; Piccolo, O. Stereochemical Aspects of the Nickel-
Catalyzed Alkylation of Allylic Alcohols. J. Am. Chem. Soc. 1981, 103,
1846–1847. (c) Kobayashi, Y.; Ikeda, E. Nickel-Catalysed Substitution
Reactions of Allylic Carbonates with Aryl- and Alkenyl-Borates. J.
Chem. Soc., Chem. Commun. 1994, 1789–1790. (d) Didiuk, M. T.;
Morken, J. P.; Hoveyda, A. H. Phosphine-Directed Stereo- & Regiose-
lective Ni-Catalyzed Reactions of Grignard Reagents with Allylic
Ethers. Tetrahedron, 1998, 54, 1117–1130. (e) Zhou, Q.; Srinivas, H.
D.; Zhang, S.; Watson, M. P. Accessing Both Retention and Inversion
Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of
Allylic Pivalates. J. Am. Chem. Soc. 2016, 138, 1198911995.
4
5
6
7
8
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REFERENCES
(1) (a) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: In-
creasing Saturation as an Approach to Improving Clinical Success. J.
Med. Chem. 2009, 52, 6752−6756. (b) Geist, E.; Kirschning, A.;
Schmidt, T. sp3sp3 Coupling Reactions in the Synthesis of Natural
Products and Biologically Active Molecules. Nat. Prod. Rep. 2014, 31,
441448. (c) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Enanti-
oselective and Enantiospecific Transition-Metal-Catalyzed Cross-Cou-
pling Reactions of Organometallic Reagents to Construct C–C Bonds.
Chem. Rev. 2015, 115, 9587–9652. (d) Jana, R.; Pathak, T. P.; Sigman,
M. S. Advances in Transition Metal (Pd, Ni, Fe)-Catalyzed Cross-Cou-
pling Reactions Using Alkyl-organometallics as Reaction Partners.
Chem. Rev. 2011, 111, 1417–1492. (e) Choi, J.; Fu, G. C. Transition
Metal-Catalyzed Alkyl-Alkyl Bond Formation: Another Dimension in
Cross-Coupling Chemistry. Science. 2017, 356, eaaf7230. (f) Lucas, E.
L.; Jarvo, E. R. Stereospecific and Stereoconvergent Cross-Couplings
Between Alkyl Electrophiles. Nat. Rev. Chem. 2017, 1, 0065.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Zhang, S.-Q.; Taylor, B. L. H.; Ji, C.-L.; Gao, Y.; Harris, M. R.;
Hanna, L. E.; Jarvo, E. R.; Houk, K. N.; Hong, X. Mechanism and Ori-
gins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki–
Miyaura Coupling with Benzylic Esters: A Computational Study. J. Am.
Chem. Soc. 2017, 139, 1299413005.
(2) (a) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. Stere-
ospecific Nickel-Catalyzed Cross-Coupling Reactions of Alkyl Ethers:
Enantioselective Synthesis of Diarylethanes. J. Am. Chem. Soc. 2011,
133, 389391. (b) Harris, M. R.; Hanna, L. E.; Greene, M. A.; Moore,
C. E.; Jarvo, E. R. Retention or Inversion in Stereospecific Nickel-Cat-
alyzed Cross-Coupling of Benzylic Carbamates with Arylboronic Esters:
Control of Absolute Stereochemistry with an Achiral Catalyst. J. Am.
Chem. Soc. 2015, 135, 33033306. (c) Wisniewska, H. M.; Swift, E. C.;
Jarvo, E. R. Functional-Group-Tolerant, Nickel-Catalyzed Cross-Cou-
pling Reaction for Enantioselective Construction of Tertiary Methyl-
Bearing Stereocenters. J. Am. Chem. Soc. 2013, 135, 90839090. (d)
Harris, M. R.; Konev, M. O.; Jarvo, E. R. Enantiospecific Intramolecu-
lar Heck Reactions of Secondary Benzylic Ethers. J. Am. Chem. Soc.
2014, 136, 78257828. (e) Tollefson, E. J., Hanna, L. E.; Jarvo, E. R.
Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic
Ethers and Esters. Acc. Chem. Res. 2015, 48, 23442353.
(8) Tollefson, E. J.; Dawson, D. D.; Osborne, C. A.; Jarvo, E. R. Stere-
ospecific Cross-Coupling Reactions of Aryl-Substituted Tetrahydrofu-
rans, Tetrahydropyrans, and Lactones. J. Am. Chem. Soc. 2014, 136,
1495114958.
(9) For related computational studies on Ni-catalyzed C–O bond acti-
vation, see: (a) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L. Mecha-
nism of Ni-Catalyzed Selective C−O Bond Activation in Cross-Cou-
pling of Aryl Esters. J. Am. Chem. Soc. 2009, 131, 88158823. (b) Hong,
X.; Liang, Y.; Houk, K. N. Mechanisms and Origins of Switchable
Chemoselectivity of Ni-Catalyzed C(aryl)–O and C(acyl)–O Activa-
tion of Aryl Esters with Phosphine Ligands. J. Am. Chem. Soc. 2014, 136,
20172025. (c) Lu, Q.; Yu, H.; Fu, Y. Mechanistic Study of Chemose-
lectivity in Ni-Catalyzed Coupling Reactions Between Azoles and Aryl
Carboxylates. J. Am. Chem. Soc. 2014, 136, 82528260. (d) Xu, H.;
Muto, K.; Yamaguchi, J.; Zhao, C.; Itami, K.; Musaev, D. G. Key Mech-
anistic Features of Ni-Catalyzed C–H/C–O Biaryl Coupling of Azoles
and Naphthalen-2-yl Pivalates. J. Am. Chem. Soc. 2014, 136,
1483414844. (e) Liu, X.-Q.; Hsiao, C.-C.; Kalvet, I.; Leiendecker, M.;
Guo, L.; Schoenebeck, F.; Rueping, M. Lewis Acid Assisted Nickel-
Catalyzed Cross-Coupling of Aryl Methyl Ethers by C−O Bond-Cleav-
ing Alkylation: Prevention of Undesired β-Hydride Elimination. Angew.
Chem. Int. Ed. 2016, 55, 60936098. (f) Yang, Z.-K.; Wang, C.;
Uchiyama, M. DFT Studies Provide Mechanistic Insight into Nickel-
Catalyzed Cross-Coupling Involving Organoaluminum-Mediated C–O
Bond Cleavage. Synlett. 2017, 28, 25652568. (g) Schwarzer, M. C.;
Konno, R.; Hojo, T.; Ohtsuki, A.; Nakamura, K.; Yasutome, A.;
Takahashi, H.; Shimasaki, T.; Tobisu, M.; Chatani, N.; Mori, S. Com-
bined Theoretical and Experimental Studies of Nickel-Catalyzed
Cross-Coupling of Methoxyarenes with Arylboronic Esters via C–O
Bond Cleavage. J. Am. Chem. Soc. 2017, 139, 1034710358. (h) Xu, Z.;
Yang, Y.; Jiang, J.; Fu, Y. Theoretical Investigation on Ni-Catalyzed
C(sp3)F Activation and Ring Contraction of Tetrahydropyrans: Ex-
ploration of an SN2 Pathway. Organometallics. 2018, 37, 11141122.
(3) (a) Tollefson, E. J.; Erickson, L. W.; Jarvo, E. R. Stereospecific In-
tramolecular Reductive Cross-Electrophile Coupling Reactions for Cy-
clopropane Synthesis. J. Am. Chem. Soc. 2015, 137, 97609763. (b) See
reference 1f.
(4) For reviews and representative experimental studies of cross-cou-
pling reactions of phenol derivatives, see: (a) Yu, D.-G.; Li, B.-J.; Shi,
Z.-J. Exploration of New C−O Electrophiles in Cross-Coupling Reac-
tions. Acc. Chem. Res. 2010, 43, 14861495. (b) Rosen, B. M.; Quasdorf,
K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec,
V. Nickel-Catalyzed Cross-Couplings Involving Carbon−Oxygen
Bonds. Chem. Rev. 2011, 111, 13461416. (c) Tobisu, M.; Chatani, N.
Cross-Couplings Using Aryl Ethers via CO Bond Activation Enabled
by Nickel Catalysts. Acc. Chem. Res. 2015, 48, 17171726. (d) Zarate,
C.; van Gemmeren, M.; Somerville, R. J.; Martin, R. Phenol Derivatives:
Modern Electrophiles in Cross-Coupling Reactions. Adv. Organomet.
Chem. 2016, 66, 143222.
(5) For reviews and representative experimental studies of related
cross-coupling reactions of alcohol derivatives: (a) see reference 4a. (b)
Guan, B.-T.; Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.; Zhao, K.-
Q.; Shi, Z.-J. Direct Benzylic Alkylation via Ni-Catalyzed Selective Ben-
zylic sp3 C−O Activation. J. Am. Chem. Soc. 2008, 130, 3268–3269. (c)
Pound, S. M.; Watson, M. P. Asymmetric Synthesis via Stereospecific
C–N and C–O Bond Activation of Alkyl Amine and Alcohol Derivatives.
Chem. Commun. 2018, 54, 12286–12301. (d) Zhou, Q.; Srinivas, H. D.;
Dasgupta, S.; Watson, M. P. Nickel-Catalyzed Cross-Couplings of Ben-
zylic Pivalates with Arylboroxines: Stereospecific Formation of Dia-
rylalkanes and Triarylmethanes. J. Am. Chem. Soc. 2013, 135,
(10) Lucas, E. L.; Jarvo, E. R. Keeping Track of the Electrons. Acc.
Chem. Res. 2018, 51, 567–572.
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Pe-
tersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Iz-
maylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
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Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
Aryl, and Alkenyl Grignard Reagents with Aryl and Alkenyl Grignard
Reagents with Aryl and Alkenyl Halides: General Scope and Limita-
tions. Bull. Chem. Soc. Jpn. 1976, 49, 19581969.
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannen-
berg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.;
Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian 09, revision C.01;
Gaussian Inc.: Wallingford, CT, 2016.
1
2
3
4
5
6
7
8
(22) Felkin, H.; Swierczevski, G. Stereochemical Evidence in Favour
of -Allylnickel Intermediates in the Formation of Olefins from Allylic
Alcohols and Grignard Reagents, Catalysed by Nickel Complexes. Tet-
rahedron Lett. 1972, 13, 14331436.
(23) (a) Jonas, K.; Pörschke, K. R.; Krüger, C.; Tsay, Y.-H. Carbanion
Complexes of Nickel(0). Angew. Chem., Int. Ed. Engl. 1976, 15,
621622. (b) Terao, J.; Kambe, N. Cross-Coupling Reaction of Alkyl
Halides with Grignard Reagents Catalyzed by Ni, Pd, or Cu Complexes
with -Carbon Ligands(s). Acc. Chem. Res. 2008, 41, 1545–1554.
(12) (a) Becke, A. D. Density Functional Thermochemistry. III. The
Role of Exact Exchange. J. Chem. Phys. 1993, 98, 56485652. (b) Lee,
C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correla-
tion-Energy Formula into a Functional of the Electron Density. Phys.
Rev. B. 1988, 37, 785789.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24) The dimer form of Grignard reagent involves two solvent (dime-
thyl ether) ligands. For related mechanistic studies involving Grignard
reagent, see: (a) Ashby, E. C.; Smith, M. B. Concerning the Structure
of the Grignard Reagent. II.1 In Diethyl Ether. Relevance of Grignard
Composition to the Mechanism of Addition to Ketones. J. Am. Chem.
Soc. 1964, 86, 4363−4370. (b) Jiménez-Osés, G.; Brockway, A. J.; Shaw,
J. T.; Houk, K. N. Mechanism of Alkoxy Groups Substitution by Gri-
gnard Reagents on Aromatic Rings and Experimental Verification of
Theoretical Predictions of Anomalous Reactions. J. Am. Chem. Soc.
2013, 135, 6633−6642.
(13) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Tri-
ple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: De-
sign and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7,
3297–3305.
(14) Grimme, S., Anthony, J., Ehrlich, S.; Krieg, H. A Consistent and
Accurate Ab Initio Parametrization of Density Functional Dispersion
Correction (DFT-D) for the 94 Elements H-Pu. J. Chem. Phys. 2010,
132, 154104−1−154104−19.
(25) Schlenk, W.; Schlenk, W. Ü ber die Konstitution der Gri-
gnardschen Magnesiumverbindungen. Ber. Dtsch. Chem. Ges. B. 1929,
(15) Weigend, F. Accurate Coulomb-Fitting Basis Sets for H to Rn.
Phys. Chem. Chem. Phys. 2006, 8, 1057−1065.
62, 920−924.
(16) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation
Model Based on Solute Electron Density and on a Continuum Model
of the Solvent Defined by the Bulk Dielectric Constant and Atomic Sur-
face Tensions. J. Phys. Chem. B. 2009, 113, 63786396.
(26) (a) Wurtz, A. Sur une nouvelle classe de radicaux organiques. An-
nales de chimie et de physique. 1855, 44, 275–312. (b) Wurtz, A. Ueber
eine neue Klasse organischer Radicale. Annalen der Chemie und Phar-
macie. 1855, 96, 364–375.
(17) Legault, C. Y. CYLview, version 1.0b; Universitꢀ de Sherbrooke,
2009 (http://www.cylview.org).
(27) For simplicity, DFT calculations were performed using (R)-
BINAP as the ligand and (2S,4R)-1 and (2S,4R)-24. In experimental
studies, it has been demonstrated that there is no match/mismatch ef-
fect between the enantiomers of BINAP and substrate. See references
3a and 8.
(18) Martin, R. L.; Hay, P. J.; Pratt, L. R. Hydrolysis of Ferric Ion in
Water and Conformational Equilibrium. J. Phys. Chem. A. 1998, 102,
35653573.
(19) (a) Yu, Z. X.; Houk, K. N. Intramolecular 1,3-Dipolar Ene Reac-
tions of Nitrile Oxides Occur by Stepwise 1,1-Cycloaddition/Retro-
Ene Mechanisms. J. Am. Chem. Soc. 2003, 125, 13825–13830. (b) Chen,
Y.; Ye, S.; Jiao, L.; Liang, Y.; Sinha-Mahapatra, D. K.; Herndon, J. W.;
Yu, Z.-X. Mechanistic Twist of the [8+2] Cycloadditions of Dienyl-
isobenzofurans and Dimethyl Acetylenedicarboxylate:ꢀ Stepwise [8+2]
versus [4+2]/[1,5]-Vinyl Shift Mechanisms Revealed through a Theo-
retical and Experimental Study. J. Am. Chem. Soc. 2007, 129, 10773–
10784. (c) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Mechanism, Re-
gioselectivity, and the Kinetics of Phosphine-Catalyzed [3+2] Cy-
cloaddition Reactions of Allenoates and Electron-Deficient Alkenes.
Chem. - Eur. J. 2008, 14, 43614373.
(28) For a related experimental study that confirms the stability of
Ni((R)-BINAP)2 species, see: Ge, S.-Z.; Green, R. A.; Hartwig, J. F.
Controlling First-Row Catalysts: Amination of Aryl and Heteroaryl
Chlorides and Bromides with Primary Aliphatic Amines Catalyzed by a
BINAP-Ligated Single-Component Ni(0) Complex. J. Am. Chem. Soc.
2104, 136, 1617−1627.
(29) Given a comparison between -extended systems and regular
arenes, a scenario that the former binds more strongly to low-valent
metal complexes in an 2-fashion than the latter is probably due to the
retention of a certain degree of aromaticity. For a related study, see:
Bauer, D. J.; Krueger, C. Bonding of Aromatic Hydrocarbons to
Nickel(0). Structure of Bis(tricyclohexylphosphine)(1,2-.eta.2-anthra-
cene)nickel(0)-toluene. Inorg. Chem. 1977, 16, 884891.
(20) (a) Li, H.; Jiang, J.; Lu, G.; Huang, F.; Wang, Z.-X. On the “Re-
verse Gear” Mechanism of the Reversible Dehydrogenation/Hydro-
genation of a Nitrogen Heterocycle Catalyzed by a Cp*Ir Complex: A
Computational Study. Organometalics. 2011, 30, 31313141. (b) Li, H.;
Wen, M.; Wang, Z.-X. Computational Mechanistic Study of the Hydro-
genation of Carbonate to Methanol Catalyzed by the RuIIPNN Com-
plex. Inorg. Chem. 2012, 51, 57165727. (c) Wen, M.; Huang, F.; Lu,
G.; Wang, Z.-X. Density Functional Theory Mechanistic Study of the
Reduction of CO2 to CH4 Catalyzed by an Ammonium Hydridoborate
Ion Pair: CO2 Activation via Formation of a Formic Acid Entity. Inorg.
Chem. 2013, 52, 1209812107. (d) Qu, S.; Dang, Y.; Song, C.; Wen,
M.; Huang, K.−W.; Wang, Z.−X. Catalytic Mechanisms of Direct Pyr-
role Synthesis via Dehydrogenative Coupling Mediated by PNP-Ir or
PNN-Ru Pincer Complexes: Crucial Role of Proton-Transfer Shuttles
in the PNP-Ir System. J. Am. Chem. Soc. 2014, 136, 49744991.
(30) For early studies relates to distortion/interaction analysis, see: (a)
Kitaura, K.; Morokuma, K. A New Energy Decomposition Scheme for
Molecular Interactions within the Hartree-Fock Approximation. Int. J.
Quantum Chem. 1976, 10, 325340. (b) Ziegler, T.; Rauk, A. A Theo-
retical Study of the Ethylene-Metal Bond in Complexes between Cop-
per(1+), Silver(1+), Gold(1+), Platinum(0) or Platinum(2+) and
Ethylene, Based on the Hartree-Fock-Slater Transition-State Method.
Inorg. Chem. 1979, 18, 15581565.
(31) For reviews of distortion/interaction analysis, see: (a) van Leeu-
wen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Ligand
Bite Angle Effects in Metal-catalyzed C−C Bond Formation. Chem. Rev.
2000, 100, 27412770. (b) Van Zeist, W.-J.; Bickelhaupt, F. M. The
Activation Strain Model of Chemical Reactivity. Org. Biomol. Chem.
2010, 8, 31183127. (c) Fernandez, I.; Bickelhaupt, F. M. The Activa-
tion Strain Model and Molecular Orbital Theory: Understanding and
Designing Chemical Reactions. Chem. Soc. Rev. 2014, 43, 49534967.
(21) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M. Nickel-Phosphine
Complex-Catalyzed Grignard Coupling. I. Cross-Coupling of Alkyl,
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Page 16 of 17
(d) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the
(41) (a) Anh, N. T.; Minot, C. Conditions Favoring Retention of Con-
Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed.
2017, 56, 1007010086.
figuration in SN2 Reactions. A Perturbational Study. J. Am. Chem. Soc.
1980, 102, 103107. (b) Glukhovtsev, M. N.; Pross, A.; Schlegel, H. B.;
Bach, R. D.; Radom, L. Gas-Phase Identity SN2 Reactions of Halide An-
ions and Methyl Halides with Retention of Configuration. J. Am. Chem.
Soc. 1996, 118, 1125811264.
1
2
3
4
5
6
7
8
(32) (a) Greene, M. A.; Yonova, I. M.; Williams, F. J.; Jarvo, E. R.
Traceless Directing Group for Stereospecific Nickel-Catalyzed Al-
kylAlkyl Cross-Coupling Reactions. Org. Lett. 2012, 14, 42934296.
(b) Dawson, D. D.; Jarvo, E. R. Stereospecific Nickel-Catalyzed Cross-
Coupling Reactions of Benzylic Ethers with Isotopically-Labeled Gri-
gnard Reagents. Org. Process. Res. Dev. 2015, 19, 1356–1359.
(42) For representative studies on C−O bond activation in which the
presence of -extended systems was required, see: (a) reference 5b (b)
Tobisu, M.; Shimasaki, T.; Chatani, N. Nickel-Catalyzed Cross-Cou-
pling of Aryl Methyl Ethers with Aryl Boronic Esters. Angew. Chem., Int.
Ed. 2008, 47, 48664869.
(33) Blackmond, D. G. Reaction Progress Kinetic Analysis: A Powerful
Methodology for Mechanistic Studies of Complex Catalytic Reactions.
Angew. Chem. Int. Ed. 2005, 44, 43024320.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(34) Singleton, D. A.; Thomas, A. A. High-Precision Simultaneous De-
termination of Multiple Small Kinetic Isotope Effects at Natural Abun-
dance. J. Am. Chem. Soc. 1995, 117, 93579358.
(35) (a) Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-
Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl Hal-
ides. J. Am. Chem. Soc. 2013, 135, 16192–16197. (b) Cherney, A. H.,
Kadunce, N. T.; Reisman, S. E. Catalytic Asymmetric Reductive Acyl
Cross-Coupling: Synthesis of Enantioenriched Acyclic -Disubsti-
tuted Ketones. J. Am. Chem. Soc. 2013, 135, 7442–7445. (c) Knappke,
C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi von
Wangelin, A. Reductive Cross-Coupling Reactions between Two Elec-
trophiles. Chem. Eur. J. 2014, 20, 6828–6842. (d) Weix, D. J. Methods
and Mechanisms for Cross-Electrophile Coupling of Csp2 Halides with
Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767–1775. (e)See refer-
ence 1f.
(36) Intermolecular reactions of allylnickel complexes with alkyl bro-
mides result in racemization of the alkyl halide and are proposed to pro-
ceed via a radical chain mechanism. See: Hegedus, L. S.; Miller, L. L.
Reactions of -Allylnickel Bromide Complexes with Organic Halides.
Stereochemistry and Mechanism. J. Am. Chem. Soc. 1975, 97, 459–460.
(37) (a) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N.
Nickel-Catalyzed Cross-Coupling Reaction of Grignard Reagents with
Alkyl Halides and Tosylates: Remarkable Effect of 1,3-Butadienes. J.
Am. Chem. Soc. 2002, 124, 42224223. (b) Terao, J.; Ikumi, A.; Kuni-
yasu, H.; Kambe, N. Ni- or Cu-Catalyzed Cross-Coupling Reaction of
Alkyl Fluorides with Grignard Reagents. J. Am. Chem. Soc. 2003, 125,
56465647. (c) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe,
N. Nickel-Catalyzed Cross-Coupling Reaction of Alkyl Halides with
Organozinc and Grignard Reagents with 1,3,8,10-Tetraenes as Addi-
tives. Angew. Chem. Int. Ed. 2004, 43, 61806182. (d) See reference
23b.
(38) (a) Chan, T. H.; Fleming, I. Electrophilic Substitution of Organo-
silicon Compounds- Applications to Organic Synthesis. Synthesis. 1979,
761786. (b) Sakurai, H. Reactions of Allylsilanes and Application to
Organic Synthesis. Pure Appl. Chem. 1982, 54, 122.
(39) (a) Corey, E. J.; Semmelhack, M. F. Organonickel Compounds as
Reagents for Selective Carbon-Carbon Bond Formation Between Un-
like Groups. J. Am. Chem. Soc. 1967, 89, 27552757. (b) Hegedus, L.
S.; Wagner, S. D.; Waterman, E. L.; Siirala-Hansen, K. Reaction of -
Allylnickel Bromide Complexes with Ketones and Aldehydes. Synthe-
sis of -Methylene--Butyrolactones. J. Org. Chem. 1975, 40, 593−598.
(c) Johnson, J. R.; Tully, P. S.; Mackenzie, P. B.; Sabat, M. A Practical
Reversed-Polarity Alternative to Organocuprate Conjugate Addition
Chemistry. Halocarbon Coupling Reactions of Enal- and Enone-De-
rived Allylnickel Reagents. J. Am. Chem. Soc. 1991, 113, 6172−6177. (d)
Kondo, T.; Ono, H.; Satake, N.; Mitsudo, T.; Watanabe, Y. Nucleo-
philic and Electrophilic Allylation Reactions. Synthesis, Structure, and
Ambiphilic Reactivity of (3-Allyl)ruthenium(II) Complexes. Organo-
metallics. 1995, 14, 1945−1953.
(40) Pearson, R. G. Hard and Soft Acids and Bases, HSAB, Part I: Fun-
damental Principles. J. Chem. Educ. 1968, 45, 581587.
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