Aldehydes and ketones influence reactivity and selectivity in nickel-catalysed Suzuki-Miyaura reactions

Article abstract of DOI:10.1039/c9sc05444h

The energetically-favorable coordination of aldehydes and ketones-but not esters or amides-to Ni⁰ during Suzuki-Miyaura reactions can lead either to exquisite selectivity and enhanced reactivity, or to inhibition of the reaction. Aryl halides w

Full text of DOI:10.1039/c9sc05444h

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DOI: 10.1039/C9SC05444H
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Aldehydes and Ketones Influence Reactivity and Selectivity in
Nickel-Catalysed Suzuki-Miyaura Reactions
Alasdair K. Cooper,a David K. Leonard,a‡ Sonia Bajo,a‡ Paul M. Burton,b and David J. Nelsona
Received 00th January 20xx,
Accepted 00th January 20xx
The energetically-favorable coordination of aldehydes and ketones – but not esters or amides – to Ni0 during Suzuki-Miyaura
reactions can lead either to exquisite selectivity and enhanced reactivity, or to inhibition of the reaction. Aryl halides where
the C-X bond is connected to the same π-system as an aldehyde or ketone undergo unexpectedly rapid oxidative addition
to [Ni(COD)(dppf)] (1), and are selectively cross-coupled during competition reactions. When aldehydes and ketones are
present in the form of exogenous additives, the cross-coupling reaction is inhibited to an extent that depends on the strength
of the coordination of the pendant carbonyl group to Ni0. This work advances our understanding of how common functional
groups interact with Ni0 catalysts and how these interactions affect workhorse catalytic reactions in academia and industry.
DOI: 10.1039/x0xx00000x
Introduction
(a) Previous work: a reactivity scale for oxidative addition to [Ni(COD)(dppf)]
R
Ph Ph
P
Ph Ph
P
Nickel catalysis has the potential to replace palladium catalysis
in some reactions and to enable new reactivity that can be
exploited in organic synthesis.1 These reactions include tandem
X
comproportionation
X
Fe
Fe
Ni
P
Ph
Ni
P
Ph
 Ar-Ar,
ArH
Ar
Ph
Ph
1
photocatalysis/cross-coupling,2, reductive cross-electrophile
3
PPh2
Reaction Rate
Fe
Ni
X
coupling,4 and the cross-coupling of phenol derivatives,5 aryl
fluorides,6, 7 and amides.8 Several issues remain to be resolved
before the full potential and impact of nickel catalysis can be
realised. We must understand how nickel interacts with the
functional groups that are present in target molecules in the
fine chemicals, agrochemicals, and pharmaceutical industries,
to understand the scope and limitations of existing methods
and the opportunities and challenges to consider when
developing new ones. The underlying reaction mechanisms in
nickel catalysis, and how these depend on substrate and ligand
structure, remain relatively poorly understood compared to
palladium catalysis, and so nickel-catalysed reactions are often
treated as a ‘black box’. Correspondingly, reaction design and
optimisation rely heavily on empirical observations.
X = I > Br > Cl > OTs > OCO2Et > OTf >
OCONEt2 > OSO2NMe2 > OPiv > OMe  F
PPh2
(b) This work: aldehydes and ketones influence rate and selectivity
O
O
R
R
R = H, Me, CF3, Ph
R = H, Me, CF3, Ph
X
Privileged Substrates
 Enhanced oxidative addition rate
 Selectivity over other substrates
Catalyst Inhibitors
 Coordinates to nickel(0)
 Inhibit catalytic reactions
Figure 1. (a) Previous work. (b) This work.
addition or halide abstraction, depending on the ligand and
substrate structure.13-17 [Ni(COD)(dppf)] (1)18 undergoes
oxidative addition to aryl halides, followed by rapid
comproportionation to form [NiX(dppf)] (Figure 1(a));19 we have
established the order of reactivity of a series of aryl (pseudo)
halides. It was noted during our previous studies that aryl
halides that had aldehyde or ketone substituents underwent
unexpectedly fast oxidative addition. Further investigations
have revealed that aldehyde and ketone functional groups can
act either as directing groups for selective synthesis or as
inhibitors of catalytic reactions (Figure 1(b)). Our initial
empirical study showed that various coordinating groups elicit
these effects, and that they are considerably more marked for
nickel than for palladium.20 Here, we examine the specific case
The mechanisms of nickel-catalysed cross-coupling
reactions remain relatively poorly understood and show a
complex dependence on ligand and/or substrate. The
mechanistic landscape is further complicated by the often-
ambiguous role of nickel(I) species in catalysis.9-12 [Ni(NHC)2]
and [Ni(PR3)4] complexes react with aryl halides by oxidative
a. WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde,
295 Cathedral Street, Glasgow, G1 1XL, Scotland. david.nelson@strath.ac.uk
b. Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42
6EY, UK.
† Current address for DKL: Leibniz-Institute for Catalysis, Albert-Einstein-Straße 29a,
18059 Rostock, Germany. Current address for SB: Institute for Chemical Research
(IIQ), CSIC-University of Sevilla, Avda. Américo Vespucio 49, 41092 Sevilla, Spain
Electronic Supplementary Information (ESI) available: rate constants, reaction
procedures, characterisation data for compounds, and energies and geometries
from DFT studies. See DOI: 10.1039/x0xx00000x
of aldehydes and ketones in depth using
experimental and computational techniques.
a range of
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Table 1. Psuedo-first order and relative rate constants for the
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0.1
DOI: 10.1039/C9SC05444H
reactions between 1 and substrates 2-6. All rate constants are
the average of two measurements. [nd] = not determined.
0.0
-0.1
-0.2
-0.3
-0.4
y = 1.15x - 0.01
R² = 0.99
20 equiv.
R
Ph Ph
P
Ph Ph
P
X
y = -1.5964x + 0.6659
Fe
Fe
Ni
P
Ph
Ni
P
Ph
X
C6D6
Ph
Ph
1
-0.50
-0.25
0.00
0.25
0.50
0.75
Oxidative Addition Rate Constants
σp
°
°
Substrate
kobs (20 C)
kobs (50 C)
krel
Figure 2. Hammett plot for oxidative addition of aryl chlorides to 1 from reactions at 50
°C in benzene-d6.19
O
2.5(3) x 10-4 s-1
4.2(3) x 10-4 s-1
3.0(2) x 10-4 s-1
[nd]
[nd]
[nd]
0.32
2a-Cl
Cl
Cl
Results and Discussion
Kinetic Studies of Oxidative Addition
O
0.54
0.38
Aldehyde and ketone-substituted aryl chlorides undergo
surprisingly rapid oxidative addition, compared to the oxidative
addition rates for a set of other substrates (Figure 2). The
consumption of 1 in the presence of excess aryl halide was
monitored using 31P NMR spectroscopy and exhibited pseudo-
first order behaviour; rate data are recorded in Table 1. The
ultimate nickel-containing products are [NiX(dppf)] complexes,
2b-Cl
O
Cl
2c-Cl
O
1
as confirmed by EPR and H NMR spectroscopies.21 In contrast
1.41(1) x 10-4 s-1
[nd]
0.18
H
to cross-coupling reactions (vide infra) where transmetalation
and reductive elimination can take place, the only pathway
available to the arylnickel(II) halide intermediates formed
during these kinetic experiments is comproportionation with 1
to form NiI products.
Substrates 2-Cl to 4-Cl undergo oxidative addition much
more rapidly than electron-deficient aryl chloride 5-Cl or
bromide 5-Br. These large rate differences cannot be attributed
simply to inductive or mesomeric electronic effects; Hammett
σp is 0.4 – 0.5 for ketones, aldehydes and esters and 0.54 for
trifluoromethyl.22 The Hammett plot for oxidative addition of
aryl chlorides to 1 is shown in Figure 2.19
Ligand exchange, where COD is replaced with the aryl
halide, and the oxidative addition event that follows cannot be
deconvoluted; we propose that the favourable coordination of
aldehydes and ketones to Ni0 (vide infra) improves the
equilibrium position of the ligand exchange (COD versus aryl
halide), leading to a reaction that is more rapid overall.
Consistent with this, signals that are tentatively assigned to an
η2(CO) complex are observed during the oxidative addition
reactions of 3-Cl; various complexes of this type are known,23-30
and have been implicated in nickel-mediated reactions.31 The
observed signals in the 31P{1H} NMR spectrum are consistent
with a square planar complex (two doublets with 2JPP of 31 Hz).
This geometry is a result of electron donation from the
bisphosphine ligand into the 3d(x2-y2) orbital, which is also
engaged in d to π* back-bonding.32, 33 The measured Keq for the
displacement of COD from 1 using benzaldehyde (>20),
benzophenone (0.65), and acetophenone (0.02) are sufficiently
large that under catalytic conditions – i.e. in the presence of a
3-Cl
Cl
O
9.2(2) x 10-5 s-1
[nd]
0.12
Ph
4-Cl
Cl
Cl
CF3
[nd]
2.39(3) x 10-4 s-1
0.007
5-Cl
CF3
2.38(4) x 10-5 s-1
7.8(1) x 10-4 s-1
[nd]
1.02(1) x 10-3 s-1
0.031
1.0
5-Br
Br
CF3
5-I
O
[nd]
I
1.85(4) x 10-4 s-1
0.005
MeO
6-Cl
Cl
large excess (ca. 10 – 100 equiv.) of each cross-coupling partner
– that this coordination would be expected to occur to the
extent that between 2 and 100% of the Ni0 present would be
coordinated to a carbonyl group. The lack of a similar effect for
esters (e.g. 6-Cl) is attributed to n to π*CO resonance effects
between the oxygen lone pair and the ester carbonyl group.
2 | Chem. Sci., 2020, 00, 1-3
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Cross-Coupling Selectivity
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DOI: 10.1039/C9SC05444H
CF3 -26.5
R
Grel
The coordination of aldehydes and ketones to Ni0 can be
leveraged to achieve selective cross-coupling. Optimised cross-
coupling conditions were developed for the prototypical cross-
coupling of 2a-Br with p-tolylboronic acid, catalysed by well-
defined [NiCl(o-tol)(dppf)] pre-catalyst 7,34 using factorial
experimental design.‡ To dissect the contributions of electronic
and coordination effects, experiments were performed in which
bromobenzene and a functionalized aryl bromide competed for
a limiting amount of boronic acid (Figure 3 (a)).§ Data were
interpreted by quantifying selectivity using equation (1) (Figure
3 (b)); this has values between -1 and +1 which represent
complete selectivity for bromobenzene and functionalised aryl
bromide, respectively. The reaction selectivity was plotted
versus σ (Figure 3(c)).35 These data show that selectivity is
typically insensitive to the electronic properties of the aryl
halide, but significant selectivity is achieved when the aryl
halide has a ketone or aldehyde functional group.36 This
selectivity trend is observed for both meta- and para-
substituted aryl bromides. These data confirm that aldehyde
and ketone substituents can be used to induce selective cross-
coupling at one substrate present within the reaction.
(a)
Ph Ph
P
H
-16.8
O
Fe
Ni
P
Ph
Ph -16.7
Me -13.7
OMe -4.3
R
Br
Ph
‡
(b)
Ph Ph
P
3.8
1.3
Br
Fe
B
Ni
-2.1
-3.3
0.0
-0.1
-1.4
P
Ph Ph
Ph
Ph
P
Ni
P
X
Fe
Ph Ph
P
Br
Ph
Ph
Fe
Ni
P
8
-7.3
-9.7
Ph
Ph
X = NMe2
X = H
Ph Ph
-24.4
C
X
Br
P
Fe
Ni
-28.2
-31.6
-32.2
X = CF3
X = CHO
P
X
Ph
Br
Ph
A
‡
‡
(c)
O
R
Br
Computational Modelling of Ring Walking and Oxidative Addition
O
R
DFT calculations give further insights into these reactions.§§
[Ni(dppf)(η2-benzene)] (8) was assigned Grel = 0. Consistent with
experiment, aldehydes and ketones coordinate [Ni(dppf)]
exergonically via the carbonyl group (Figure 4 (a)). Free energy
profiles were calculated for the oxidative addition reactions of
selected aryl bromides (Figure 4 (b));37 reactions proceed via
transition state B to irreversibly form NiII products C. The
aldehyde substrate can also form the η2(CO) complex.
Ni0
-4.1
-6.4
Ni0
P
P
P
P
Grel = 0
-0.6
-1.3
R
-8.8
-9.7
O
-8.4
Ni0
Br
P
P
R
-9.7
Br
R
-13.6
-17.1
O
R = Me
R = H
(a)
R
R
Ni0
Br
5 mol% 7
O
Ni0
P
P
1 equiv. p-tolB(OH)2
P
P
A
B
3 equiv. K3PO4, 85 C, 2 h
PhMe, 10 equiv. H2O
Figure 4. (a) Coordination to aldehydes, ketones, and esters. (b) Free energy profile for
oxidative addition. (c) Calculations on the ring-walking process. All energies are free
energies in toluene solution and are quoted in kcal mol-1.
Br
Br
p-tol
p-tol
(1 equiv. each)
(b) Selectivity = [ B ] - [ A ] / [ A ] + [ B ]
(1)
Further calculations were undertaken to model the ring-
walking38-42 step, using 2a-Br and 3-Br as substrates. In each
case, three η2-complexes are linked by two transition states,
leading from the carbonyl group to the halide site (Figure 4 (c)).
The transition states for these ring-walking steps are all lower in
energy than 8 and so this process is more energetically
favourable than the dissociation of the aryl halide and
coordination of a new aryl halide; once an aldehyde- or ketone-
containing substrate coordinates the nickel centre via the
carbonyl ligand, it will undergo oxidative addition after ring
walking, rather than ligand exchange for an alternative
substrate. Substrate 2c-Br undergoes a similar ring-walking
process, again with no intermediates or transition states that
have Grel > 0.‡ These data are consistent with two key
experimental observations: (i) the enhanced rate of oxidative
(c)
Figure 3. Competition experiments: (a) reaction conditions; (b) quantification of
selectivity; and (c) reactions in toluene with 10 equiv. water. Each individual competition
experiment is plotted as a separate point
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5 mol% 7
1.1 equiv. p-tolylB(OH)2
Robustness
Screening a
Competition
DOI: 10.1039/C9SC05444H
CF3
CF3
Reactions b
p-tol
3 equiv. K3PO4, 85 C, 2 h
PhMe, 10 equiv. H2O
p-tol
no additive
58% (53-62%)
Br
R = CHO 52(5)%
vs
Ph2P
PPh2
no additive
88% (88-93%)
Ni
Results quoted as: Average conversion (min - max)
1 equiv. PhCHO
Cl
R = CF3 0%
Robustness Screening
5% (0-10%)
20
R
O
O
O
10
Ph
88% (87-89%)
11
12
Ph
O
Ph
OMe
Ph
NH2
p-tol
9
no additive
73% (66-79%)
O
R = CHO 11(3)%
vs
R = CF3 0%
78% (73-83%)
78% (75-81%)
86% (86-87%)
O
Cl
1 equiv. PhCHO
22% (16-27%)
O
Ph2P
Ni
PPh2
O
O
13
14
15
Ph
21
R
CF3
Ph
Ph
Ph
H
38% (33-43%)
12% (11-13%)
1% (1-1%)
a) 5 mol% catalyst, 1 equiv. 5-Br, 1.1 equiv. p-tolB(OH)2, 3 equiv. K3PO4,
10 equiv. H2O, PhMe, 85 °C, 2 h. b) 5 mol% catalyst, 1 equiv. 3-Br, 1 equiv.
5-Br, 1 equiv. p-tolB(OH)2, 3 equiv. K2PO4, 4:1 v/v THF/water, 85 °C, 2 h.
O
O
19
Ph
87% (85-88%)
16
17
18
H
N
OMe
NMe2
S
Ph
Ph
Ph
Ph
86% (81-90%)
Figure 5. Results from the robustness screen.
Figure 6. Results with dppe and Xantphos catalysts.
77% (72-81%)
83% (82-84%)
containing aryl halides than they do on the cross-coupling of
aryl halides that do not contain these functional groups.
The robustness screening data are consistent with
coordination of an exogenous additive to the Ni0 catalyst
inhibiting the reaction. No ring-walking is possible from such
intermediates to a site for oxidative addition or other exergonic
onward reaction.
addition, because η2(CO) coordination renders aldehyde- and
ketone-containing aryl halides competitive ligands (versus
COD); and (ii) selective cross-coupling, because aldehyde- and
ketone-containing aryl halides are much better ligands for Ni0
than aryl halides without such strongly coordinating groups.
Catalyst Inhibition by Aldehydes and Ketones
On the Generality of These Effects
The coordination of ketones and aldehydes to Ni0 might be
expected to have a detrimental effect on the performance of
cross-coupling reactions if this behaviour sequesters the active
catalyst. A ‘robustness screen’43, 44 was used, in which a model
reaction was carried out in the presence of 1 equiv. of each of a
series of additives (9 – 19).§ This provides a rapid and
quantitative measure of the effect of each additive. A palette of
additives was examined (Figure 5).
These observations are not limited to dppf-based (pre)catalysts.
[NiCl(o-tol)(L)n] (L = dppe (20), Xantphos (21))34 were applied in:
(i) competition reactions between 5-Br and 3-Br, in which 3-Br
reacts exclusively; and (ii) robustness screening reactions using
5-Br as the substrate and benzaldehyde as the additive, showing
significant reaction inhibition (Figure 6).§ Complexes 20 and 21
perform significantly less well than 7 but may yield better
results if further reaction optimisation was carried out. The
results in Figure 6 illustrate that the effect is general to nickel
phosphine complexes, and not limited to dppf-based catalysts.
Palladium, specifically [PdCl2(dppf)], shows a far reduced
propensity to undergo selective cross-coupling reactions, but
has far better functional group tolerance. 20
Most additives had little effect on the reaction conversion.
Aldehyde and ketone additives – except for acetophenone (12)
– had a significant and detrimental effect, with the reaction
almost completely ceasing when
1 equiv. of 2,2,2-
trifluoroacetophenone (15) was present. The degree of
inhibition of the reaction is correlated to Keq for the
displacement of COD from 1 (vide supra); it may be necessary
to protect aldehydes and ketones in some reactions to prevent
their coordination to Ni0. If catalyst decomposition was
responsible for the decrease in yield then we would expect that
at the end of the reaction ≥5% of the additive would have been
consumed;45 in the case of 13 and 14, ≤ 2% of the additive is
unaccounted for, while 15 hydrates in the presence of water,
resulting in the absence of 12 – 15% of 15 at the end of the
reaction. There is no correlation between the degree of
inhibition and the amount of additive unaccounted for.
Control experiments where one equivalent of benzaldehyde
was added to the cross-coupling of 4-Cl and p-tolylboronic acid
showed complete conversion to the cross-coupling product.
Aldehyde and ketone additives therefore have less of an effect
on the cross-coupling reactions of aldehyde- and ketone-
Opportunities for Exploitation
The carbonyl coordination effect was leveraged to achieve site
selectivity in cross-coupling reactions, both intermolecularly
and intramolecularly (Figure 7). The aldehyde/ketone effect
allows the normal reactivity order of aryl halides (I > Br > Cl)19
to be entirely overridden, to the extent that an aryl chloride (2a-
Cl) undergoes selective coupling in the presence of an electron-
deficient aryl bromide (5-Br) and even in the presence of an aryl
iodide (5-I) (Figure 7 (a)). Reactions are selective for aldehydes
over ketones, as judged from further competition experiments.‡
Ketones that are not in conjugation with the aryl halide π-
system are not selectively coupled (e.g. 22-Br) (Figure 7 (b)).
Intramolecular competition experiments were carried out using
23-Cl, which has two aryl chloride sites that are available for
4 | Chem. Sci., 2020, 00, 1-3
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ketone. Intrinsic differences in the reactivities of aryl chlorides,
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F
F
(a)
F
F
F
F
O
O
5 mol% 7
1 equiv. p-tolB(OH)2
3 equiv. K3PO4
bromides, and iodides have been leveDraOgI:e1d0.1i0n39t/hCe9SpCa0s5t44f4oHr
selective cross-coupling reactions,46 but this work shows that
the substitution pattern of the aryl halide can significantly
change the order of reactivity, opening new avenues for
creative organic synthesis using nickel-catalysed cross-coupling.
vs
plus
4:1 v/v THF/H2O
85 °C, 2 h
X'
p-tol
X
p-tol
X = Br
X = Cl
X = Cl
X = Cl
X' = I
2.1
>20
20
:
:
:
:
1
1
1
1
X' = Cl
X' = Br
X' = I
Conclusions
1.6
This work establishes how aldehydes and ketones can have
positive or negative effects on nickel-catalysed reactions,
depending on their location. The formation of η2-complexes has
been implicated in some nickel-catalysed reactions30, 31, 39, 47, 48
but this work shows that coordination effects can influence
even simple and ubiquitous Suzuki-Miyaura reactions.
(b)
O
Ph
O
Ph
Ph
O
Ph
O
5 mol% 7
1 equiv. p-tolB(OH)2
3 equiv. K3PO4
vs
plus




Aryl halides with aldehyde and ketone functional groups
undergo rapid oxidative addition because of favourable
ligand exchange and ring-walking processes.
Selectivity is achieved for aldehyde- or ketone-containing
aryl halides over other aryl halide substrates because of this
favourable coordination.
Aldehydes and ketones that are present in cross-coupling
reactions but are not in conjugation with the aryl halide act
as inhibitors of catalysis.
Aldehydes and ketone-containing aryl halides undergo
successful cross-coupling.
4:1 v/v THF/H2O
85 °C, 2 h
Br
p-tol
Br
p-tol
4-Br
22-Br
>20
:
1
(c)
Cl
Ph
Ph
5 mol% 7
2 equiv. PhB(OH)2
23-Cl
plus
O
O
O
3 equiv. K3PO4
4:1 v/v THF/H2O
85 °C, 2 h
Figure 8 summarises the conclusions of this study using
Ni0/NiII cycles based on literature evidence from studies of
nickel/dppf-catalysed reactions.18, 19, 49-53 Figure 8 (a) shows a
cycle for a reaction in which an aldehyde or ketone is present as
an additive; a low energy η2(CO) complex sequesters the active
catalyst and slows the reaction because the η2-complex with the
aryl halide is higher in energy. Figure 8 (b) shows a cycle for an
aryl halide with an aldehyde or ketone substituent.
Cl
Cl
Ph
20 ± 3%
7 ± 2%
Figure 7. (a) Overriding the intrinsic reactivity differences between aryl halides.
(b) Selectivity between different carbonyl-containing substrates. (c) Site-
selectivity within a molecule, enforced by carbonyl coordination.
cross-coupling but only one is in conjugation with a ketone
(Figure 7 (c)); reactions with 23-Cl establish that selective cross-
coupling occurs at the site that is in conjugation with the
Aldehyde or Ketone Additive
Aldehyde or Ketone Substrate
(a)
(b)
R
C(O)R
R
C(O)R
oxidative
addition
oxidative
addition
X
X
X
X
Ni0
NiII
Ni0
NiII
NiII
Ni0
P
P
P
P
P
P
P
P
P
P
ArB(OH)2
base, H2O
X
ArB(OH)2
base
ring
walking
transmetallation
B(OH)3, MX
C(O)R
H2O
R'
R'
R
R
O
O
O
R
R
Ar
Ni0
Ni0
Ni0
R
X
P
P
P
P
O
P
P
Ar
Ni0
X
thermodynamic
sink for Ni0
Ar
P
P
B(OH)3
MX
reductive
elimination
R
C(O)R
R
C(O)R
Ni0
Ar
R
C(O)R
reductive
elimination
Ar
Ar
Ar
P
Ni0
NiII
P
P
P
P
P
P
P
Figure 8. (a) Catalytic cycle for nickel-catalysed Suzuki-Miyaura reactions in the presence of exogenous aldehyde or ketone. (b) Catalytic cycle for nickel-catalysed Suzuki-Miyaura
reactions of aldehyde- and ketone-containing aryl halides.
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We are grateful for funding from: a Syngenta/Engineering and
Physical Sciences Research Council (EPSRC) Industrial CASE
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O
O
DOI: 10.1039/C9SC05444H
R
R
Ni
X
Catalyst Inhibitors
Privileged Substrates
 Coordinates to nickel(0)
 Inhibit catalytic reactions
 Enhanced oxidative addition rate
 Selectivity over other substrates
Aldehydes and ketones can have either a beneficial or detrimental effect on nickel-catalysed
reactions, depending on their locus within the reaction. When present on the aryl halide, excellent
site-selectivity can be achieved; when present as additives, they inhibit the reaction.