Experimental and Computational Studies towards Chemoselective C?F over C?Cl Functionalisation: Reversible Oxidative Addition is the Key

Article abstract of DOI:10.1002/cctc.202001462

Catalytic cross-coupling is a valuable tool for forming new carbon-carbon and carbon-heteroatom bonds, allowing access to a variety of structurally diverse compounds. However, for this methodology to reach its full potential, precise control over all competing cross-coupling sites in poly-functionalised building blocks is required. Carbon-fluorine bonds are one of the most stable bonds in organic chemistry, with oxidative addition at C?F being much more difficult than at other C-halide bonds. As such, the development of methods to chemoselectively functionalise the C?F position in poly-halogenated arenes would be very challenging if selectivity was to be induced at the oxidative addition step. However, metal-halide complexes exhibit different trends in reactivity to the parent haloarenes, with metal-fluoride complexes known to be very reactive towards transmetalation. In this current work we sought to exploit the divergent reactivity of Ni?Cl and Ni?F intermediates to develop a chemoselective C?F functionalisation protocol, where selectivity is controlled by the transmetalation step. Our experimental studies highlight that such an approach is feasible, with a number of nickel catalysts shown to facilitate Hiyama cross-coupling of 1-fluoronapthalene under base free conditions, while no cross-coupling with 1-chloronapthalene occurred. Computational and experimental studies revealed the importance of reversible C?Cl oxidative addition for the development of selective C?F functionalisation, with ligand effects on the potential for reversibility also presented.

Full text of DOI:10.1002/cctc.202001462

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Experimental and computational studies towards chemoselective
C-F over C-Cl functionalisation: reversible oxidative addition is
the key
Authors: Emily Jacobs and Sinead Teresa Keaveney
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.202001462
Link to VoR: https://doi.org/10.1002/cctc.202001462
01/2020

10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
Experimental and computational studies towards chemoselective
C-F over C-Cl functionalisation: reversible oxidative addition is
the key
Emily Jacobsa and Sinead T. Keaveneya,*
Abstract: Catalytic cross-coupling is a valuable tool for forming new
carbon-carbon and carbon-heteroatom bonds, allowing access to a
variety of structurally diverse compounds. However, for this
methodology to reach its full potential, precise control over all
competing cross coupling sites in poly-functionalised building blocks
is required. Carbon-fluorine bonds are one of the most stable bonds
in organic chemistry, with oxidative addition at C-F being much more
difficult than at other C-halide bonds. As such, the development of
methods to chemoselectively functionalise the C-F position in poly-
halogenated arenes would be very challenging if selectivity was to
be induced at the oxidative addition step. However, metal-halide
complexes exhibit different trends in reactivity to the parent
haloarenes, with metal-fluoride complexes known to be very reactive
towards transmetalation. In this current work we sought to exploit the
divergent reactivity of Ni-Cl and Ni-F intermediates to develop a
chemoselective C-F functionalisation protocol, where selectivity is
controlled by the transmetalation step. Our experimental studies
highlight that such an approach is feasible, with a number of nickel
catalysts shown to facilitate Hiyama cross coupling of 1-
fluoronapthalene under base free conditions, while no cross coupling
with 1-chloronapthalene occurred. Computational and experimental
studies revealed the importance of reversible C-Cl oxidative addition
for the development of selective C-F functionalisation, with ligand
effects on the potential for reversibility also presented.
relatively robust substrates. In addition, elegant strategies to
selectively functionalise C-F in the presence of C-H have been
7]
developed,[3a,
however catalytic procedures to selectively
functionalise C-F in the presence of other C-halides are limited
(Figure 1, top). Stoichiometric reactions of nickel complexes with
activated pyrimidines marks the first demonstration of
chemoselective C-F activation in the presence of C-Cl,[8] with
use of a directing group also shown to be effective.[9] In addition,
Ni-fluoride complexes have been shown to readily undergo
transmetalation with boronic acids, while other Ni-halides do
not.[4a] In this current work we sought to contribute to this
emergent field through investigating a new approach to selective
C-F functionalisation, where C-F over C-Cl selectivity could be
induced at the transmetalation step (Figure 1, bottom).
In the proposed concept, selectivity is controlled by the
divergent reactivity of the intermediate generated following
oxidative addition: a metal-F intermediate can undergo direct
and base-free transmetalation with organosilanses and boronic
acids, whereas other metal-halides cannot.[4] Thus, base-free
Hiyama or Suzuki cross coupling could allow chemoselective C-
F functionalisation, in the presence of typically more active C-
halide bonds, to be realised. This proposed selectivity is the
opposite of what could be achieved if selectivity was controlled
by the rate of C-halide oxidative addition to nickel.[10] Through
combined experimental and computational investigations we
demonstrate the feasibility of this approach, and uncover the key
role that reversible oxidation addition will play in developing
Introduction
Selec0ve C-F over C-Cl func0onalisa0on
Carbon – fluorine bond activation remains a key challenge in
synthetic chemistry, with research in this field driven by the
prevalence of commercially available fluoroarenes,[1], as well as
the widespread industrial applications of fluorinated compounds
in the pharmaceutical, materials chemistry and agrochemical
sectors.[2] Catalytic cross coupling at the stable C-F bond is
particularly attractive as it can permit derivatisation of poly- or
per-fluorinated building blocks,[3] as well as providing a robust
synthetic handle for late-stage diversification of complex
molecules. Importantly, oxidative addition of C-F to a transition
metal centre generates an active metal-F intermediate, which
can also allow unique reactivity to be developed through the use
of fluorinated substrates.[4]
X
X
Previous work:
PdCl2(PCy3)2
F
R
F
F
R-MgBr
Ni(COD)2
PCy3
N
N
N
N
Cy3P
Ni
X = OH or NH2
Cl
Cl
F
F
F
F
Cl
Cl
§ꢀ Cataly,c reac,on
Cy3P
§ꢀ Direc,ng group required
§ꢀ 3 examples
§ꢀ Stoichiometric reac,on
§ꢀ Ac,vated substrate
ref. 8
ref. 9
Divergent reac,vity of Ni-halide complexes demonstrated
X
R
Cy3P Ni PCy3
Cy3P Ni PCy3
X = F
X = Cl or Br
R-B(OH)2
R-B(OH)2
No reac,on
ref. 4a
No general method to selec0vely func0onalise C-F over C-Cl
While there have been substantial breakthroughs in
fluoroarene cross coupling methodologies in recent years, the
majority of procedures require nucleophillic organomagnesium[5]
or organozinc[6] coupling partners, limiting applications to
This work…towards a general, transmetala<on controlled method
for selec<ve C-F over C-Cl func<onalisa<on
Cl
F
Ni
Ln
Cl or F
Ni
Ln
R
R-SiX3
Ni
Ni
R-SiX3
[a]
Ms Emily Jacobs and Dr Sinead T. Keaveney*
Department of Molecular Sciences
Macquarie University
North Ryde, NSW, 2019, Australia
*E-mail: sinead.keaveney@mq,edu,au
✓
No reac,on
Figure 1: Top: previous work on selective C-F over C-Cl functionalisation, and
studies on metal halide reactivity. Bottom: the concept explored in this work.
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
transmetalation-controlled selectivity. The insight presented in
this current work lays the groundwork for designing
chemoselective C-F functionalisation methodology in the future,
as well as allowing the more rational design of ligands that could
permit reversible oxidative addition.
S5). Lastly, increasing the metal loading to 20 mol% raised the
yield of 3 to 75%, with additional improvement offered by
increasing the scale of the reaction. Ultimately, an excellent
isolated yield of 85% was achieved (Table 1 and S6), with the
remaining material being 1-methoxynapthalene which forms
through methoxy group transfer, similar to that observed
previously for activated fluoroarenes.[4c]
Results and Discussion
Table 1: Development of the reaction conditions to promote base free Hiyama
cross coupling of 1-fluoronapthalene 1. See Tables S1-6 for additional data.
Bimetallic C-F activation is often postulated in the Kumada or
Negishi cross coupling of fluoroarenes, where the magnesium or
zinc species are directly involved in the oxidation addition
step.[11] This Lewis acid assisted activation accounts for the
prevalence of Kumada and Negishi type C-F cross coupling
approaches, with no reported examples of Hiyama cross
coupling of unactivated fluoroarenes. As such, the first challenge
is to develop a base-free Hiyama cross coupling protocol that
can be applied to an unactivated fluoroarene. We chose the
Temperature /
°C
Ni:ligand
ratio
Ni
loading
Yield
3 / %
Ligand
Solvent
-
100
100
100
100
100
100
100
100
100
130
80
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
-
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
0
0
PPh3
SPhos
PBu3
PCyp3
PCy3
PtBu3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:1
1:1
0
0
model
reaction
between
1-fluoronapthlene
1
and
5
trimethoxyphenylsilane 2 (Scheme 1), with 1-fluoronapthalene 1
simply chosen to allow the homo- and cross coupling products to
be differentiated.
5
0
F
Ph
O
Ni(COD)2
ligand
2
O
O
Si
+
+ F-Si(OMe)3
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
10
4
16 h, 80°C
3
1
2
Scheme 1: The model cross coupling reaction between 1-fluoronapthalene 1
and trimethoxyphenylsilane 2.
trace
trace
10
100
80
As oxidative addition at the inert C-F bond will be challenging,
we initially chose to focus on the use of electron rich phosphine
ligands, and the abundant metal nickel. A range of ligands were
examined using a Ni:ligand ratio of 1:2, with poor sigma
donating ligands, such as PPh3, being ineffective (Tables 1 and
S1). Surprisingly, use of the more electron rich and bulky biaryl
phosphine ligands widely used for C-Cl activation,[12] such as
SPhos, were also ineffective. While the electron rich PBu3 ligand
did not facilitate cross coupling, some product formation was
observed for PCy3 and PCyp3 (where Cy = cyclohexyl and Cyp =
cyclopentyl). This suggests that both increased sigma donating
ability and steric bulk of the ligand favours cross coupling, with
the latter likely due to promotion of the reductive elimination
step. Interestingly, there appears to be a limit to which steric
bulk promotes cross coupling, with no product formation
observed when using PtBu3.
A variety of solvents were then considered, with 2-
methyltetrahydrofuran (2-MeTHF) being most effective (Table
S2). However, the reaction temperature was limited to 100 °C,
with no product 3 formation observed at 80 °C (Table 1). While
an additive free approach was desirable, we also tested a range
of Lewis acid and base additives to probe their effect on this
process. Despite broad screening, no increase in product
formation was observed in any case (Table S3). The nickel to
ligand ratio was found to impact cross coupling, with use of a 1:1
ratio allowing the reaction to proceed at 80 °C (Tables S4 and
10
mol%
32
80
(41a)
20
mol%
75
PCy3
80
2-MeTHF
1:1
(85a)
Reaction conditions: 1-Fluoronapthalene
1
(13 µL, 0.1 mmol),
trimethoxyphenylsilane 2 (37 µL, 0.2 mmol), Ni(COD)2, ligand and solvent (0.3
mL) were added to a 4 mL pressure tube in an argon atmosphere glovebox.
The tube was sealed, removed from the glovebox and heated for 16 hours. 4-
Trifluoromethoxyanisole (15 µL, 0.1mmol) was added as the internal standard,
and the crude reaction mixture was analysed using GC-MS, with the yield of
product 3 determined using a calibration curve (see Figure S1). aIsolated yield,
with the reaction performed on a larger scale (1 mmol of 1-fluoronapthalene
1).
As this is the first example of Hiyama cross coupling of an
unactivated fluoroarene, a small scope of substrates were
considered, focusing on unactivated fluoroaromatic compounds
(Scheme 2). We found that Hiyama cross coupling of 2-
fluoronapthalene to give the product 4 proceeded well (63%),
however some unreacted 2-fluoronapthalene, as well as 2-
methoxynapthalene, was observed. Surprisingly, when using 2-
fluorobiphenyl and 4-fluorobiphenyl lower yields of the cross-
coupled products 5 (15%) and 6 (<5%) were observed, with
mainly unreacted starting material remaining. The higher
reactivity of 2-fluorobiphenyl compared to 4-fluorobiphenyl
suggests that steric bulk promotes cross coupling.
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10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
starting materials remained, with 19F NMR spectroscopic
analysis finding that >95% of 1-fluoronapthalene 1 was still
Ni(COD)2 (20 mol%)
PCy3 (20 mol%)
Ph
F
O
O
O
Si
+
+
F-Si(OMe)3
2-MeTHF
R
present
(relative
to
the
internal
standard
4-
R
16 h, 80°C
trifluoromethoxyanisole).
2
Ph
Ph
Ph
N
Ni(COD)2 (20 mol%)
PCy3 (20 mol%)
Ph
Cl
Ph
O
Ph
O
O
Ph
Si
+
+ Cl-Si(OMe)3
2-MeTHF
CF3
7, 5%b
Ph
6, 25%a
16 h, 80°C
3, 0%
3, 85%
4, 63%
5, 21%
12
2
Ph
Scheme 3: The key control reaction with 1-chloronapthalene 12, highlighting
that cross coupling only occurs at C-F, not at C-Cl, under the developed
conditions.
Ph
Ph
Ph
Bu
Ph
11, 65%c
F
8, 67%
9, 76%
10, 80%
O
Ph
O
Ni(COD)2 (20 mol%)
PCy3 (20 mol%)
O
O
F-Si(OMe)3
+
Scheme 2: Scope of the nickel catalysed, base free Hiyama cross coupling of
fluoroaromatic compounds and trimethoxyphenylsilane 2. Reaction conditions:
Fluoroarene (1 mmol), trimethoxyphenylsilane 2 (2 mmol), Ni(COD)2 (0.2
mmol), PCy3 (0.2 mmol) and solvent (3 mL). Isolated yields are reported,
unless otherwise stated. aReaction performed using PAd2Bu (0.8 mmol),
instead of PCy3. bYield determined by 19F NMR, using 4-
trifluoromethoxyanisole as internal standard. cYield determined by 1H NMR,
using 4-trifluoromethoxyanisole as internal standard.
Si
1
+
+
+
Cl
2-MeTHF
Cl-Si(OMe)3
16 h, 80°C
2
3, 0%
12
Scheme 4: The competition experiment between 1-fluoronapthalene 1 and 1-
chloronapthalene 12, where no cross coupling is observed.
As phenyl-based fluoroaromatic compounds will be considered
in the chemoselectivity section of this manuscript, we sought to
increase conversion of 4-fluorobiphenyl to the product 6 by using
a different ligand. We found that the more bulky ligand di(1-
adamantyl)-n-butylphosphine (PAd2Bu) could effectively promote
cross coupling, giving the product 6 in 25% isolated yield. The
effectiveness of this more bulky ligand, relative to PCy3, further
suggests that increased steric bulk favours cross coupling, likely
due to promotion of the reductive elimination step. Interestingly,
when using an activated pyridine-based substrate low yields of
the cross coupled product 7 was observed, with a significant
To provide insight into the reaction mechanism, and to probe the
origin of the observed reaction inhibition when both C-F and C-
Cl are present, we turned to Density Functional Theory (DFT)
calculations. All calculations were performed using Gaussian
16,[13] with geometry optimisations and frequency calculations
performed using the ωB97X-D level of theory with the 6-31G (d)
basis set for H, C, P, O, N, F and Cl, and the SDD basis set for
Ni and Si. Single point energy calculations were performed using
the M06L level of theory and the def2TZVP basis set, with the
CPCM model used to incorporate the implicit solvent effects of
THF (see the Supporting Information for more details, and
testing of other computational methods). Our experimental data
suggest that a less bulky NiPCy3, not Ni(PCy3)2, based species
is the active catalyst, thus a typical 3-centred oxidative addition
transition state is likely.[14] Moreover, as no P-F formation was
observed experimentally, ligand-assisted oxidative addition can
be excluded,[15] and as no homo-coupling was observed, the
formation of a Ni(I) species is unlikely.[10] Thus, in our DFT
studies, 3-centered oxidative addition transition states were
considered, which is consistent with that frequently reported for
Ni catalysed oxidative addition of C(sp2) electrophiles.[11b, 15-16]
Comparing the reaction profiles for Hiyama cross coupling
at the C-F and C-Cl sites (Figure 2), it is clear that oxidative
addition at C-Cl is favoured over C-F, as expected based on the
reported rate constants for oxidative addition of different
electrophiles to nickel.[10] Interestingly, two different transition
states were located - one that involves explicit 2-MeTHF
coordination, and one that does not. For the transition states that
involve explicit 2-MeTHF coordination, the barriers for C-F and
C-Cl oxidative addition were 28.4 and 8.0 kcal mol-1,
respectively. When considering the transition states that do not
amount of homo-coupling detected. Lastly,
a number of
substituted napthalenes were considered, with good yields of the
products 8-11 observed, highlighting that electron-donating
groups are tolerated.
With this protocol now in hand, we then moved onto the
main focus of this work – studies towards the development of a
selective C-F over C-Cl cross coupling protocol. The key proof of
principle experiment, where 1-chloronapthalene 12 was used in
place of 1-fluoronapthalene 1, was performed. To our delight, we
found that the product 3 did not form when 1-chloronapthalene
12 was used (Scheme 3), which is strong evidence of the
divergent reactivity of the generated Ni-F and Ni-Cl
intermediates. That is, the Ni-F intermediate will undergo direct
transmetalation with the silane 2, whereas the analogous Ni-Cl
intermediate will be unreactive. While this is proof that the
proposed transmetalation based selectivity approach is feasible,
it is necessary for this selectivity to hold when both C-F and C-Cl
groups are present. Unfortunately, in the competition experiment
between 1-fluoronapthalene 1 and 1-chloronapthalene 12, no
product formation was observed (Scheme 4). Analysis of the
crude reaction mixture by GC-MS indicated that only unreacted
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10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
involve 2-MeTHF coordination, the barrier for C-Cl oxidative
addition is unchanged (8.2 kcal mol-1), however there is a
significant decrease in the barrier for C-F oxidative addition
(23.8 kcal mol-1). The differences in the Gibbs free energy for
oxidative addition when considering the two transition states
suggest that direct solvent coordination does not affect C-Cl
oxidative addition, yet disfavours oxidative addition at C-F. As
such, use of non-coordinating solvents may be a useful tool to
help promote selective C-F activation.
C-F oxida*ve addi*on transi*on states
Cy3P
O
Ni
X
Ni
Si(OMe)3
Cy3P
X
X = Cl
Cy3P Ni
> 50
28.4
X
23.8
C-F transmetala*on transi*on state
O Ni
X
Gibbs free energy
given in kcal mol-1
PCy3
8.2
8.0
O = 2-MeTHF
X = F
2-MeTHF
O Ni PCy3
X
COD-Ni-PCy3
2.1
X = Cl
0.6
0.0
Ni
X
PCy3
-12.4
-12.4
-14.1
-25.5
Cy3P Ni
Ph
X = F
-22.5
C-Cl oxida*ve addi*on transi*on states
-26.1
Figure 2: The calculated reaction profiles for the Hiyama cross coupling reaction between trimethoxyphenylsilane 2 and either 1-fluoronapthalene 1 (red) or 1-
chloronapthalene 12 (blue), focusing on the key oxidative addition and transmetalation steps. CPCM (THF) M06L/def2TZVP//ωB97X-D/6-31G(d)+SDD, Gibbs
free energy given in kcal mol-1.
Following oxidative addition, a number of different intermediates
could form. For the intermediates that feature direct 2-MeTHF
coordination, the lowest energy species for both Ni-F and Ni-Cl
have the naphthalene and halide moieties trans to each other.
Prior to transmetalation the 2-MeTHF molecule will likely
dissociate to form the three coordinate naphthalene-Ni-halide
species.
A significant difference between the 1-fluoronapthalene 1
and 1- chloronapthalene 12 reaction pathways was observed at
the transmetalation step; while a low energy transition state
could be located for the Ni-F analogue, no low energy transition
state could be located for direct transmetalation with the Ni-Cl
The reaction profiles also provide key insights into the
origin of the experimentally observed reaction inhibition when
both C-Cl and C-F are present. While the only productive cross
coupling pathway begins with oxidative addition at C-F, the
competing oxidative addition at C-Cl will lead to the very stable
Ni-Cl intermediate (-26.1 kcal mol-1). Under the developed
reaction conditions, it is likely that formation of the Ni-Cl
intermediate is irreversible, thus the nickel catalyst gets trapped
as the Ni-Cl intermediate, inhibiting cross coupling. As such, to
achieve chemoselective cross coupling at C-F, oxidative addition
at C-Cl needs to be reversible. To examine how to promote
reversible oxidative addition at C-Cl, a series of ligands were
investigated (Figure 3). This is particularly important as there is
a growing interest in harnessing reversible oxidative addition to
develop unique reactivity,[18] thus further insight into ligand
effects on reversibility is needed. In addition, there is precedent
for reversible oxidative addition at Ni allowing the higher energy
reaction pathway to be followed, leading to selective product
formation.[18e] As such, achieving selective C-F over C-Cl
functionalisation is feasible if the C-Cl oxidation addition step is
reversible.
intermediate.
This
is
in
agreement
with
previous
computational[17] and experimental[4a] studies on direct
transmetalation at metal-halide intermediates, and suggests that
the barrier for direct transmetalation at the generated Ni-Cl
intermediate is very high. This computational data further
supports the conclusion from our experimental work – that base
free Hiyama cross coupling cannot occur for 1- chloronapthalene
12 due to the challenging transmetalation step.
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10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
Me
P
P
P
P
P
P
Key
Me
Me
PMe3
PCyp3
PCy3
PtBu3
PCy2CyPh
PCy2PhPh
30
20
10
0
24.4
24.3
23.9
22.5
Ligand Ni
X
17.7
15.9
10.4
9.2
8.8
8.3
7.6
4.0
COD-Ni-Ligand
ΔG
-10
-20
-30
-6.6
-11.5
-12.3
-12.7
-13.6
-15.9
Red: X=F
-23.1
Blue: X=Cl
-24.8
-24.8
Ni
X
-26.0
-26.0
-29.0
-29.0
-29.0
Ligand
-29.9
ΔG (Cl):
-29.0
-29.9
-23.1
iPr iPr
iPr iPr
iPr iPr
iPr
iPr
N
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
40
30
20
10
0
Im-tBu
29.3
Im-Ph
29.3
diMe
SiPr
6-SiPr
30.2
iPr
7-SiPr
27.2
Im-Me
25.3
Im-iPr
Im-Cy
26.1
26.7
26.6
26.6
26.5
12.6
11.5
11.2
11.0
10.5
10.4
10.4
9.6
9.2
9.2
-0.5
-2.7
-5.5
-10
-20
-30
-6.4
-6.6
-9.6
-11.3
-12.7
-13.1
-15.4
-16.0
-17.2
-20.2
-22.9
-22.9
-23.9
-23.9
-24.8
-24.8
-26.6
-26.6
-27.3
-27.3
-27.5
-27.5
-28.6
-28.6
-20.2
-16.0
-17.2
Figure 3: Assessment of the ability of a range of Ni-ligand species to promote oxidative additive at either 1-fluoronapthalene 1 (red) or 1-chloronapthalene 12
(blue), with a focus on the potential for reversible C-Cl oxidative addition. CPCM (THF) M06L/def2TZVP//ωB97X-D/6-31G(d)+SDD, Gibbs free energy given in
kcal mol-1.
In this section, the focus was on understanding how the ligand
affects the relative barriers for oxidative addition at C-F and C-
Cl, as well as the stability of the generated Ni-Cl intermediate. Of
particular importance was the potential for reversible C-Cl
oxidative addition, which can be assessed by comparing the
energy difference between the Ni-Cl intermediate and the resting
state of the catalyst (∆G(Cl), see Figure 3 ‘Key’). A negative
value indicates that the Ni-Cl intermediate is more stable than
the catalyst ground state. As such, as this value becomes less
negative (and ideally, positive), the potential for reversible
oxidative addition increases. It should be noted that the true
nature of the catalyst resting state would play a key role in
determining whether oxidative addition is reversible. For
example, when using multiple equivalents of ligand a more
stable Ni complex may form, which would make reversible
oxidative addition more likely as ∆G(Cl) will be less negative.
However, for consistency, in all calculations the resting state of
the catalyst was the ligand-Ni-COD species, and the oxidation
addition transition states did not involve explicit 2-MeTHF
coordination.
To begin with, the ligands PMe3, PCyp3, PCy3 and PtBu3
were examined (Figure 3). These ligands were chosen as they
have comparable sigma donating abilities, yet highly varied
steric bulk. Interestingly, it was found that, in general, the barrier
for oxidative addition at C-Cl decreases with increasing steric
bulk, with the best ligand being PtBu3. In contrast, less bulky
ligands were generally favoured for C-F oxidative addition, with
PCyp3 being most effective. In terms of Ni-halide intermediate
stability, as the steric bulk on the ligand increases, both the Ni-F
and Ni-Cl intermediates become less stable. This is important,
as it indicates that the potential for reversible oxidative addition
increases with greater steric bulk on the ligand. This effect can
be clearly seen when comparing the difference in energy
between the ground state catalyst and the Ni-Cl intermediate
(∆G(Cl)): the PMe3 and PCyp3 ligands have the most negative
∆G(Cl) (-29.0 and -29.9 kcal mol-1, respectively), and the PtBu3
ligand has the least negative ∆G(Cl) of -23.1 kcal mol-1. As such,
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10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
in this series the PtBu3 ligand is most likely to facilitate selective
cross coupling at C-F over C-Cl.
substituted carbenes were considered (Im-Me, Im-iPr, Im-Cy and
Im-tBu, Figure 3). As expected based on the phosphine series, it
was found that, in general, bulkier substituents on the carbene
ligand destabilised the Ni-halide intermediates, with the Im-tBu
ligand having the least negative ∆G(Cl) of -20.2 kcal mol-1.
However, experimental tests using Im-tBu found that this ligand
was unable to promote cross coupling between 1-
fluoronapthalene 1 and trimethoxyphenylsilane 2, with only 0-5%
yield of the product 3 observed under the conditions examined
(Table S11).
We next moved to aryl substituted N-heterocyclic carbene
ligands, as these can allow increased steric bulk around the Ni
centre to be introduced. In our computational analyses of the
phenyl-substituted N-heterocyclic carbene series Im-Ph, diMe
and iPr (Figure 3), it was surprising to see that the inclusion of
ortho substituents on the phenyl ring had little effect on the
potential for reversibility, with all ligands having ∆G(Cl) within -
23.9 to -26.6 kcal mol-1. The data for the iPr and SiPr ligands
were also very similar, suggesting that saturation of the
backbone of the imidazolium ring has little effect on the energy
of the oxidative addition transition states, or the Ni-halide
intermediates.
As steric bulk around the Ni centre will likely increase the
potential for C-Cl reversibility, the ring expanded carbenes 6-
SiPr and 7-SiPr were considered next. It was found that there
was a significant difference in ∆G(Cl) between SiPr and 6-SiPr (-
22.9 and -16.0 kcal mol-1, respectively), due to destabilisation of
the Ni-Cl intermediate when moving from SiPr to 6-SiPr.
Interestingly, there were only minor changes in ∆G(Cl) when
moving from 6-SiPr to the ring expanded 7-SiPr analogue, likely
due to the buckling of the 7-membered ring to reduce steric
congestion around the NCN centre.
Overall, based on the computational data for the aryl
substituted N-heterocyclic carbene ligands, the 6-SiPr ligand has
the greatest potential for promoting chemoselective C-F over C-
Cl cross coupling. As such, the 6-SiPr ligand was synthesised,
along with the iPr and SiPr ligands for comparison (see
Supporting Information for details). We also examined the
commonly used IMes ligand as an additional comparison. We
first performed a series of optimisation reactions to refine the
developed reaction conditions so that cross coupling between 1-
fluoronapthalene 1 and trimethoxyphenylsilane 2 would occur
(Table S11). We found that while iPr and SiPr could promote
In the initial development of our base-free Hiyama cross
coupling reaction we found that use of Ni(COD)2 with PtBu3 was
ineffective at promoting cross coupling (Table 1), which is
consistent with the ineffectiveness of bulky phosphines in nickel
catalysis observed previously.[19] However, considering the
potential of this ligand to promote reversible oxidative addition at
C-Cl, we re-visited the use of PtBu3. Unfortunately, even after a
thorough investigation of different reaction conditions when
using Ni-PtBu3 or Pd-PtBu3 based catalysts, no cross coupling
between 1-fluoronapthalene 1 and trimethoxyphenylsilane 2 was
ever observed (Tables S7, S8, S9 and S10). These results
highlight a key challenge we have encountered: fluoroarene
cross coupling does not proceed when the ligand is too bulky,
however reversible C-Cl oxidative addition requires a bulky
ligand. These contradicting requirements make the development
of the desired chemoselective C-F over C-Cl functionalisation
protocol very difficult.
Despite this challenge, we examined a more diverse range
of ligands using DFT, to probe their potential for promoting
chemoselective C-F cross coupling. Considering the widespread
use of biarylphosphine-type ligands for chloroarene cross
coupling reactions,[12] we next examined PCy3 and PCy2Ph
derivatives with an ortho phenyl substituent (PCy2CyPh and
PCy2PhPh, respectively). We were particularly interested in
examining how potential interactions between the phenyl
substituent and the Ni centre affect the oxidative addition
transition states and Ni-halide intermediate stability. It was found
that there was a significant decrease in the barrier for both C-F
and C-Cl oxidative addition when using PCy2CyPh and PCy2PhPh,
relative to PCy3 (Figure 3). This is likely due to favourable Ph-Ni
interactions, as can be seen in both the C-F and C-Cl oxidative
addition transition states (see Figure 4 for the PCy2PhPh
analogues). However, the Ni-halide intermediates had similar
stability to the PCy3 analogues, with ∆G(Cl) ranging between -
24.8 to -29.0 kcal mol-1 for this series. As such, PCy2CyPh and
PCy2PhPh are unlikely to be able to promote selective C-F
functionalisation, in the presence of C-Cl.
cross
coupling
between
1-fluoronapthalene
1
and
trimethoxyphenylsilane
2
in good yields (62% and 58%,
respectively, see Table S11), no product 3 formation occurred
when both 1-fluoronapthalene 1 and 1-chloronapthalene 12
were present in the reaction mixture (Table S12). In contrast, the
IMes ligand was ineffective at promoting cross coupling between
1-fluoronapthalene 1 and trimethoxyphenylsilane 2, with <5%
conversion to the product
3 observed (Table S11). This
Figure 4: The calculated transition states for oxidative addition of either 1-
difference in activity between the iPr and iMes ligands suggests
that the ortho isopropyl groups on the ligand are important for
promoting fluoroarene cross coupling.
fluoronapthalene 1 (left) or 1-chloronapthalene 12 (right) to Ni-PCy2PhPh
.
Experimental studies on the key 6-SiPr ligand found that
this species was also ineffective at promoting cross coupling
between 1-fluoronapthalene 1 and trimethoxyphenylsilane 2
(<1% product 3 formed). As such, the ability of the 6-SiPr ligand
Considering that use of an electron-rich ligand is likely key to
achieving C-F functionalisation, we next examined a range of N-
heterocyclic carbene ligands, as variation of the N-substituent
allows fine-tuning of steric bulk. To begin with, simple alkyl
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10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
to facilitate chemoselective C-F over C-Cl functionalisation was
unable to be properly investigated. This parallels our results
from the PtBu3 ligand – while ligand bulk increases the potential
for reversible oxidative addition at C-Cl, ligands that are too
bulky are not able to facilitate nickel catalysed cross coupling
between 1-fluoronapthalene 1 and the silane 2 (Figure 5).
As an additional investigation into chemoselective C-F
found that toluene was a more effective solvent than 2-MeTHF –
for example, when using a Ni to ligand ratio of 1:4, use of
toluene led to 85% of the product 3, whereas use of 2-MeTHF
only gave 54% of the product 3 (Table S7). This data supports
the conclusions from our DFT analyses – that use of non-
coordinating solvents may increase fluoroarene cross coupling
through decreasing the barrier for oxidative addition. We next
performed competition experiments between 1-fluoronapthalene
t
functionalisation, the ligands PCy2 Bu and PAd2Bu were
t
examined experimentally (Figure 5). These asymmetric
phosphine ligands were chosen as they are more sterically
congested than PCy3, however less crowded than PtBu3, and
therefore might lie in the ‘sweet-spot’ of steric congestion to
allow both C-F cross coupling and C-Cl reversibility to occur.
Through analysis of a range of reaction conditions it was found
1 and 1-chloronapthalene 12 using the ligands PCy2 Bu and
PAd2Bu. For all of the conditions examined, cross coupling was
inhibited when 1-chloronapthalene 12 was added to the reaction
mixture, with only unreacted starting materials present in the
mixture (Table S10). As it has been previously demonstrated
that excess ligand can help promote reversible oxidative
addition,[18f] nickel to ligand ratios of 1:2, 1:4 and 1:8 were also
examined. However, in all cases no formation of the cross
coupling product 3 was observed when 1-chloronapthalene 12
was present (Figure 5).
t
that both PCy2 Bu and PAd2Bu promote cross coupling between
1-fluoronapthalene 1 and trimethoxyphenylsilane 2 in high yields
(85% and 92%, respectively, see Table S7), highlighting that
these bulky phosphine ligands are excellent at promoting
t
fluoroarene cross coupling. For the bulky ligand PCy2 Bu it was
F
Various condi,ons were examined, including:
qꢀ Solvents
Ph
O
Ni(COD)2 (20 mol%)
Ligand
O
O
F-Si(OMe)3
§ꢀ 2-MeTHF, toluene and dioxane
qꢀ Temperatures
§ꢀ 80, 110 and 130 °C
Si
1
+
+
+
+
Cl
Solvent
Temperature
16 h
Cl-Si(OMe)3
2
qꢀ Ni to ligand ra4os
3
§ꢀ 1:1, 1:2, 1:4 and 1:8
12
Does cross
coupling occur?
P
P
P
P
P
t
PCyp3
PCy3
PAd2Bu
PCy2 Bu
PtBu3
C-F 1 only:
✓
✓
✓
✓
C-F 1 and C-Cl 4:
iPr iPr
iPr iPr
iPr iPr
N
N
N
N
N
N
N
N
N
N
iPr
iPr
iPr
iPr
iPr
iPr
Im-tBu
IMes
iPr
SiPr
6-SiPr
✓
✓
Figure 5: Summary of the results of the experimental investigations into the base-free Hiyama cross coupling reaction between 1-fluoronapthalene 1 and
trimethoxyphenylsilane 2 when different ligands are used. See the Supporting Information for further details, and the specific reaction conditions examined.
Lastly, a number of fluoroarenes that feature a competing cross
coupling site were considered (Figure 6, compounds 14-20). In
this section we used reaction conditions identified as being most
promising for promoting chemoselective C-F functionalisation
phenyl-based (not napthyl). Under the three sets of reaction
conditions examined (Figure 6) the desired product 6 formed in
relatively low yields (10-35%, see Table S13). Despite these
lower yields, this data confirms that fluoroarene cross coupling
can occur with compound 13 under the reaction conditions
considered, and thus the competition experiments with
compounds 14-20 are valid.
t
(see Tables S7-S12), focusing on the ligands PCy2 Bu, PAd2Bu
and iPr. Initially, the control compound 4-fluorobiphenyl 13 was
tested to confirm that C-F cross coupling can occur under these
reaction conditions, as the majority of compounds 14-20 are
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10.1002/cctc.202001462
ChemCatChem
RESEARCH ARTICLE
tolerated, with the bulky PtBu3 and 6-SiPr ligands unable to
promote cross coupling. The mechanistic insight we have
provided into mono-metallic C-F activation lays the groundwork
for developing effective Suzuki and Hiyama fluoroarene cross
coupling methodology. Many of the current C-F functionalisation
protocols involve bimetallic C-F activation through the use of
nucleophillic organomagnesium or organozinc cross coupling
partners. As such, greater functional group tolerance may be
achieved through the use of milder boronic acid or silane
reagents.
Ph
Ni(COD)2 (20 mol%)
F
O
O
O
16 h, 80°C, and either:
Si
R
a) PCy2tBu (80 mol%), toluene, or
b) PAd2Bu (80 mol%), toluene, or
c) iPr (20 mol%), 2-MeTHF
+
R
2
+
F-Si(OMe)3
Does C-F func-onalisa-on occur?
F
F
F
F
Br
Cl
NO2
Ph
Cl
15
16
13
14
✓
✓
We have also demonstrated that the divergent reactivity of
Ni-Cl and Ni-F intermediates could permit selective,
Ph
OMe
Ph
Cl
NO2
transmetalation
controlled
C-F
functionalisation,
with
6, 10-35%
21, 5-15%
chloroarene cross coupling ineffective under the developed
base-free conditions. However, reversible oxidative addition at
the C-Cl position is needed for chemoselective C-F
functionalisation to be realised. Detailed computational and
experimental studies provided valuable insight into ligand effects
on the barriers for oxidative addition and the stability of the
generated Ni-halide intermediates. In general, the Ni-halide
intermediates become less stable when the ligand gets more
bulky, with the 6-SiPr, 7-SiPr, Im-tBu and PtBu3 ligands found to
be the most promising candidates for promoting reversible C-Cl
oxidative addition. A key challenge we encountered is that
fluoroarene cross coupling does not proceed when the ligand is
too bulky, however destabilisation of the Ni-Cl intermediate
requires a very bulky ligand. These contradicting requirements
make the development of the desired chemoselective C-F over
C-Cl functionalisation protocol challenging. In future work,
alternative approaches to destabilising the Ni-Cl intermediate will
be explored, such as the design of new ligands or the use of
destabilising additives.
F
F
F
F
TfO
TsO
I
17
18
19
20
Br
Figure 6: Competition experiments using fluoroarenes that feature an
additional site for cross coupling. Ts p-toluenesulfonyl, and Tf
trifluoromethanesulfonyl. See Table S13 for additional data.
=
=
To begin with, compounds 14 and 15 were considered, as they
both feature a competing C-Cl site. No cross coupling was
observed for 1-chloro-4-fluorobenzene 14, with GC-MS analysis
of the crude reaction mixture indicating that mainly unreacted
starting material was present, as well as a small amount (<5%)
of 4,4'-difluoro-1,1'-biphenyl, which would arise from homo-
coupling at the C-Cl site. Pleasingly, for 4-chloro-1-fluoro-2-
nitrobenzene 15 chemoselective C-F functionalisation was
observed, however the methoxy based product 21 formed. While
this highlights that selective functionalisation at C-F is possible,
the desired cross coupling pathway leading to phenyl group
incorporation did not occur. In addition, the nitro substituent on
compound 15 is likely activating the C-F bond, which would bias
C-F functionalisation.
Experimental Section
See the Supporting Information for all experimental details,
additional catalytic data and control experiments.
Compounds 16-20 performed similar to 1-chloro-4-
fluorobenzene 14, with no fluoroarene cross coupling observed.
The main species present in the crude reaction mixtures were
unreacted starting materials, however homo-coupling was
observed in varying amounts for compounds 15-19 (5-50%, see
Table S13). Interesting, no 4,4'-difluoro-1,1'-biphenyl was
observed for compound 20, suggesting that homo-coupling does
not occur as readily at the C-OTs bond (where Ts = p-
toluenesulfonyl).
Acknowledgements
The authors would like to thank the Chemical Analysis Facility at
Macquarie University, in particular Dr Nicole Cordina and Dr
Remi Rouquette. We also thank Dr Donald Cameron and Dr Ian
Jamie for training and assistance with GC-MS. This project was
undertaken with the assistance of resources and services from
the National Computational Infrastructure (NCI), which is
supported by the Australian Government. We would like to thank
Dr Damian Moran and Richard Miller for assistance with using
the NCI. EJ acknowledges the support of Macquarie University
through the Research Training Program (RTP) scholarship. STK
acknowledges the support of Macquarie University through the
receipt of a Macquarie University Research Fellowship (MQRF).
Conclusions
In summary, we have developed the first example of base free
Hiyama cross coupling of unactivated fluoroarenes. This is
important as it highlights that efficient, mono-metallic C-F
activation can be achieved under relatively mild conditions using
nickel catalysis, with a number of phosphine and carbene
ligands shown to be effective. In general, bulky and electron rich
ligands are required, however there is a limit to the steric bulk
Keywords: chemoselectivity • DFT • C-F activation • reversibility
• mechanism
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10.1002/cctc.202001462
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RESEARCH ARTICLE
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RESEARCH ARTICLE
Entry for the Table of Contents
Cl
F
Ni
Ln
Cl or F
Ni
Ln
R
R-SiX3
Ni
Ni
R-SiX3
✓
Base-free Hiyama cross coupling of unactivated fluoroarenes was developed, demonstrating that efficient, mono-metallic C-F
activation can be achieved using nickel catalysis. Experimental and computational investigations into the potential for selective C-F
cross coupling in the presence of more active C-halides were performed, highlighting that transmetalation-controlled C-F selectivity
may be possible if reversible oxidative addition can be achieved.
Institute and/or researcher Twitter usernames: @SineadKeaveney @MQSciEng @MQMolSci
This article is protected by copyright. All rights reserved.