Bimetallic oxidative addition involving radical intermediates in nickel-catalyzed alkyl-alkyl Kumada coupling reactions

Article abstract of DOI:10.1021/ja4051923

Many nickel-based catalysts have been reported for cross-coupling reactions of nonactivated alkyl halides. The mechanistic understanding of these reactions is still primitive. Here we report a mechanistic study of alkyl-alkyl Kumada coupling catalyzed by a preformed nickel(II) pincer complex ([(N ₂N)Ni-Cl]). The coupling proceeds through a radical process, involving two nickel centers for the oxidative addition of alkyl halide. The catalysis is second-order in Grignard reagent, first-order in catalyst, and zero-order in alkyl halide. A transient species, [(N₂N)Ni-alkyl ²](alkyl²-MgCl), is identified as the key intermediate responsible for the activation of alkyl halide, the formation of which is the turnover-determining step of the catalysis.

Full text of DOI:10.1021/ja4051923

Article
pubs.acs.org/JACS
Bimetallic Oxidative Addition Involving Radical Intermediates in
Nickel-Catalyzed Alkyl−Alkyl Kumada Coupling Reactions
Jan Breitenfeld, Jesus Ruiz, Matthew D. Wodrich, and Xile Hu*
́ ́
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne (EPFL), ISIC-LSCI, BCH 3305,
Lausanne, CH 1015, Switzerland
S
* Supporting Information
ABSTRACT: Many nickel-based catalysts have been reported
for cross-coupling reactions of nonactivated alkyl halides. The
mechanistic understanding of these reactions is still primitive.
Here we report a mechanistic study of alkyl−alkyl Kumada
coupling catalyzed by a preformed nickel(II) pincer complex
([(N2N)Ni−Cl]). The coupling proceeds through a radical
process, involving two nickel centers for the oxidative addition
of alkyl halide. The catalysis is second-order in Grignard
reagent, first-order in catalyst, and zero-order in alkyl halide. A
transient species, [(N2N)Ni-alkyl2](alkyl2-MgCl), is identified
as the key intermediate responsible for the activation of alkyl
halide, the formation of which is the turnover-determining step of the catalysis.
1. INTRODUCTION
Cross-coupling reactions of nonactivated alkyl halides are
challenging, yet potentially powerful, transformations in organic
synthesis.1−8 Recent studies show that with judicious choices of
metal, ligands, and conditions the normally problematic β-H
elimination can be suppressed, and the coupling of non-
activated alkyl halides can be achieved with high yields and
selectivity.9−20 While significant progress has been made in the
development of novel synthetic methods based on these
coupling reactions,21−34 the mechanistic understanding of such
reactions remains limited.34−41 In the majority of cases, the
active catalysts are unidentified and unknown.42 Many reactions
are shown to involve radicals, yet how the radicals recombine to
give the coupling products is unclear.43,44
Figure 1. Proposed reaction sequence for alkyl−alkyl Kumada
coupling reactions catalyzed by nickel(II) pincer complexes.
Our group recently developed nickel-catalyzed alkyl−alkyl
Kumada coupling reactions using preformed nickel pincer
complexes as catalysts.45−47 The reactions were proposed to
occur through the sequence depicted in Figure 1. A nickel(II)
halide complex reacts with an alkyl Grignard reagent to make a
nickel(II) alkyl complex. The latter reacts with an alkyl halide
to give the coupling product and to regenerate the nickel halide
complex. This proposed reaction sequence was supported by
the following experimental observations: (1) The individual
steps of this sequence could be reproduced in stoichiometric
reactions. (2) Both the nickel(II) chloride complex
([(N2N)Ni−Cl], 1) and the nickel(II) methyl complex
([(N2N)Ni-Me], 2) were competent (pre)catalysts. (3) Either
a nickel(II) halide complex or a nickel(II) alkyl complex could
be isolated in high yields after the completion of the catalysis,
depending on the limiting reagent. The activation of alkyl
halides was shown to be a radical process, evidenced by
experiments using radical-clock substrates and, more unambig-
uously, by the diastereoselectivity in the coupling of remotely
substituted cyclohexyl halides.48 The proposed reaction
sequence and the individual pieces of mechanistic information,
however, do not constitute a concrete catalytic cycle because
the following questions remain unaddressed: (1) How are the
coupling products formed from the alkyl radicals? (2) Is the
proposed reaction sequence kinetically relevant under catalytic
conditions? (3) What is the turnover-determining step of the
catalysis?
Herein, we describe a mechanistic study of alkyl−alkyl
Kumada coupling reactions catalyzed by complex 1. The study
establishes a bimetallic oxidative addition mechanism for the
reactions, uncovers a key transient species that is responsible
Received: May 23, 2013
© XXXX American Chemical Society
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for the activation of alkyl halides, and reveals the kinetics of the
catalysis.
1.2. Exclusion of the Cage-Rebound Mechanism and
Confirmation of the Radical Mechanism. To differentiate
these three mechanisms, we examined the coupling of substrate
n
RESULTS AND DISCUSSION
3-(2-bromoethoxy)prop-1-ene (9) with BuMgCl (Scheme 2).
■
1. From Oxidative Addition to C−C Bond Formation.
1.1. General Mechanistic Considerations. We first probed the
details of the radical process that led to C−C bond formation.
Several different radical mechanisms might account for the
reaction outcome (Scheme 1). Assuming that a nickel alkyl
Scheme 2. Coupling Reactions of a Radical-Clock Substrate
Scheme 1. Three Possible Radical Mechanisms for Nickel-
Catalyzed Alkyl−Alkyl Kumada Coupling
Radical activation of 9 generates the alkyl radical 10, which can
undergo a fast intramolecular rearrangement (k1 ≈ 106 s−1) to
give another alkyl radical 11.54,55 The ensuing reactions, via one
of the three mechanisms in Scheme 1, lead to the formation of
both liner product 12 and cyclic product 13 (Scheme 2).
The ratio of 12 to 13 can be used as a probe to differentiate
the cage-rebound mechanism from the bimetallic oxidative
addition and escape-rebound mechanisms.54,55 This ratio is a
function of r1/r2; r1 = k1[10]. In the cage-rebound mechanism,
r2 = k2[10], as the rate is zero-order with respect to species 4.
The ratio r1/r2 is then a constant, independent of the catalyst
concentration. In the bimetallic mechanism, r2 = k2[10][3]; in
the escape-rebound mechanism, r2 = k2[10][4]. The ratio r1/r2
is then linearly dependent on the concentration of the catalyst.
Figure 2 shows the dependence of the ratio of 12 to 13 on
the loading of catalyst under otherwise identical conditions. To
species (3) activates alkyl halides, the first step is a single
electron transfer (SET) to give an alkyl radical and an oxidized
nickel complex (4, nickel(III) or nickel(II) ligand cation). As
the reduction potentials of alkyl halides are more negative than
the oxidation potential of nickel(II) alkyl complexes, the SET is
most likely inner-sphere and takes place through a halide
bridge.49 In a cage-rebound mechanism (Scheme 1, A), the
alkyl radical remains in the solvent cage and recombines with
the oxidized nickel complex to give a bis(alkyl) nickel complex
(5, formally nickel(IV) but the ligand might be oxidized in
place of metal). Reductive elimination from this bis(alkyl)
nickel species leads to the coupling product and a nickel(II)
halide complex (6). In a bimetallic oxidative addition
mechanism (Scheme 1, B),50−53 the first SET step is the
same. The resulting alkyl radical, however, escapes the solvent
cage and recombines with a second molecule of nickel(II) alkyl
species to give a formally nickel(III) bis(alkyl) species (7).
Reductive elimination from this species leads to the coupling
product and a nickel(I) species (8) which is deemed unstable
and reacts quickly with 4 to give 3 and 6. A third possibility is
the escape-rebound mechanism (Scheme 1, C). Again the first
SET step is the same. After the alkyl radical escapes the solvent
cage, it might recombine with the oxidized complex (4) to form
the bis(alkyl) nickel complex (5). Reductive elimination from
this bis(alkyl) nickel species leads to the coupling product and a
nickel(II) halide complex (6), just as in the cage-rebound
mechanism.
Figure 2. Ratio of 12 to 13 as a function of the loading of catalyst (1)
in the coupling reaction of 9 and BuMgCl. At each loading, four
independent trials were conducted to obtain an averaged ratio.
n
ensure a high yield in this coupling reaction, the Grignard
reagent was added slowly. The ratio is first-order in the
concentration of the catalyst. The ratio of 12/13 might be
influenced by the concentration of Grignard reagent. Thus, this
ratio was also determined for reactions in which the Grignard
reagent was added at once in the beginning of the reaction.56
The coupling yields were lower; however, the same linear
dependence of 12/13 on the loading of catalyst (1) was
observed (Figure S1, Supporting Information). These results
exclude the cage-rebound mechanism.
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n
The coupling of 9 with BuMgCl was also conducted in the
diastereomeric coupling products by 1H and 13C NMR
1
presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO).56 TEMPO-nBu was identified as the major product,
from the reaction of TEMPO with [(N2N)Ni-nBu]. No
trapping of alkyl radical by TEMPO is observed, either because
the trapping of the alkyl radical by the nickel catalyst is much
faster or because the reaction of TEMPO with [(N2N)Ni-nBu]
is much faster than that with the alkyl radical, or both.
The preceding considerations are only valid if 12 and 13 are
indeed produced from radical reactions as suggested in Scheme
2. While compound 9 is widely used as a radical probe, it can
also engage in nonradical reactions to give the same products.
For example, nucleophilic substitution of alkyl bromide
followed by migratory insertion gives a nickel alkyl complex
with a hydrofuran side chain, which, after reductive elimination,
gives a ring-closed product (Scheme 3). We have several pieces
spectroscopy. This turned out to be successful. The H and
13C NMR spectra of the coupling product, 3-(3-phenylpropyl)-
tetrahydrofuran (14), were assigned with the help of HMQC
and COSY (Figure S43 and S44, Supporting Information).56 In
1
both H and 13C NMR spectra, splitting of peaks due to two
diastereomers was observed (Figure 3 and Figures S40 and S42,
Supporting Information). Thus, the coupling of 9D with
phenylethyl-MgCl gives 14D with a d.r. of about 1:1,
confirming the radical mechanism for this reaction (eq 1).
Scheme 3. Nonradical Reaction Sequences That Lead To
Ring-Open and Ring-Closed Coupling Products
1.3. Confirmation of the Bimetallic Oxidative Addition
Mechanism. The outcome of coupling reactions using the
radical-probe substrate 9 excludes the cage-rebound mecha-
nism; it cannot be used to distinguish, however, the bimetallic
oxidative addition and the escape-rebound mechanisms
(Scheme 1, B and C). In the latter two mechanisms, the nickel
species with which the escaped alkyl radical recombines are
different. In the bimetallic mechanism, the alkyl radical
recombines with the nickel(II) alkyl species (3); in the
escape-rebound mechanism, the alkyl radical recombines with
the oxidized nickel species (4). Because of the so-called
persistent radical effect,59−62 the escape-rebound mechanism
can give a high yield in cross-coupling reactions of two radicals,
as long as there is a significant difference in the reactivity of the
two radicals. In the current case, one can imagine that a nickel-
based metalloradical is more stable than an alkyl radical.
Therefore, the high efficiency in cross-coupling reactions does
not exclude an escape-rebound mechanism a priori.
To demonstrate the feasibility of the reaction of 3 with an
alkyl radical to give the coupling product, we monitored the
reaction of ([(N2N)Ni-nPr] with an independently generated
alkyl radical (Scheme 5). Photolysis of tert-butyl-4-phenyl-
butaneperoxoate yielded the phenylpropyl radical;63 in the
presence of [(N2N)Ni-nPr], hexylbenzene was produced in a
yield of 13% (relative to ([(N2N)Ni-nPr]). This result proves
that a nickel(II) alkyl complex can react with an alkyl radical to
give the cross-coupling product. Thus, the bimetallic oxidative
addition mechanism is feasible. As the formally nickel(III) alkyl
species 4 cannot yet be isolated, an analogous experiment
cannot be conducted to probe the feasibility of the reaction of 4
with an alkyl radical.
Thus, density functional theory (DFT) computations at the
M0664,65/def2-TZVP66 level were used to compare reaction
free energies and transition state barrier heights for the
reactions of 3 and 4 with an alkyl (ethyl) radical (full
computational details available in the SI).56 The DFT-
optimized structures of the reactants, products, and the
transition state from 4 to 5 are given in Figure 4. The reaction
of 3 with an ethyl radial to form 7 is both exergonic (∼−5 kcal/
mol) and barrierless (Figure 5). In contrast, the reaction of 4
with an ethyl radial to form 5 is endergonic (∼4 kcal/mol) and
has a large transition state barrier (∼24 kcal/mol) (Figure 5). It
should also be mentioned that the concentration of 3 is much
higher than 4 during catalysis. Therefore, the DFT
of circumstantial evidence against this concerted reaction
mechanism: (1) The concerted mechanism predicts a zero-
order dependence of the ratio of 12 to 13 on the catalyst
concentration, whereas a first-order was observed. (2) The
diastereoselectivity in alkyl−alkyl coupling reactions of
disubstituted cyclohexyl halides confirmed that the coupling
reactions occurred via radical intermediates.48 (3) We showed
earlier that these nickel(II) alkyl complexes do not insert into
olefins; rather, olefin exchange reactions took place via β-H
elimination.57 To further confirm that coupling reactions of
compound 9 occur by a radical mechanism as suggested in
Scheme 2, we analyzed the reaction outcome of 9D (the E
isomer), where a deuterium is placed at the terminal olefinic
position. If a radical mechanism is operating, the insertion of a
radical into the exoposition of the olefin gives both R and S
stereoisomers; the following coupling steps at the terminal
position also give both R and S isomers (Scheme 4, A). Overall,
two diastereoisomers are produced. If a concerted mechanism
is operating, assuming a syn-insertion and reductive elimi-
nation, only one diastereoisomer is produced (Scheme 4, B).
Indeed, this method was recently successfully applied to
establish a radical mechanism in the copper-catalyzed Ullmann
reaction.58
The main experimental difficulty encountered was the
differentiation of diastereomeric coupling products. Initially
n
2
we coupled 9D with BuMgCl. The H-NMR spectrum of the
product shows only a broad peak and is inconclusive.56 The 13C
NMR spectrum shows splitting patterns consistent with the
presence of two diastereomers; however, the splitting is small
and vague (Figure S46, Supporting Information). We then
coupled 9D with phenylethyl-MgCl, hoping that the more rigid
phenylethyl group would lead to a bigger differentiation of the
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a
Scheme 4. Stereochemical Outcomes of Coupling Reactions of 9D
a
The ligand N2N is simplified for clarity.
1
Figure 3. Detection of diastereomers of 14D by 13C and H NMR. The splitting of signals for Ca and Cb in the 13C spectrum (left) is evident,
1
indicating a pair of diastereomers; likewise, the splitting of signals for each diastereotopic proton Ha is also evident in the H spectrum (right).
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Scheme 5. Reaction of an Alkyl Radical with a Nickel(II) Alkyl Complex
with alkyl Grignard reagents: different diastereoselectivity was
observed for different nickel catalysts,48 whereas the same
diastereoselectivity is expected for a direct coupling of the alkyl
radical with the Grignard reagent.
The preceding results establish the bimetallic oxidation
mechanism as the major mechanism by which the nickel
catalysis occurs. Bimetallic oxidative addition of organic halides
involving radical intermediates is rare but does have some
precedent. For example, Cr(II),51 Co(0),52 and Fe(II)−ligand
diradical50 complexes were shown to activate alkyl and aryl
halides in stoichiometric reactions through bimetallic oxidative
addition. However, this is the first time that convincing
evidence is reported for such a mechanism in catalytic cross-
coupling reactions. Given the tendency of first-row transition
metal complexes to undergo one-electron redox chemistry, this
type of mechanism might be prevalent for cross-coupling
reactions of nonactivated alkyl halides catalyzed by nickel,
cobalt, and iron. Recently, bimetallic oxidative addition and
reductive elimination are proposed to occur in preorganized
bimetallic Pd and Ni complexes.53,70,71 In such ″preassociated″
bimetallic catalysis, two adjacent metals function together to
perform the chemistry. The current bimetallic catalysis differs
from those systems in that the oxidative addition involves
sequentially two monometallic complexes.
Figure 4. Structures (optimized at the M06/def2-SVP level) of
relevant species for the bimetallic oxidative addition and escape-
rebound mechanisms.
2. Nature of the Active Nickel Alkyl Intermediate.
2.1. Reactivity of Different Nickel Alkyl Species. After the
mechanism of oxidative addition and C−C bond formation was
established, the nature of the key alkyl species responsible for
oxidative addition was probed. Earlier we believed that this
species was simply a four-coordinate nickel(II) alkyl species,
i.e., ([(N2N)Ni-alkyl2] (3). Indeed, a [(N2N)Ni-alkyl2]
complex could react with an alkyl halide to yield a coupling
product in high yield. Yet, whether such a reaction would be
kinetically relevant to the catalysis had not been examined. We
studied the reaction of [(N2N)Ni-nPr] with nC4H9I under
catalytically relevant conditions (THF/DMA as solvent and at
−15 °C). The reaction took place smoothly to give [(N2N)Ni−
Figure 5. Reaction free energies computed at the M06/def2-TZVP
level (in implicit THF solvent with the SMD model67) for the
bimetallic oxidative addition and escape-rebound mechanism. Values
in kcal/mol.
n
I] and C7H16 (eq 2). However, the reaction was significantly
slower than the catalysis: the half-life of the reaction was 6 h,
whereas the catalysis normally completed within 30 min. The
same reaction was, however, much faster in the presence of 1
n
equiv of PrMgCl (eq 3). The half-life was less than 5 min, so
computations unambiguously identify the bimetallic oxidative
addition pathway (3 + Et• → 7) as the likely mechanism; the
escape-rebound mechanism is excluded.
that the rate of this reaction was compatible to that of the
catalysis. These results indicate that the reaction of a
[(N2N)Ni-alkyl2] complex with an alkyl halide is not the
major pathway to the formation of the coupling product in the
catalysis. Instead, the reaction of [(N2N)Ni-alkyl2] with alkyl2-
MgCl seems to yield a species [(N2N)Ni-alkyl2](alkyl2-MgCl)
that reacts much faster with an alkyl halide to give the coupling
product. This species is the key alkyl species (3′). As no
apparent reaction was observed between [(N2N)Ni-alkyl2] and
alkyl2-MgCl (eq 4), 3′ shall be a thermodynamically unstable
An alternative pathway to the coupling product is the direct
reaction of the alkyl radical with an alkyl Grignard reagent, as
oxidative coupling of Grignard reagents has been reported.68,69
To probe this possibility, photolysis of tert-butyl-4-phenyl-
56
n
butaneperoxoate was conducted in the presence of PrMgCl.
If the photogenerated alkyl radical could couple with nPrMgCl,
then hexylbenzene would be generated. However, this product
was not detected, suggesting that direct coupling of the alkyl
radical with the alkyl Grignard reagent may not be a viable
pathway in the catalysis. The diastereoselectivity of alkyl−alkyl
coupling reactions of substituted cyclohexyl halides provides
further evidence against the direct coupling of the alkyl radical
n
intermediate. Interestingly, a lithium alkyl reagent, BuLi, did
not accelerate the reaction of [(N2N)Ni-nPr] with nC4H9I. The
half-life of the reaction was again 6 h (eq 5). Likewise, MgCl2
did not accelerate the reaction.56
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coupling of 2-phenylethylbromide with nBuMgCl (4 mol % 1 as
catalyst) were measured using the initial rate approximation.
Figure 6A depicts the dependence of the reaction rate on the
concentration of BuMgCl. The rate order is approximately
two.
−15°C
n
[(N2N)Ni‐nC3H7] + C4H9I ⎯⎯⎯⎯⎯⎯→ [(N2N)Ni‐I]
n
+ C7H16
n
t(1/2) = 6 h
(2)
nC3H7MgCI + [(N2N)Ni‐nC3H7] + C4H9I
n
−15°C
n
⎯⎯⎯⎯⎯⎯→ [(N2N)Ni‐I] + C7H16 + MgICl
t(1/2) < 5 min
(3)
(4)
nC3H7MgCI + [(N2N)Ni‐nC3H7]
−15°C
⎯⎯⎯⎯⎯⎯→ no alkylation product observed
n
nC4H9Li + [(N2N)Ni‐nC3H7] + C4H9I
−15°C
n
⎯⎯⎯⎯⎯⎯→ [(N2N)Ni‐I] + C7H16
t(1/2) = 6 h
(5)
Next, the reaction of [(N2N)Ni-nPr] with nC8H17I was
n
examined in the presence of BuMgCl (Table 1). Both C11H24
Table 1. Crossover Experiments of Stoichiometric Cross-
a
Coupling Reactions
n
n
[(N2N)Ni‐nC3H7] + C8H17I + C4H9MgCl
x equiv
n
n
→ [(N2N)Ni‐I] + C11H24 + C12H26
(6)
equiv of
C4H9MgCl
conversion of
C8H17I (%)
yield of
C11H24 (%)
yield of
C12H26 (%)
entry
1
2
3
4
1
100
100
98
58
60
64
53
34
30
23
5
0.7
0.5
0.3
74
a
See the Supporting Information for experimental details; yields were
determined by GC analysis and are relative to C8H17I; results are
averaged over three independent trials and are for reactions in which
the Grignard reagents were added last.
and C12H26 were produced, originating from the coupling of
n
n
C8H17I with Pr and Bu fragments, respectively. However, the
n
selectivity for the coupling with the Pr fragment was higher.
n
For example, when 1 equiv of BuMgCl was present, C11H24
and C12H26 were produced in a ratio of 1.7:1, and when 0.3
equiv of nBuMgCl was present, C11H24 and C12H26 were
produced in a ratio of 12:1. On the other hand, coupling of the
two nucleophiles (which would give C7H16 as the product) was
negligible. If [(N2N)Ni-nPr] was premixed with nBuMgCl
n
n
before reacting with C8H17I, coupling of Pr with C8H17 was
still dominant (Figure S7, Supporting Information). Further-
more, reaction of [(N2N)Ni-nPr] and MeMgCl was monitored
by NMR, but no exchange of alkyl ligand was observed.56
These results suggest that formation of both C11H24 and C12H26
in Table 1 does not originate from a fast alkyl exchange reaction
of [(N2N)Ni-nPr] and nBuMgCl. The selectivity for coupling of
nPr fragment implies that the two alkyl groups in [(N2N)-
Ni-nPr](nBuMgCl), the presumed active species for eq 6 in
Table 1, are inequivalent and nonexchangeable.
Figure 6. Rate orders of Grignard reagent (A), catalyst (B), and alkyl
halide (C). At each loading, three independent trials were conducted
to obtain an averaged value. The slopes of log rate vs log reagent are
the rate order.
The dependence of the rate of the coupling reaction on the
concentration of catalyst and alkyl halide was also determined.
The catalysis is approximately first-order in catalyst (1) and
zero-order in alkyl halide (Figure 6B and C). Both results are
consistent with the scenario that the formation of 3′ is
turnover-determining. The zero-order dependence on alkyl
2.2. Kinetics of Catalysis. The acceleration of the reaction
between [(N2N)Ni-alkyl2] and alkyl1-X by an alkyl Grignard
reagent prompted us to determine the rate order of the catalysis
with respect to the Grignard reagent. Thus, the rates of the
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Figure 7. Proposed catalytic cycle of alkyl−alkyl Kumada coupling catalyzed by 1.
halide indicates that the activation of alkyl halide occurs after
the transmetalation step in the catalytic cycle.
A scenario that might explain the observed second-order in
Grignard reagent is that alkyl2-MgCl coexists with (alkyl2)2Mg
in solution through the Schlenk equilibrium (eq 7).
the true transmetalation reagent, one expects an influence of
MgCl2 in the reaction. The lack of such an influence suggests
that the Schlenk equilibrium is not responsible for the observed
rate order in Grignard reagent.
An alternative scenario that might lead to a second-order in
Grignard reagent is the following: [(N2N)Ni-Cl] is in
equilibrium with [(N2N)Ni-Cl](alkyl2-MgCl) (15); the latter
undergoes a turnover-determining alkylation step with alkyl2-
MgCl to form [(N2N)Ni-alkyl2](alkyl2-MgCl) (3′). If the pre-
equilibrium disfavors [(N2N)Ni-Cl](alkyl2-MgCl), then a
second-order in alkyl2-MgCl is to be observed. A variant of
this scenario is that [(N2N)Ni-Cl] first reacts with 1 equiv of
alkyl2-MgCl to give [(N2N)Ni-alkyl2], which further reacts with
another equiv of alkyl2-MgCl to give 3′. To reach a second-
order in alkyl2-MgCl, the first transmetalation reaction needs to
be a fast pre-equilibrium favoring the starting reagents.
However, the reaction of [(N2N)Ni-X] with alkyl2-MgCl to
form [(N2N)Ni-alkyl2] and MgClX was previously found to
favor the products.45,46 Therefore, this variant is ruled out by
the kinetics of the catalysis.
As the catalysis is second-order in Grignard reagents, the
transmetalation reaction should also be second-order in
Grignard reagent. To verify this, the reaction of [(N2N)Ni-
Cl] with EtMgCl was followed by dip-probe UV−vis
spectroscopy. Indeed, this reaction had an order of ca. 1.7 in
Grignard reagent (Figure S14, Supporting Information).56 The
result is consistent with that obtained from catalytic reactions.
2alkyl2‐MgCl ⇌ (alkyl2)2Mg + MgCl
(7)
2
If (alkyl2)2Mg is the real transmetalation reagent and the
transmetalation step is turnover-determining, a second-order
dependence on alkyl2-MgCl is expected. To test this
hypothesis, the coupling of 2-phenylethylbromide with
(nBu)2Mg was studied. The yield of this coupling reaction
was below 10% after 90 s and 25% after 50 min. These yields
were significantly lower than those of the coupling of 2-
n
phenylethylbromide with BuMgCl (40% after 90 s and 77%
after 50 min). Furthermore, a significant amount of the
n
homocoupling product, C8H18, could be detected only when
(nBu)2Mg was used as the coupling partner.
The above experiment alone does not exclude the critical
involvement of Schlenk equilibrium, as MgCl2 was not present
in the reaction mixture. The coupling of 2-phenylethylbromide
with (nBu)2Mg was then conducted in the presence of MgCl2,
yet a similar reaction profile was observed.56 Furthermore, the
coupling of 2-phenylethylbromide with nBuMgCl was also
conducted in the presence of MgCl2; again the reaction profile
remained similar.56 If (alkyl2)2Mg or other higher-order
alkylmagnesium species in equilibrium with alkyl2-MgCl are
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In intermediates 3′ and 15, the amide and amine donors of
the pincer N2N ligand are possible binding sites for Mg2+. This
is reasonable as we reported previously that the N2N−Mg
complex could be formed in a small amount by reaction of
[(N2N)Ni-Cl] with an alkyl Grignard reagent.46 As tetrame-
thylethylenediamine (TMEDA) is a good binder for Mg2+, we
monitored the coupling of 2-phenylethylbromide with
nBuMgCl in the presence of TMEDA.56 It turned out that
TMEDA significantly slowed down the catalytic coupling
reaction. We speculate that TMEDA competes with one or
more nitrogen donors in the N2N ligand for binding of Mg2+,
thereby slowing the transmetalation reaction. If this is the case,
then we can propose that (alkyl2-MgCl) is associated with the
nickel complex through a nitrogen donor of the ligand in 3′ and
15. In this way, the two alkyl2 ligands in [(N2N)Ni-
alkyl2](alkyl2-MgCl) (3′) are different, which is consistent
with their inability to exchange with one another (see above).
On the other hand, TMEDA can influence the reaction in other
ways, for example, by changing the nature of the Grignard
reagents or by influencing the Schlenk equilibrium. It is
important to recognize that the alkyl2-MgCl component in 3′
and 15 might bind to nickel via a halide or alkyl bridge as well.
2.3. Catalytic Cycle. A catalytic cycle for the nickel-catalyzed
alkyl−alkyl Kumada coupling can be proposed based upon the
aforementioned results and discussion (Figure 7). Catalyst 1
first reacts with alkyl2-MgCl to form [(N2N)Ni-Cl](alkyl2-
MgCl) (15) in a pre-equilibrium; reaction of 15 with another
equivalent of alkyl2-MgCl gives the key intermediate
[(N2N)Ni-alkyl2](alkyl2-MgCl) (3′). The latter is in equili-
brium with [(N2N)Ni-alkyl2] (3), which is thermodynamically
more stable but less reactive toward alkyl halide. Intermediate
3′ reacts with alkyl1-X through an inner sphere SET to give the
alkyl1• radical and a one-electron oxidized complex [(N2N)-
Ni(X)(alkyl2)] (16). At this point alkyl2-MgCl might have left
the nickel complex. The alkyl1• radical then escapes from the
solvent cage and reacts with a second molecule of [(N2N)Ni-
alkyl2](alkyl2-MgCl) (3′) or [(N2N)Ni-alkyl2] (3) to give
[(N2N)Ni(alkyl2)(alkyl1)] (17) (for simplicity, only reaction
with 3 is drawn in Figure 7). Reductive elimination from 17
gives alkyl2−alkyl1 as the coupling product and a formally
nickel(I) species [(N2N)Ni] (18) as an unstable intermediate.
Species 18 reacts with the formally nickel(III) species 16 to
give [(N2N)Ni-X] (6) and [(N2N)Ni-alkyl2] (3), both of
which can re-enter the catalytic cycle.
halide complex (1 or 6). To support this hypothesis, the
coupling of octyl-I with EtMgCl was monitored by UV−vis
spectroscopy.56 The absorption spectra of nickel(II) halide and
ethyl complexes are significantly different in the visible region46
so that their concentrations can be determined by analysis of
the spectra. It is found that a significant amount (ca. 60%) of
nickel-containing species during catalysis (at partial conver-
sions) was [(N2N)Ni−Cl].56 This result is consistent with
[(N2N)Ni−X] being the resting state.72 [(N2N)Ni−Et] was
also present, consistent with its role as the dormant species.
CONCLUSION
■
In conclusion, a bimetallic oxidative addition mechanism
involving radical intermediates has been revealed for alkyl−
alkyl Kumada cross-coupling reactions catalyzed by the
nickel(II) pincer complex 1. The oxidative addition of alkyl
halide involves two nickel centers, and the highest formal
oxidation state of nickel in the intermediates is +3.73−75 The
catalysis is second-order in Grignard reagent, first-order in
catalyst, and zero-order in alkyl halide. The key intermediate
species for the activation of alkyl halide is the complex
[(N2N)Ni-alkyl2](alkyl2-MgCl); the formation of this species is
the turnover-determining step of the catalysis. One or more
nitrogen donors in the pincer N2N ligand is proposed to assist
the catalysis in binding to the Mg2+ ion in the Grignard
reagents. To the best of our knowledge, this is the first time that
a bimetallic radical mechanism has been established for nickel-
catalyzed cross-coupling reactions of alkyl halides. While the
study is specific to the reactions catalyzed by 1 and its
derivatives, a similar mechanism might be operating in many
other systems known to involve radical processes. The work
significantly enhances the current understanding of these
challenging, yet potentially useful, chemical transformations.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental and computational details and characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
xile.hu@epfl.ch
■
Notes
The catalytic cycle in Figure 7 reinforces the notion that the
two alkyl ligands in intermediate 3′ are inequivalent. When 3′
activates an alkyl halide, it is oxidized to a formally nickel(III)
complex. If there are two identical alkyl ligands in 3′, they will
undergo reductive elimination to give the product of alkyl2−
alkyl2 homocoupling. Such a product, however, was not
observed.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by the EPFL and the Swiss National
Science Foundation (no. 200021_126498). We thank Prof.
■
Clem
́
ence Corminboeuf (EPFL) for helpful suggestions and
comments. X.L. Hu thanks Prof. Armido Studer (University of
The role of [(N2N)Ni-alkyl2] (3) warrants some comments.
3 is a stable species that can be isolated from the reaction
mixture and is catalytically competent. The kinetics of the
catalysis indicates that it is not the key species for the activation
of alkyl halide; thus, 3 can be considered as a dormant species
in the catalytic cycle. Equations 2 and 4 show 3 can be
transformed into the active species 3′ by alkylation with a
Grignard reagent. The binding of Mg2+ by 3 seems essential for
Munster) for an insightful discussion on the behavior of
̈
persistent radicals.
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