Unexpected Nickel Complex Speciation Unlocks Alternative Pathways for the Reactions of Alkyl Halides with dppf-Nickel(0)

Article abstract of DOI:10.1021/acscatal.0c02514

The mechanism of the reactions between dppf-Ni0 complexes and alkyl halides has been investigated using kinetic and mechanistic experiments and DFT calculations. The active species is [Ni(κ2-dppf)(κ1-dppf)], which undergoes a halide abstraction reaction with alkyl halides and rapidly captures the alkyl radical that is formed. The rates of the reactions of [Ni(COD)(dppf)] with alkyl halides and the yields of prototypical nickel-catalyzed Kumada cross-coupling reactions of alkyl halides are shown to be significantly improved by the addition of free dppf ligand.

Full text of DOI:10.1021/acscatal.0c02514

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Article
Unexpected Nickel Complex Speciation Unlocks Alternative
Pathways for the Reactions of Alkyl Halides with dppf-Nickel(0)
Megan Greaves, Thomas Oliver Ronson, Guy C. Lloyd-Jones,
Feliu Maseras, Stephen Sproules, and David James Nelson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02514 • Publication Date (Web): 21 Aug 2020
Downloaded from pubs.acs.org on August 21, 2020
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ACS Catalysis
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Unexpected Nickel Complex Speciation Unlocks Alternative Pathways
for the Reactions of Alkyl Halides with dppf-Nickel(0)
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Megan E. Greaves,a,b Thomas O. Ronson,b Guy C. Lloyd-Jones,c Feliu Maseras,d Stephen Sproules,e and
David J. Nelsona*
(a) WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1
1XL, Scotland.
(b) Chemical Development, Pharmaceutical Technology and Development, Operations, AstraZeneca, Macclesfield, SK10
2NA, UK.
(c) EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, Scotland.
(d) Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain.
(e) WestCHEM School of Chemistry, University of Glasgow, University Avenue, Glasgow, G12 9QQ, Scotland.
KEYWORDS: nickel, homogenous catalysis, cross-coupling, reaction mechanisms, organometallic chemistry
ABSTRACT: The mechanism of the reactions between dppf-Ni0 complexes and alkyl halides has been investigated using kinetic
and mechanistic experiments and DFT calculations. The active species is [Ni(κ2-dppf)(κ1-dppf)], which undergoes a halide
abstraction reaction with alkyl halides and rapidly captures the alkyl radical that is formed. The rates of the reactions of
[Ni(COD)(dppf)] with alkyl halides and the yields of prototypical nickel-catalysed Kumada cross-coupling reactions of alkyl halides
are shown to be significantly improved by the addition of free dppf ligand.
the latter arising from β-hydride elimination;18 studies were
INTRODUCTION
typically carried out by combining Ni0 and alkyl halide at low
temperatures in situ in the NMR spectrometer and carefully
increasing the temperature and observing spectral changes.
Wang explored the reactions of a diphosphinodithio-ligated
nickel(0) complex with alkyl halides, which were followed by
the addition of NaBPh4; these led to alkylnickel(II) complexes
which degenerated to hydride species via β-hydride
elimination.19 Diao probed the reactions of [NiI(Ar)(Xantphos)]
with alkyl halides and also proposed a halide abstraction
The coupling of sp3 centers is a frontier in modern cross-
coupling catalysis research1-2 and is closely aligned to the drive
in areas such as the pharmaceutical industry to target sp3-rich
molecules.3-4 Due to differences in oxidative addition behavior
and the occurrence (and often the dominance) of deleterious
side reactions such as β-hydride elimination, couplings of sp3
centers are typically far more challenging than the palladium-
catalysed sp2-sp2 couplings that have become routine in
academia and industry. In order to overcome these synthetic
challenges, chemists have looked towards alternative catalyst
systems, often based on metals such as iron,5 cobalt,6 and
nickel.7-9 Several useful catalytic systems have been disclosed.
Practical nickel-catalysed reductive cross-electrophile
couplings have also been developed, which allow sp3-sp2
couplings of an aryl halide and an alkyl halide.10 However,
despite synthetic advances in this field we require further and
deeper mechanistic understanding to underpin future
developments.
mechanism (Xantphos
= 4,5-bis(diphenylphosphino)-9,9-
dimethyl-xanthene).20 Jarvo and Hong studied the
nickel/dppm-mediated synthesis of cyclopropanes from 1,3-
dimesylates and uncovered a halide abstraction mechanism
involving the initially-formed 1,3-diiodide (dppm
=
bis(diphenylphosphino)methane).21
The present study builds on our recent investigations of the
oxidative addition of aryl halides to Ni0,22-26 and works towards
the understanding of reaction mechanisms and
structure/reactivity relationships in nickel catalysis (Scheme
1). We work with bidentate phosphine ligands because they
exhibit favorable reactivity in cross-coupling reactions;27-29
[Ni0(COD)(dppf)] (1), a thermally-stable and readily-prepared
model Ni0 complex, has been used for mechanistic studies of
nickel catalysis and for catalytic reactions in organic synthesis
(dppf = 1,1’-bis(diphenylphosphino)ferrocene).30 This is known
to be the catalyst that is formed in reactions where [Ni(COD)2]
and dppf are combined in situ. 30 Our key finding in this study
Mechanistic studies of the reactions of alkyl halides with
nickel are relatively few, and many studies of sp3-couplings
(both synthetic and mechanistic) invoke nickel(I)
intermediates.11-15 Tilley has reported the oxidative addition of
methyl iodide to a nickel(I) species, forming a nickel(III)
complex.16-17 Baird has studied the reactions of alkyl halides
with [Ni0(PPh3)4] which occurred via halide abstraction and
which generate mixtures of alkane and alkene products, with
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is that the active Ni0 species must bear two dppf ligands, even and [Ni(COD)2] which yields 1 as the major product,30, 35 but the
1
2
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4
5
6
7
8
though
presence of 5 appears to be essential for these reactions with
(a) Oxidativeadditionof arylhalidesto [Ni(COD)(dppf)](previous work)
2-X
Ph
Ph
1/2 H2
PPh2
Ni
PPh2
PPh2
Ni
PPh2
X
PPh2
Ni
PPh2
Ni
ArX, - COD, - ArAr/ArH
Fe
Fe
X
Fe
Fe
X
benzene-d6
PPh2
PPh2
via [NiArX(dppf)]
1
3-X
(a)
•EPR spectroscopy
•GC-MS
Rate of reaction:
Products
detected:
•1H NMR spectroscopy •GC-FID
I > Br > Cl > OTs > OCO2Et > OTf > OCONEt2 > OSO2NMe2 > OPiv > OMe  F
(b) Reactions with 15 equiv. 2-X monitored by 31P{1H} NMR spectroscopy
(b) Reactionsof alkylhalideswith[Ni(COD)(dppf)](this work)
9
+ dppf
- COD
Halide
Abstraction
2-Cl
2-Br
2-I
X = Cl
X = Br
X = I
T = 323 K
T = 303 K
T = 293 K
kobs = 0.016(1) mol L-1 s-1
kobs = 0.014(1) mol L-1 s-1
kobs = 0.023(1) mol L-1 s-1
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Ph2
P
PPh2
Ni
PPh2
PPh2
Ni
PPh2
Fe
Fe
Fe
P
+ COD
- dppf
Ph2
(c) Reactions with 15 equiv. 2-Br monitored by 31P{1H} NMR spectroscopy
Ph
X
at 303 K, with 1 equiv. of an additive
PPh2
Ni
PPh2
X
P
PPh2
Ni
PPh2
Fe
Ph
Additive: 4-Cl
Additive: 3-Cl
Additive: dppf
kobs = 0.034 mol L-1 s-1
kobs = 0.012(1) mol L-1 s-1
t1/2 << 300 s
Fe
Ph
X
Ph2
Fe
- dppf
- H2
Ph2P
(d) Reactions with 15 equiv. 2-X monitored by 31P{1H} NMR spectroscopy
with 0.3 equiv. of dppf as an additive, in benzene-d6 or toluene-d8
Scheme 1. (a) Our previous work. (b) This study.
most pre-catalysts with bidentate phosphine ligands have a 1:1
ligand to nickel ratio.
X = Cl
X = Br
X = I
T = 313 K (benzene-d6)
T = 283 K (benzene-d6)
T = 273 K (toluene-d8)
kobs = 8.4(3) x 10-4 s-1
kobs = 1.29(1) x 10-3 s-1
kobs = 3.5(2) x 10-3 s-1
RESULTS AND DISCUSSION
1. Kinetic Studies of Reactions With [Ni(COD)(dppf)] (1)
Scheme 2. (a) Stoichiometric reactions. (b) Initial kinetic studies,
exhibiting zero order behavior. (c) Control experiments. (d) Kinetic
studies with added dppf, exhibiting pseudo-first order behavior.
Stoichiometric experiments in which [Ni(COD)(dppf)] (1) was
exposed to (2-haloethyl)benzene reagents (2-X) showed that
the major products were styrene and [NiX(dppf)] (3-X), as
confirmed by GC-FID/GC-MS analysis and EPR spectroscopy,
respectively (Scheme 2(a));31 these NiI complexes have been
reported previously.30, 32 No ethylbenzene was detected in any
of these reactions. Styrene must arise from a β-hydride
elimination process. The reactions between [Ni(COD)(dppf)]
(1) and an excess of each of the three alkyl halides (2-X, 15
equiv.) in benzene-d6 solution were monitored over time using
31P{1H} NMR spectroscopy (Scheme 2(b)). Surprisingly, these
reactions were pseudo-zero order in 1 (Figure 1(a)) and
displayed saturation behavior in 2-Br. This is in stark contrast
to the reactions of 1 with aryl halides, which are pseudo-first
order in 1 under the same conditions.22 These results
suggested that 1 was not the active species in these reactions.
2. Identification of [Ni(dppf)2] as the Active Species
Control reactions were conducted with additives to
understand what the active species in these reactions might be
(Scheme 2(c)). The addition of [NiCl2(dppf)] (4-Cl) led to an
increase in the rate of reaction, prompting speculation that
[NiCl(dppf)] (3-Cl), formed from comproportionation between
[Ni(COD)(dppf)] (1) and 4-Cl,22, 30, 33 might be the active species.
However, added 3-Cl did not affect the reaction rate. When
additional dppf ligand was present there was a significant
increase in the reaction rate. Further analysis of [NiCl2(dppf)]
(4-Cl) by 31P{1H} NMR spectroscopy revealed small quantities
of free dppf, thus accounting for its accelerating effect.
[Ni(COD)(dppf)] (1) contained approximately 1% of what was
assigned as [Ni(dppf)2] (5) by comparison with literature 31P
NMR data (δP = ca. 15 ppm).34 Complex 1 is prepared from dppf
Figure 1. Kinetic data from the reactions of [Ni(COD)(dppf)] (1) (22
mmol L-1) in benzene-d6 at 283 K with 0.33 mol L-1 (2-
bromoethyl)benzene (2-Br) (unless otherwise stated): (a) pseudo-
zero order behavior (no added dppf; 303 K); (b) pseudo-first order
behavior (2.2 mmol L-1 dppf; 283 K); (c) first order in dppf (open
green circles) and 2-Br (closed purple circles) (6.6 mmol L-1 dppf
for varied [2-Br]); and (d) inhibition by COD (6.6 mmol-1 dppf).
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ACS Catalysis
alkyl halides. The equilibrium constant for the formation of 5
from 1 plus dppf was measured (Keq = 6.8).
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R
R'
Br
3. Kinetic Studies of Reactions with [Ni(dppf)2]
(a)
(15 equiv.)
PPh2
Ni Br
PPh2
3-Br
Ph
1
2
3
4
5
6
Attempts were made to prepare a sample of 5 for kinetic
studies but a sufficiently pure sample could not be obtained.
Instead, a series of experiments were carried out in which
additional dppf was present during the reactions of
[Ni(COD)(dppf)] (1) with (2-haloethyl)benzene substrates (2-X)
(Scheme 2(d)). The products of these reactions were again
styrene and [NiX(dppf)] (3-X).
Fe
6-Br (R = Me, R' = H)
7-Br (R, R' = Me)
PPh2
Ni
PPh2
Fe
dppf (0.3 equiv.)
benzene-d6, room temp.
R
1/2 H2
1
Ph
R'
7
8
(b)
Ph
Cl
8-Cl
In the presence of added dppf these kinetic studies showed
pseudo-first order behavior in 1, were first order in 2-X and
dppf, and were inhibited by COD (Figure 1(b) – (d)). Notably
the reactions of aryl halides with 1 are inhibited by added dppf,
as established by control experiments; the reactions of aryl
halides therefore proceed via [Ni(dppf)], but the reactions of
alkyl halides proceed via [Ni(dppf)2] (5).
PPh2
Ni
PPh2
PPh2
Ni Cl
PPh2
3-Cl
9
(15 equiv.)
Ph
1/2 H2
Fe
Fe
9
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dppf (0.3 equiv.)
benzene-d6
353 K
1
Ph
via:
Ph
A rate expression can be formulated for the reactions of
alkyl halides with 1. If an equilibrium between [Ni(COD)(dppf)]
(1) plus dppf and [Ni(dppf)2] (5) plus COD is rapidly established
then the concentration of 5 can be defined according to eq. 1.
Scheme 3. Experiments to probe the involvement of radicals.
change occurred within 30 seconds of substrate addition at
room temperature (ca. 293 K) so kobs is at minimum ca. 0.2 s-1
and therefore at least two orders of magnitude faster than for
the reaction of 2-Br; the color change is proposed to be due to
the formation of [NiBr(dppf)] (3-Br) which is darker in color
than [Ni(COD)(dppf)] (1). This significant rate enhancement on
moving from primary to secondary and tertiary alkyl halides is
consistent with a reaction that generates alkyl radicals.
K1
=
=
[5][COD] / [1][dppf] ∴
K1·[1]·[dppf]·[COD]-1
[5]
(1)
If the reaction proceeds through a rate determining reaction
between 5 and the alkyl halide (2-X) with rate constant k2 then
the reaction rate can be expressed as in eq. 2; the expression
for [5] can then be substituted to give eq. 3.
Rate
Rate
kobs
=
≈
=
k2·[5]·[2-X]
(2)
kobs·[Ni]tot; where
K1·k2·[1]·[2-X]·[dppf]·[COD]-1
Reasoning that styrene formation occurs due to a β-hydride
elimination process, (1-chloro-2-methylpropan-2-yl)benzene
(8-Cl) was used as the reaction substrate (Scheme 3(b)). The
putative alkylnickel(II) bromide intermediate cannot undergo
β-hydride elimination. Instead, 2-methyl-1-phenylprop-1-ene
(9) was obtained as the organic product. No tert-butylbenzene
was detected in the reaction mixture. This result is further
evidence of radical intermediates; a [1,2]-phenyl shift explains
the observation of 9 in the reactions of 8-Cl.
(3)
An alternative treatment based on the steady-state
approximation leads to the same rate expression (see the
Supporting Information).
An Eyring-Polanyi treatment of the reaction between
[Ni(COD)(dppf)] (1) and 15 equiv. of 2-Cl in the presence of 0.3
equiv. dppf yielded activation parameters (see the Supporting
Information); ΔS° ≈ 0 for the equilibrium between 1 and 5 and
so ΔH‡ is estimated at 26.2 kcal mol-1 and ΔS‡ at 15 cal K-1 mol-
1. The latter value indicates a decrease in order as the reaction
proceeds through the transition state.
Attempts to trap a radical intermediate with TEMPO or BHT
were unsuccessful (TEMPO = (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl; BHT
= 2,6-di(tert-butyl)-4-methylphenol). TEMPO
reacts directly with [Ni(COD)(dppf)] (1), while reactions with 1
– 15 equiv. BHT with respect to 1 yielded no alkane products.
The radical intermediate formed is therefore rapidly trapped
by the nickel complex – as is required to yield the β-hydride
elimination products – more quickly than it can undergo
reaction with BHT. Intramolecular rearrangement processes
such as the [1,2]-phenyl shift in Scheme 3 (b), with a rate
constant of 500 s-1 at 20 °C,37 can outpace the capture of the
primary alkyl radical by NiI.
4. Evidence for Radical Intermediates
The formation of styrene in the reactions of (2-
haloethyl)benzene substrates requires the intermediacy of
alkylnickel(II) halide complexes that then undergo β-hydride
elimination; however, it is possible that these might form
directly from Ni0 or through the formation of NiI and a radical,
which then recombine to form NiII. The direct formation of
styrene from ethylbenzene radical is ruled out as
recombination to produce 1,4-diphenylbutane is favored by
ca. 7-fold over disproportionation to styrene and
ethylbenzene;36 no 1,4-diphenylbutane or ethylbenzene is
detected in any of these reactions.
5. Events After Radical Capture and β-Hydride Elimination
The evidence points to a mechanism in which [Ni(dppf)2] (5)
reacts with alkyl halides to form a NiI complex and an alkyl
radical, which in turn combine to form a NiII complex that can
undergo β-hydride elimination to form styrene. This would
also produce [Ni(H)(X)(dppf)] (10-X), which must then form
[NiX(dppf)] (3-X), as this is the ultimate product identified by
EPR spectroscopy.
The reactions of secondary and tertiary alkyl halides with
[Ni(COD)(dppf)] (1) (and added dppf) were studied (Scheme
3(a)). The reactions of (2-bromopropyl)benzene (6-Br) and (2-
bromo-2-methylpropyl)benzene (7-Br) were both far too fast
to allow the measurement of rate constants. A distinct color
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ACS Catalysis
Attempts to obtain an authentic sample of halides (dppe
=
1,2-bis(diphenylphosphino)ethane); this
1
[NiCl(CH2CH2Ph)(dppf)] (11-Cl) by reaction of [NiCl2(dppf)] (4-
Cl) with the appropriate Grignard reagent led only to
decomposition products including styrene and ethylbenzene;
no NiI products were detected by EPR analysis, suggesting that
the NiI in the reactions between Ni0 and alkyl halides must arise
through comproportionation and therefore does not form in
the absence of Ni0. The instability of 11-Cl makes any
comproportionation pathways between this complex and Ni0
unlikely. Attempts to prepare [Ni(H)(Cl)(dppf)] (10-X) by
reaction of [NiCl2(dppf)] (4-Cl) with various hydride sources did
not produce any tractable nickel hydrides and no structurally-
similar nickel hydrides have been reported in the literature.38
complex is known to be unreactive towards a range of species
found in typical cross-coupling reactions35 but is capable of
undergoing outer-sphere electron transfer.44 The dppe ligand
has similar electronic properties to dppf, as judged from IR
spectra of [Ni(CO)2(dppf)] (νCO (DCM) = 2001, 1939 cm-1)45 and
[Ni(CO)2(dppe)] (νCO (CHCl3) = 2006, 1945 cm-1).46 [Ni(dppe)2]
(12) does not undergo reaction with alkyl halides at all. If the
reaction proceeded via outer-sphere electron transfer, then
both [Ni(dppf)2] (5) and [Ni(dppe)2] (12) should be competent.
However, only 5, which can open a vacant site, undergoes
reaction while 12, which cannot open a vacant site, is inert.
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We propose that putative hydride complex 10-X undergoes
7. DFT Calculations of a Halide Abstraction Mechanism
decomposition
comproportionation
to
form
with
[NiX(dppf)]
(3-X)
via
The halide abstraction pathway was modelled using DFT
calculations.47 Pathways via [Ni(dppf)2] (5) are discussed here;
alternative pathways that are ruled out based on experimental
evidence are discussed in the Supporting Information.
Throughout this manuscript energies from DFT calculations are
quoted as free energies in benzene solvent with respect to
[Ni(COD)(dppf)] (1) unless otherwise stated;48 a 1.89 kcal/mol
correction is applied to the free energy of each molecule so
that the standard state is then 1 mol/L rather than 1 atm.49
Ni0.
Reactions
between
[Ni(COD)(dppf)] (1) and 1 equiv. of 2-X (in the presence of 0.3
equiv. dppf) were followed by 1H NMR spectroscopy, and
showed a signal consistent with that for hydrogen;39 when the
sample was placed under a hydrogen atmosphere, the
intensity of this signal increased, supporting the assignment.
It has been shown using computational techniques that
complexes of the form [NiH2(PR3)2] exist most favorably as
non-classical dihydrogen complexes, suggesting the release of
hydrogen from such a species to be facile;40 no such complexes
The formation of [Ni(dppf)2] (5) from [Ni(COD)(dppf)] (1) is
energetically favorable (Figure 2); [Ni(κ2-dppf)(κ1-dppf)] (5’) in
which one phosphine is dissociated from the nickel center is
slightly higher in energy than 5 (by 2.6 kcal mol-1) so is also a
plausible intermediate. DFT calculations overestimate the
stability of 5, compared to experimental data for the
equilibrium between 1 and 5, but qualitatively agrees in that
the formation of 5 is favorable. Complexes 5 or 5’ might be able
to undergo outer-sphere electron transfer to the alkyl halide,
and so the barrier for these processes was estimated using
Marcus-Hush theory;50 the barriers are rather high (26 – 33 kcal
mol-1 for 5; 31 – 38 kcal mol-1 for 5’; see the Supporting
Information).
have been experimentally characterized.
A sample of
[Ni(COD)(dppf)] (1) placed under a hydrogen atmosphere at
room temperature decomposed slightly over the course of
several hours, forming free dppf and COD; the analogous
experiment with additional dppf formed COD and cyclooctene,
with the latter presumably arising from COD hydrogenation by
a putative nickel hydride intermediate.41
6. Ruling Out Outer-Sphere Electron Transfer
Two possible mechanisms for the reactions of [Ni(dppf)2] (5)
with alkyl halides can lead to the formation of alkyl radicals:
outer-sphere electron transfer or halide abstraction.18, 23-24, 42
These differ in that the latter requires a vacant site for
coordination of the substrate prior to halide abstraction. A
sample of [Ni(dppe)2] (12) was prepared43 and exposed to alkyl
Halide abstraction provides an alternative pathway; it is
proposed to be the predominant mechanism in this reaction
due to the lack of reactivity of [Ni(dppe)2] with alkyl halides
(vide supra). The binding of alkyl halides to 5’ via the halide is
20
10
0
‡
-hydride elimination
[Cl: 14.7]
Br: 10.5
[I: 7.1]
Ph
halide
abstraction
Br
Ni
Ph
H
Ni
Br
P
P
P
P
P
1
P
P
P
Ni
[Cl: -4.1]
Br: -5.1
[I: -5.2]
[Cl: -7.1]
Br: -7.1
[I: -7.2]
10-X
5'
[Cl: 2.8]
Br: 2.7
[I: 1.2]
P
0.0
P
P
[Cl: -12.6]
Br: -11.5
[I: -10.9]
P
P
Ni
H
[Cl: -7.3]
Br: -6.3
[I: -7.7]
P
Ni
Ph
Br
Ph
-11.9
-10
-20
-9.3
H
Ph
P
Ph
Br
Ni
Ni
Br
P
P
P
P
P
P
P
[Cl: -11.1]
Br: -12.3
[I: -14.2]
Ni
Br
P
Ni
P
11-X
P
P
P
P
P
Br
Ni
5
P
Figure 2. DFT studies of the reaction between [Ni(COD)(dppf)] (1) and (2-haloethyl)benzene substrates (2-X) via [Ni(dppf)2] (5). All energies
are free energies in kcal mol-1 in benzene solution and are quoted relative to complex 1. The profile is drawn for the case of (2-
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bromoethyl)benzene (2-Br) with energies provided in square brackets for the reactions of (2-chloroethyl)benzene (2-Cl) and (2-
iodoethyl)benzene (2-I). The dppf ligand is abbreviated to two linked P atoms for clarity.
1
2
3
4
5
6
7
8
9
‡
‡
30
Ph
oxidative addition
halide
abstraction
Br
Ni
14.4
Br
P
P
P
P
P
P
Br
P
Ni
P
P
Ph
Ni Br
P
‡
20
10
0
Ni
P
P
Br
Ni
P
P
14.3
Br
P
P
Br
14.1
13.5
12.5
P
Ph
Ni
P
10.7
P
P
P
Ni
P
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
5.3
0.6
Ni
1
P
P
0.9
Ph
Br
Ph
0.0
Br
Ni
P
P
P
P
P
P
Ni
-9.3
P
P
-11.9
-10
5'
P
P
Ni
P
P
P
P
P
P
Ph
Br
Ni
5
Ni
-19.0
P
P
-20
Figure 3. DFT studies of the reaction between [Ni(COD)(dppf)] (1) and bromobenzene. All energies are free energies in kcal mol-1 in benzene
solution and are quoted relative to complex 1. The dppf ligand is abbreviated to two linked P atoms for clarity.
endergonic by ca. 2 - 3 kcal mol-1, but the halide abstraction
transition state is then accessible (19 – 26 kcal mol-1 from 5).
previously been modelled for [Ni(PR3)3] complexes (PR3 =
PMe3, PMe2Ph, PMePh2, PPh3),23 and halide abstraction.
Oxidative addition would require the formation of an
intermediate η2-complex that is very high in energy (Grel = 13.5
kcal/mol), followed by a transition state that is higher in energy
still (Grel = 14.1 kcal/mol). Halide abstraction would proceed
through [Ni(κ2-dppf)(κ1-dppf)(BrPh)] (Grel = 0.9 kcal/mol),
leading to a halide abstraction transition state that is even
higher in energy (Grel = 14.4 kcal/mol). These data establish
that 1 will react with bromobenzene through oxidative
addition to a dppf-Ni(0) species; the formation of [Ni(dppf)2] as
a low-energy off-cycle species would impede this reaction by
increasing the barrier to oxidative addition, consistent with the
observed rate decrease when dppf is added to the reaction of
aryl bromides with 1.
Halide abstraction by [Ni(η2-COD)(dppf)]21 is ruled out based
on the experimentally-determined first order behavior in dppf.
In addition, computational studies of halide abstraction by
[Ni(dppf)(η2-ethene)] (as a model for [Ni(η2-COD)(dppf)]) show
that this process is less competent than halide abstraction by
5’, with a barrier that is 5.7 kcal/mol higher in energy (see the
Supporting Information for details).
The radical formed by halide abstraction recombines with
the NiI complex to form an alkylnickel(II) halide species with
the concomitant loss of a dppf ligand (Figure 2). The resulting
complex [Ni(CH2CH2Ph)(X)(dppf)] (11-X) is known to be
unstable
(vide
supra)
and
so
a
bimolecular
comproportionation pathway for this species is ruled out.
Instead β-hydride elimination forms [Ni(H)(X)(dppf)(η2-
styrene)] which can then dissociate styrene to form
[Ni(H)(X)(dppf)] (10-X). We have not modelled the subsequent
8. Relevance to Catalysis
The results discussed above allow new insight into steps that
can proceed under cross-coupling reaction conditions. It is
important to link these to an understanding of synthetically-
relevant catalytic reactions. This is especially important given
the significant interest in the synthesis of sp3-rich molecules for
medicinal chemistry and other applications, especially in fields
such as pharmaceuticals and agrochemicals.3-4 The
prototypical cross-coupling reactions of (2-haloethyl)benzene
substrates (2-X) with phenylmagnesium chloride were
selected (Scheme 4 (a)). These produced 1,2-diphenylethane
(13), regioisomeric side product 1,1-diphenylethane (14),
styrene, biphenyl, and ethylbenzene. Control reactions
without catalyst showed that the latter two products do not
processes
but
propose
that
10-X
undergoes
comproportionation with Ni0 present in the reactions to form
[NiX(dppf)] (3-X) and [Ni(H)dppf]. The latter complex could
undergo disproportionation to Ni0 and [Ni(H)2(dppf)], which
would then reductively eliminate hydrogen.
We have studied the corresponding reactions with an aryl
halide (bromobenzene) to understand why these proceed
more slowly in the presence of added dppf (Figure 3). The
oxidative addition of bromobenzene to [Ni(COD)(dppf)] (1)
proceeds via an intermediate η2-complex, presents a modest
barrier of 10.7 kcal/mol (from 1), and is exergonic. We were
unable to locate a corresponding halide abstraction transition
state, but this would be preceded by [Ni(dppf)(BrPh)] (Grel
=
arise
via
nickel-catalysed
processes.
Complexes
12.5 kcal/mol), in which bromobenzene ligates the nickel
center via a bromine lone pair. This structure is higher in
energy than the oxidative addition transition state by 1.8
kcal/mol. Two pathways were also considered for reactions via
[Ni(κ2-dppf)(κ1-dppf)] (5’): direct oxidative addition, which has
[Ni(COD)(dppf)] (1), [NiCl(o-tol)(dppf)] (15-Cl), and [NiCl(dppf)]
(3-Cl) were deployed as catalysts (Scheme 4(b)).51 Reactions
catalysed by 1 but without additional phosphine ligand yield
very poor results in catalysis, with incomplete conversion of 2-
X and low yields of product 13 and side-product 14. The
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addition of 5 mol% dppf significantly improved reaction converged on the same reaction outcome. This suggests that
1
2
3
4
5
6
7
8
outcomes, enabling full (or close to full) conversion of 2-X.
Reactions catalysed by [Ni(COD)(dppf)] (1), [NiCl(dppf)] (3-Cl),
and [NiCl(o-tol)(dppf)] (15-Cl) with 5 mol% of added dppf
they proceed via a common pathway, despite the different
pre-catalyst oxidation states. NiI complexes
(a)
(b)
5 mol% 1 or 3-Cl or 15
1.1 equiv. PhMgCl
X
Ph
THF, 85 °C, 24 h
2-X
13
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
[expected
product]
Ph
[regioisomer]
Ph
Ph
Ph
Ph
14
[side products
not from
[side product
from -hydride
elimination]
Ph Ph
Ph
Ni-catalysed
processes]
PPh2
Ni
PPh2
PPh2
Ni Cl
PPh2
3-Cl
PPh2
Ni
PPh2
Fe
Fe
Fe
Cl
1
15-Cl
Scheme 4. (a) Prototypical Kumada-Tamao-Corriu reactions. (b) Reaction outcomes. The quantity of biphenyl is not plotted.
such as 3-Cl form NiI-aryl species upon reaction with Grignard
reagents, and so can serve as Ni0 sources for catalysis.22, 52
Complex 15-Cl undergoes transmetalation with Grignard
reagents, followed by reductive elimination to form Ni0.22, 33
of
a
4-methylstyrene additive, 1-(4-methylphenyl)-1-
phenylethane (16) was also observed (Scheme 5(a)). We note
that nickel-catalyzed migratory Suzuki-Miyaura cross-coupling
reactions have been developed by Yin and co-workers,53 and
that our reactions share some mechanistic features with such
reactions, specifically the formation and recombination of an
alkyl radical and the transposition of the nickel center along an
alkyl chain. We propose that this results from migratory
insertion into a nickel hydride intermediate, followed by
transmetalation and reductive elimination (Scheme 5(b)).
While the secondary alkylnickel(II) complexes are higher in
energy than the corresponding primary alkylnickel(II)
complexes (11-X), subsequent events in the Kumada cross-
coupling reaction such as transmetalation and reductive
elimination may have different barriers that depend on the
isomer of the alkyl ligand the identity of the halide; this will be
explored in more detail in a subsequent study.
9. Reactions Involve both Radical Intermediates and β-
Hydride Elimination
The analysis of the side products in catalytic reactions gives
additional information about plausible reaction pathways.
Side-product 14 (1,1-diphenylethane) could be generated by β-
hydride elimination from [Ni(CH2CH2Ph)(X)(dppf)] (11-X)
followed by reinsertion to form the regioisomeric alkylnickel(II)
halide species [Ni(CH(Me)(Ph))(X)(dppf)] (an overall “β-
hydrogen transfer” process) and subsequent transmetalation
and reductive elimination; the plausibility of this pathway is
supported by DFT calculations (Figure 4), which indicate
relatively low barriers of ca. 16 – 19 kcal mol-1 from 11-X to the
highest energy transition state on the pathway, and lead to
isomeric alkylnickel(II) halide species that are only ca. 4 – 6 kcal
mol-1 higher in energy. Consistent with this proposal, when a
prototypical Kumada reaction was carried out in the presence
Cross-coupling reactions were carried out using substrates
that can act as radical traps. (Chloromethyl)cyclopropane
underwent a nucleophilic substitution reaction with the dppf
ligand. The reactions of 6-bromohex-1-ene (17-Br) were more
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‡
‡
Ph
1
2
3
4
5
6
7
8
H
Ni
Br
P
P
[Cl: 6.0]
Br: 5.8
[I: 5.2]
Ph
H
Ni
Br
P
P
10
0
[Cl: -5.2]
Br: -5.0
[I: -6.5]
Ph
11-X
P
Ni
[Cl: -7.0]
Br: -7.3
[I: -8.3]
[Cl: -7.1]
Br: -7.1
[I: -7.2]
[Cl: 2.8]
Br: 2.7
[I: 1.2]
H
Ni
Br
P
P
X
P
-10
Ph
H
Ph
P
P
Ph
P
P
[Cl: -12.6]
Br: -11.5
[I: -10.9]
9
Ni
Br
Ni
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
Br
Figure 4. DFT calculations of the migratory insertion pathway to form the regioisomeric alkylnickel(II) halide species implicated in the
formation of 14.
5 mol% 1
5 mol% dppf, 1.1 equiv. PhMgCl
1 equiv. 4-methylstyrene
(a)
13
14
Ph
16
Ph
2-X
Ph Ph
Ph
Ph
Ph
Ph
X
Ph
Ph
THF, 85 °C, 24 h
[expected
product]
[regioisomer
of product]
[incorporation of
4-methylstyrene]
[side products not from
Ni-mediated processes]
[-hydride elimination
side product]
(b)
P
P
P
Ph
Ni
p-tol
+ 4-methylstyrene
- styrene
14
Ni
Ni
16
H
Ni
X
H
Ni
X
P
P
P
P
X
X
X
P
+ styrene
- 4-methylstyrene
Ph
P
P
P
P
13
Ni
Ph
p-tol
X
5 mol% 1
(c)
18
Ph Ph
5 mol% dppf, 1.1 equiv. PhMgCl
19
Ph
Br
Ph
3
THF, 85 °C, 24 h
[expected product]
(minor)
[cyclised product]
(major)
[side products not from
Ni-mediated processes]
[-hydride elimination
side product]
Scheme 5. (a) Reactions in the presence of a 4-methylstyrene additive. (b) Proposed pathway for the incorporation of 4-methylstyrene into
cross-coupling products via migratory insertion into a nickel hydride intermediate. (c) Cross-coupling reactions with 6-bromohex-1-ene.
informative and led to (phenylmethyl)cyclopentane (19) as the
major product, along with 6-phenylhex-1-ene (18) and side
products biphenyl, hexa-1,5-diene, and hex-1-ene (Scheme
5(c)). Product 19 is proposed to arise from the cyclisation of
the intermediate primary radical (k = 1.8 x 105 s-1 at 20 °C),37
followed by capture by NiI. This provides further evidence of
the intermediacy of radical species in these reactions.
through complexes with one dppf ligand. The key mechanistic
event is halide abstraction to form a NiI species and a radical;
these then recombine to form a NiII species. Some alkyl
radicals, such as those derived from alkyl halides without β-
hydrogens, can undergo rearrangement reactions before
capture by NiI. The lack of reactivity of Ni0 complexes bearing
alternative bidentate phosphine ligands which more readily
form [Ni(L)2] complexes, such as [Ni(dppe)2] (12), show that it
is necessary to generate a vacant site for the reaction to occur.
2. The Fate of the NiII Intermediate. The NiII intermediate thus
formed can either undergo transmetalation during a cross-
coupling cycle or can undergo β-hydride elimination to form
styrene. Re-insertion of styrene is proposed to lead to a
regioisomer of the alkylnickel(II) species; this is also able to
undergo
CONCLUSION
We have conducted a thorough study of the reactions of
alkyl halides with dppf-Ni0 complexes. Scheme 6 outlines a
mechanism for this process that is supported by experimental
and DFT studies. The key points from this study are as follows.
1. The Nature and Reactivity of the Active Catalyst. Reactions
proceed through [Ni(dppf)2] (5), which bears two dppf ligands,
in contrast to the reactions of aryl halides which proceed
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Ph
X
Ph
H atom
abstraction
1
2
3
4
halogen
abstraction
- dppf
+ COD
X
X
P
P
P
Ph
P
P
P
P
P
P
P
Ni
Ph
Ni
Ni
Ni
P
P
P
P
+ dppf
- COD
5
6
7
8
radical
capture
Ph
- dppf
Ph
Ph
Ph
dppf
Ph
Ph
P
P
P
P
P
dppf
PhMgCl
P
P
9
Ph
Ni X
Ni
Ni
Ni
X
10
11
12
13
14
15
16
17
Ph
transmetalation
P
Ph
Ph
-hydride
elimination
PhMgCl transmetalation
migratory
H
Ni
X
Ph
P
P
H
X
H
Ni
X
P
P
P
insertion
Ph
Ni
Ni
P
P
X
P
Ph
Scheme 6. Processes occurring during the Kumada coupling reactions of (2-haloethyl)benzene substrates (2-X) with PhMgCl, catalysed by
[Ni(COD)(dppf)] (1) in the presence of additional dppf; the dppf ligand is simplified to two linked P atoms for clarity.
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
transmetalation and reductive elimination, leading to a side
ASSOCIATED CONTENT
product. The putative nickel hydride complex [Ni(H)(X)(dppf)]
(10-X) formed from β-hydride elimination then undergoes
comproportionation with Ni0 to form [Ni(X)(dppf)] (3-X) and
(ultimately) hydrogen.
This study provides insight into the activation of sp3 C-X
bonds for cross-coupling reactions, as part of our ongoing
programme to interrogate and understand reaction
mechanisms in nickel catalysis, with the aim of exploiting this
understanding for catalyst and reaction design. Further
mechanistic studies of oxidative addition to Ni0, and how these
depend on ligand and substrate structure, are currently
underway in our laboratory.
Supporting
Information.
Synthetic
procedures
and
characterization data for organometallic compounds; procedures
for/data from kinetic studies; procedures for/data from cross-
coupling reactions; computational details and cartesian
coordinates and energies for all structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We dedicate this paper to Professor John Murphy
(University of Strathclyde) on the occasion of his 65th birthday.
We thank Professor John Murphy (University of Strathclyde)
and Professor Rubén Martìn (ICIQ) for helpful discussions. We
thank Mr Gavin Bain (now retired), Mr Craig Irving, Mrs Alaine
Martin, Ms Patricia Keating, Dr John Parkinson, and Mr Jim
Tweedie for assistance with technical and analytical facilities at
the University of Strathclyde.
The raw data underpinning this study can be downloaded
from the University of Strathclyde Knowledgebase at
http://dx.doi.org/[DOI
TBA].
Computational
data
underpinning this study can be accessed via the ioChem-BD
data repository54 at http://dx.doi.org/[DOI TBA].
AUTHOR INFORMATION
Corresponding Author
* David J. Nelson. david.nelson@strath.ac.uk
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LANL2TZ(f) basis set on Ni and Fe, the LANL2DZ(dp) basis set on Br and I,
and the 6-31G(d) basis set on all other atoms. Frequency calculations were
used to verify the nature of stationary points. Potential energies were
refined using single point calculations in benzene solvent (SMD), and with
the 6-311+G(d,p) basis set on all atoms except I. Full details and
coordinates for all structures can be found in the Supporting Information.
51.
Reaction outcomes were determined using GC-FID analysis
with an internal standard, which was calibrated using authentic samples of
all products. See the Supporting Information for full details and reaction
data
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48.
Optimisation was carried out in the gas phase, because
attempts to optimise some of these structures in solvent using PCM or
SMD methods were unsuccessful. Some structures could be optimised in
solvent, but this made rather little difference to the energetics of the
relevant steps. See the Supporting Information for more details.
Li, Y.; Luo, Y.; Peng, L.; Li, Y.; Zhao, B.; Wang, W.; Pang, H.; Deng,
9
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Harvey, J. N.; Himo, F.; Maseras, F.; Perrin, L., Scope and
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Inorganics 2019, 7 (3), 32.
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Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title,
should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem,
etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications.
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+ dppf
- COD
Ph2
PPh2
Ni
PPh2
PPh2
Ni
PPh2
P
Fe
Fe
Fe
P
+ COD
- dppf
Ph2
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Unreactive
Reactive Species
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Halide
Abstraction
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R
H2
PPh2
Ni
PPh2
PPh2
Fe
Fe
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Ni
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PPh2
R
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