Chemodivergent Nickel(0)-Catalyzed Arene C-F Activation with Alkynes: Unprecedented C-F/C-H Double Insertion

Article abstract of DOI:10.1021/acscatal.9b03620

Nickel-catalyzed C-F activations enabled chemodivergent C-C formation with alkynes by chelation assistance. The judicious choice of the alkyne electronic properties allowed the selective synthesis of double-insertion aromatic homologation or alkyne monoannulation products by C-F/C-H activation. On the basis of the unambiguous crystallographic characterization of an unprecedented nine-membered nickelacyclic intermediate and extensive DFT studies, a plausible mechanistic rationale was established for the selective C-F activation and the chemodivergent catalysis.

Full text of DOI:10.1021/acscatal.9b03620

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Article
Chemo-Divergent Nickel(0)-Catalyzed Arene C–F Activation
with Alkynes: Unprecedented C-F/C-H Double-Insertion
Lorena Capdevila, Tjark H. Meyer, Steven Roldán-Gómez, Josep María Luis, Lutz Ackermann, and Xavi Ribas
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03620 • Publication Date (Web): 09 Oct 2019
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Page 1 of 11
ACS Catalysis
Chemo-Divergent Nickel(0)-Catalyzed Arene C–F Activation with
Alkynes: Unprecedented C-F/C-H Double-Insertion
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Lorena Capdevila†, Tjark H. Meyer‡, Steven Roldán-Gómez†, Josep M. Luis†, Lutz Ackermann*‡,
and Xavi Ribas*†
†
Institut de Química Computacional i Catàlisi (IQCC) and Dep. Química, Universitat de Girona, Campus de
Montilivi, E-17003, Girona, Catalonia, Spain.
‡
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Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammanstrasse 2, 37077
Göttingen, Germany
ABSTRACT: Nickel-catalyzed C-F activations enabled chemo-divergent C-C formation with alkynes by chelation
assistance. The judicious choice of the alkynes electronic properties allowed the selective synthesis of double-insertion
aromatic homologation or alkyne mono-annulation products by C-F/C-H activation. Based on the unambiguous
crystallographic characterization of an unprecedented 9-membered nickelocyclic intermediate and extensive DFT studies,
a plausible mechanistic rationale was established for the selective C-F activation and the chemo-divergent catalysis.
INTRODUCTION
sought to develop new nickel(0)-catalyzed cyclizations of
fluorinated arene via alkyne insertion reactions.40 Herein, we
show that catalytic quantities of Ni(COD)2 enable the chemo-
divergent C-F activation over C-H activation of fluoroarenes
bearing either pyrimidin-2-amine29, 41 or 8-aminoquinoline42
groups, towards isoquinolones and polysubstituted arenes.
Mechanistic investigations were performed to clarify the
parameters that control the chemo-selectivity. Furthermore,
the use of the 8-aminoquinoline group allowed us to isolate
an unprecedented organometallic nickel(II) metalacycle
featuring a doubly inserted acetylene, as the key intermediate
in the aromatic homologation strategy (Scheme 1c).43
Fluorinated compounds are key structural moieties in
numerous areas of chemistry, with transformative
applications to crop protection, catalysis, medicine and
material sciences.1-4 The introduction of fluorinated motifs
thus changes the physical, chemical and biological properties
of a given molecule, and in the pharmaceutical industry
context, improves the stability and lifetime of F-containing
pharmaceuticals, 50% feature aryl fluorides. However, the
stability is often too pronounced and the lead compound is
frequently poorly biodegradable. Therefore, it is desirable to
develop new sustainable methods for the functionalization of
aromatic C-F bonds, as an enabling strategy to establish
novel chemo- and regio-selective transformation of
fluorinated arenes. Transition metal-catalysed Ar–F
functionalization is considerably more challenging than
classical Ar-H or Ar–Hal (Hal = I, Br, Cl) activation, generally
showing low selectivities and requiring electronically biased
polyfluorinated substrates.5-7 In particular, C–C formation
reaction via C–F cleavage of fluoroarenes using nickel catalyst
has been reported for Kumada-Corriu,8-16 Suzuki-Miyaura17-
22 and Negishi23 cross-coupling reactions. However, all these
methods use activated aryl nucleophiles, such as highly
reactive Grignard reagents, zincates and boronic acids as the
coupling partner for C–C formation via transmetallation
(Scheme 1a). Alkyne insertion reactions have emerged as a
powerful tool for the formation of cyclic compounds. Thus,
several protocols through transition metal-catalyzed C–H
activation have been established with alkynes to form
isoquinolones24-28 or indoles.29-32 The use of alkyne as a
coupling partner can also lead to the direct formation of
polysubstituted arenes.33-36 In this context, Chatani37 and
Huang38 recently reported nickel-catalyzed39 aromatic
homologation reaction by a double C-H bond activation
using 8-aminoquinoline as the directing group (Scheme 1b).
Scheme 1. (a) Nickel-catalyzed C–F activation reactions
using highly reactive, preactivated R-M nucleophiles. (b)
Alkyne annulation via C–H activation by nickel catalysts.
(c) Nickel-catalyzed C–F functionalization with internal
alkynes.
a
Nickel-catalyzed aryl fluorine cross-coupling reactions
R2
F
R2
M
R1
R1
Ni source
M
= B(OH)2, MgX, ZnX
R2 = alkyl, aryl
b
C-H activation via nickel catalysis using alkynes as coupling partner
O
Q
2-pym
N
H
DG
N
R
R
R
R
or
Ni source
H
R
R
R
R
DG = pyrimidin-2-amine
Ackermann 2013
[Ref 29]
Chatani 2016 [Ref 37]
Huang 2016 [Ref 38]
8-aminoquinoline
c
This work - selective C-F activation
H
H
O
O
H
Q
DG
N
H
R
Q
N
R
R
+
Ni source
F
R
H
H
R
R
R
R
DG = 8-aminoquinoline
Taking into account the steadily increasing interest in the
functionalization of the strongest bonds with carbon, we
via double acetylene insertion
Ni(II)-intermediate metalacycle
(XRD)
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ACS Catalysis
Page 2 of 11
functionalization reaction. The yield of the homologation
1
2
3
4
5
6
7
8
product did not increase by adding different auxiliary ligands
or changing the solvent. In addition, we synthetized substrate
1c which has two fluorides at the ortho- and meta- position
of the arene to explore the alkyne double insertion via C–F/C–
F functionalization. Here, only 12% of the homologation
product 2ca was formed (Table 1, entry 4). Interestingly, using
deactivated substrates, no alkyne annulation reaction took
place and only aromatic homologation products were
observed. The installation of a nitro group at C5 of the
quinolone moiety was not productive and only
decomposition products were obtained (Table 1, entry 5).
RESULTS
Role of N-substitution pattern. Initially, we probed the
catalytic activation of the strong C–F bond by exploring the
role of the directing group (DG) nature in the reaction with
diphenylacetylene. To this end, we used substrates with two
different well-studied directing groups, namely bidentate 8-
aminoquinoline 1a and monodentate pyrimidin-2-amine 1d
(Scheme 2). When the reaction was carried out with substrate
1d, a sluggish alkyne annulation reaction via C–H activation
took place (3da, 18%), and the C–F bond remained intact.
However, the use of 8-aminoquinoline as a bidentate
directing group was crucial for the selective functionalization
of the stronger C–F bond. Based on considerable
optimization (Table S1), the alkyne mono-annulation product
(3aa) was obtained in a 17% yield, and the aromatic
homologation product (2aa) was formed in a 63% yield
(Scheme 2). This preliminary result clearly suggested that a)
the bidentate 8-AQ was ideal for the selective C–F cleavage
whereas the monodentate DG only shows residual reactivity
on C-H activation, and b) the insertion of two alkynes
rendering the aromatic homologation product by dual C-
F/C-H activation was here clearly favoured over the alkyne
mono-annulation to form isoquinolones. Thus, we became
attracted to explore the parameters that govern this
selectivity.
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The formation of two distinct products 2 and 3 led us to
explore this reactivity further, changing the electronic
properties of the alkynes. Initial tests were performed using
1,2-di-p-tolyacetylene (Table 2, entry 2) and both products
were also formed in a similar ratio (2ab/3ab  3), although
with somewhat lower efficacy. In contrast, C-F activations
with electron-deficient para-halo-substituted tolanes,
yielded equal ratio of the two products (2ax/3ax  1, entries
3, 4 and 5). This increment in the alkyne mono-annulation
products suggests that the presence of electron-withdrawing
moieties favour the reductive elimination after the first alkyne
insertion.44-46 To address this point, we decided to study
stronger electron-withdrawing-groups (EWG), such as -
C(O)Me and -CF3 in the para-position. To our delight, the
aromatic homologation reaction was completely suppressed,
exclusively obtaining the alkyne mono-annulation products
in a 36 % for 3af (entry 6) and a 83 % for 3ag (entry 7),
respectively.
Scheme 2. Influence of N-substitution on C–F activation.
aromatic homologation alkyne annulation
DG = -NH-2-pym
N
2-pym =
Table 1. C-F functionalization using different
N
F
monodentate
2-pym
N
polyfluoroarenes.
C-H activation
R3
Ph
N
R3
Ph
Ph (2 equiv.)
R1
O
R1
O
Ni(COD)2 (10 mol%)
LiOtBu (2 equiv.)
Ph
18 % 3da
Conditions:
N
H
Ph
N
H
H
Ni(COD)2 (10 mol%)
Ph (2 equiv.)
N
1,4-dioxane, N2, 140˚C, 2h
F
DG
Ph
R2
Ph
Ph
LiOtBu (2 equiv.)
1,4-dioxane, 140 ˚C, 2 h
Ph
2xa
F
H
O
1a (R1 = R2 = H, R3 = H)
1b (R1 = F, R2 = H, R3 = H)
1c (R1 = H, R2 = F, R3 = H)
1e (R1 = R2 = H, R3 = NO2
H
O
Q
N
Q
H
C-F activation
N
Ph
+
DG = -CONH-Q
Ph
Ph
Ph
Ph
Q =
Ph
63 % 2aa
N
bidentate
17 % 3aa
Yield (%) of
2xaa
Entry
R1
R2
R3
1 b
2
H
F
H
H
H
F
H
H
63 % 2aa
13 % 2ba
34 % 2ba
12 % 2ca
traces 2ea
Influence of the electronic effect on the C-F activation.
With the optimal conditions for the C–F/C-H activation in
hand, we then turned our attention towards the
functionalization of the C–F bonds using different
fluoroarenes substrates. We performed a reaction using
substrate 1b, which has two fluorides at the ortho position of
the arene (Table 1, entry 2). In this case we could only obtain
13% of the homologation product 2ba under otherwise
identical conditions, suggesting that the presence of another
electron-withdrawing F was not beneficial for the C–F
3c
4d
5e
F
H
H
H
H
H
NO2
a
1
Yield calculated from H-NMR of crude reaction mixture
using 1,3,5-trimethoxybenzene as internal standard. b 17% of
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ACS Catalysis
alkyne annulation product3aa. c 16 h. d Other minor products
product, 2ak, was formed instead. Thus, sterically congested
alkyl groups disfavour the alkyne mono-annulation product.
1
2
were detected. e Conv = 63%.
Table 2. C-F functionalization using different
symmetric alkynes.
3
4
5
6
7
8
9
Table 3. C–F functionalization using alkyl-aryl and alkyl-
alkyl acetylenes.
R
R
R1
R2
O
(2 equiv. of a-g)
O
O
Q
(2 equiv. of h-k)
Ni(COD)2 (10 mol%)
LiOtBu (2 equiv.)
N
H
R
O
F
O
Ni(COD)2 (10 mol%)
LiOtBu (2 equiv.)
O
Q
R
Q
Q
Q
N
N
Q
N
H
N
+
H
N
H
1,4-dioxane (0.5 mL)
140 ˚C, 4 h, N2
H
R1
R2
R2
F
+
1,4-dioxane (0.5 mL)
140 ˚C, 4 h, N2
R
R
R
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1a
R
R2
R1
R1
3ax
2ax
R1
2ax2
R2
2ax1
1a
Yield
Yield
Total
yield
Entry
R’
H
of 2axa
of 3axa
Ratio
Yield (%)
of 2ax a
63 % 2aa
(60 %)
17 % 3aa
(11 %)
Entry
R1
R2
2ax1:2ax2
1b
2
80 %
54 %
83 %
73 %
74 %
36 %
88 %
b
40 % 2ab
(40 %)
14 % 3ab
(6 %)
57 % 2ah
(55 %)
Me
F
1c
2c
Ph
Ph
Ph
Pr
Me
Et
1.6:1.0
1.0:1.0
1.0:1.2
-
40 % 2ac
(36 %)
43 % 3ac
(34 %)
70 % 2ai
(49 %)
3
34 % 2ad
(30 %)
39 % 3ad
(29 %)
85 % 2aj
(41 %)
4
Cl
Br
3c,d
4d,e
Pr
37 % 2ae
(25 %)
37 % 3ae
(34 %)
53 % 2ak
(41 %)
5
Pr
36 % 3af
(22 %)
a Yields determined by 1H-NMR spectroscopy using 1,3,5-
6
MeC(O)
CF3
-
trimethoxybenzene as internal standard. Yield 2ax = 2ax1 +
b
88 % 3ag
(83 %)
2ax2; Isolated yield in parenthesis. Ratio calculated from
7
-
NMR data. c Alkyne mono-annulation products were formed
d
e
in low quantities (see SI).
8h.
Only one aromatic
1
a Yields calculated by H NMR spectroscopy using 1,3,5-
trimethoxybenzene as internal standard; Isolated yield in
parenthesis. b 2 h.
homologation product is possible (2ak).
Isolation of Reaction Intermediates. To better understand
the observed reactivity, a detailed 1H NMR-monitoring of the
reaction of 1a with diphenylacetylene was performed
(Scheme S1). At early stages (10 min), we observed the
incipient formation of the products 2aa and 3aa.
Additionally, we detected the formation of another minor
species in the first 30 min of the reaction with a characteristic
doublet at 9.06 ppm that subsequently faded away. The in
situ 1H NMR quantification of the intermediate species
between 5 and 15 min accounted for over 80% of the total
nickel content in the catalysis, indicating that this species
belonged to the productive catalytic cycle.
The trend observed in Table 2 is clearly visualized in Scheme
S2, plotting the observed 2ax/3ax ratios versus the Hammett
p parameter. These findings showcase the aromatic
homologation products being favored (2ax) when electron-
donor-groups are present, whereas the monoalkyne
annulation products (3ax) being preferentially formed with
electron-withdrawing substituents.
Study the steric effect on C-F activation. This reactivity was
also studied using a set of unsymmetrically substituted
alkynes. In all cases, both aromatic homologation and alkyne
annulation reactions took place, with the former product
being clearly preferred. A mixture of two (out of four)
aromatic homologation regioisomers was formed (Table 3,
entries 1, 2 and 3). Yet, the alkyne mono-annulation product
was isolated with the aromatic motif being preferentially
proximal to nitrogen.47 Finally, when 4-octyne was used
(Table 3, entry 4), the alkyne mono-annulation product was
not observed, and up to 53% of the aromatic homologation
Encouraged by the possibility of unravelling
a key
intermediate, we switched from catalytic to stoichiometric
conditions and stopped the scaled reaction after 5 min. Upon
chromatographic purification, a diamagnetic nickel complex
was isolated in 23% yield (INT4-E-H). The compound was
indeed very stable at room temperature and high-quality
crystals allowed unambiguous crystallographic analysis.
Strikingly, the XRD structure revealed a square planar
nickel(II) complexes with two alkynes being inserted towards
a 9-membered nickelocyclic complex (Figure 1). Here, the
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Page 4 of 11
terminal alkenyl moiety derived from the second inserted
1
alkyne is trans to the anionic amide nitrogen. The square
planar geometry around the nickel(II) center features the -
coordination of the alkene moiety corresponding to the
initially inserted alkyne.48 The latter nicely explains the
extraordinary stability of such an intermediate species
without the requirement of additional auxiliary ligands (see
below). An analogous reaction with di-p-tolylacetylene
afforded INT4-E-Me, which was likewise fully characterized
by NMR spectroscopy. Furthermore, performing the aromatic
homologation reaction using the analogous non-fluorinated
substrate in the conditions reported by Huang, but at very
short reaction times, the formation of the same INT4-E-H
complex was also achieved (18% yield, Figure 1a and S17).38
This results suggests that this 9-membered nickelocyclic
species is a common intermediate in aromatic homologation
reactions, irrespective of being a C-F/C-H or a C-H/C-H
activation route. In this line, a competition experiment using
equimolar amounts of mono-fluorinated 1a and the
analogous non-fluorinated substrate shows a kinetically
preferred C-F over C-H activation due to full consumption of
1a compared to minimal conversion of the non-fluorinated
substrate (Figure 1c). Indeed, a control experiment using only
the non-fluorinated substrate in our catalytic conditions
produced no aromatic homologation product and stilbene
was detected as byproduct, suggesting the implication of a
Ni-hydride species (see below).37-38
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R'
N
a)
O
R'
R'
O
(2 equiv.)
Ni(COD)2 (1 equiv.)
N
N
Ni
H
N
LiOtBu (2 equiv.)
1,4-dioxane, 5 min., 140 ˚C
F
H
R'
R'
R'
R' = H (23 % isolated yield) - INT4-E-H (XRD)
R' = Me (11 % isolated yield) - INT4-E-Me
18 % isolated yield
R' = H (INT4-E-H)
R'
R'
O
(4 equiv.)
Ni(COD)2 (1 equiv.)
N
H
N
DMPU, 140 ˚C, 10 min.
H
H
Huang (ref. 38)
Study of Isolated Ni(II) intermediated in Homologation
Reaction. With intermediate INT4-E-H in hand, we
investigated its evolution to the putative aromatic
homologation product (2aa) under thermal conditions
(Figure 2a), obtaining a modest 23 % yield. Under these
conditions (140 ºC) and in the presence of 5 equiv. of 1a and
base, a 41% of yield of 2aa was obtained. This is in line with
the requirement of a second aminoquinoline (AQ) chelating
unit inducing the meta C–H activation at the phenyl ring,
which finally renders the aromatic homologation product 2aa
(Figure 2a). In addition, using INT4-E-H in 10 mol% under
catalytic conditions, its full conversion to 2aa was obtained
(10% yield), although no catalytic turnover was achieved
(Figure 2b). In sharp contrast, in the presence of PivOH,
product 2aa was not observed, while up to 46% of the linear
alkenylation product 4aa was obtained (Figure 2a), providing
a new strategy towards molecular complexity by C-F
activation.
b)
O
O
c)
Q
O
N
Q
H
N
N
H
Ph
Ph
+
+
0.5 equiv.
N
N
Ph
(2 equiv.)
Ni(COD)2 (10 mol%)
F
Ph
Ph
H
Ph
+
LiOtBu (2 equiv.)
1,4-dioxane, 2 h, 140 ˚C
13 % 3aa
21 % 2aa
O
N
H
O
0.5 equiv.
H
N
H
H
N
H
H
(0.4 equiv.)
Figure 1. a) Synthesis of INT4-E-H complex via C-F/C-H (top)
and via C-H/C-H activation previously reported by Huang
(yield 18%).38 b) crystal structure of INT4-E-H complex (CCDC
1891021). Selected bond distances [Å]: Ni-C1 2.0411(19), Ni-
C2 2.1060(17), Ni-C3 1.8946(16), Ni-N1 1.9209(16), Ni-N2
1.9011(16) (orange: first inserted alkyne in E conformation;
magenta: second inserted alkyne in Z conformation; green:
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ACS Catalysis
nickel(II) center). c) Competition experiment with equimolar
amounts of 1a and the analogous non-fluorinated substrate,
obtaining 2aa and 3aa products mainly from C-F activation
(1a, full conversion).
1
2
3
4
5
6
7
8
a)
O
H
O
N
1,4-dioxane
140 ˚C
N
N
PivOH (2 equiv)
Q
Q
N
Ni
O
H
Ph
2 h
1,4-dioxane
140 ˚C
2 h
Ph
Ph
Ph
46 % 4aa
H
23 % 2aa
9
INT4-E-H
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1a (5 equiv.)
LiOtBu (5 equiv.)
41% 2aa
1,4-dioxane
140 ˚C, 2 h
b)
(2 equiv.)
O
N
H
N
INT4-E-H (10 mol%)
Q
H
N
O
LiOtBu (2 equiv.)
F
1,4-dioxane, 140 ˚C, 2 h
10 % 2aa
Figure 2. a) Diverting reactivity pathways from INT4-E-H. b)
Reactivity using INT4-E-H as catalyst for the aromatic
homologation transformation.
Mechanistic insight. Based on our findings and on the
computational study detailed below, a full mechanistic
proposal is depicted in Scheme 3. The coordination of
deprotonated substrate 1a with Ni(COD)2 forms the INT1, in
which the strong C–F bond is cleaved via oxidative addition
to generate the nickel(II) intermediate (INT2). A detailed DFT
study on this step has been performed (Figure 3). The DFT
geometry optimizations and frequency calculations have
been carried out using the M06-L functional49 and def2SVP
basis set including the solvent effects with the SMD model50
and the dispersion with Grimme GD3BJ approach. The Gibbs
energies obtained were improved with single point
calculations at M06-L/def2TZPV including both the solvent
and dispersion corrections. A complete description of the
computational details of the DFT calculations is given in the
supporting information. The results presented in Figure 3
show that the high selectivity of the oxidative addition step
towards C-F activation in front C-H activation is due to a)
smaller energy barrier for Li+ Lewis acid assisted C-F
activation compared to C-H activation by 4.6 kcal/mol, b) the
formation of the hydride-Ni(II) species (INT2-H) is strongly
endergonic and c) the generation of fluoride-Ni(II) species
(INT2-F) is clearly exergonic (49.4 kcal/mol more stable than
INT2-H). Moreover, no alkene or H2 is formed during the
reaction, which is in line with the computational data.
Scheme 3. Global mechanistic proposal. Ni(0) is depicted in
purple and Ni(II) in green.
O
O
N
H
N
N
H
R
F
N
H
Ni(COD)2
LiOtBu
R
R
R
R
R
HOtBu
aromatic homologation
DFT modeled
O
C-C reductive
elimination
N
C-F
N
R
Ni
oxidative addition
Li+
F
O
N
Li
H
R
INT1-F
O
N
H
N
N
R
Ni
N
R
R
N
Ni
R
R
F
Li
INT6
H
R
C-H activation
INT2-F
LiF
Li+
N
O
O
N
N
R
H
N
N
R
Ni
Ni
R
R
R
H
R
INT3-Z
N
O
R
HOtBu
LiOtBu
INT5
R
N
C-N reductive
elimination
N
N
Ni
+
R
R
H
NH
R
INT4-Z
R
O
R
Multistep
isomerization
N
N
R
O
N
8-AQ containing
molecule
alkyne mono-annulation
NH
N
R
N
Ni
H
R
R
R
INT4-E
(equal to XRD for INT4-E-H)
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G
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Li
(kcal/mol)
Ph
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F
DPA
=
Ph
TSC-H
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INT2-H
30
27.3
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Ni
26.5
DPA
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H
INT2-H
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TSC-F
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Ni
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DPA
Ni
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Ni
Li
F
Li
5.7
INT1-F
INT2-F
DPA
Ph
TS2-3
Ph
INT3-Z
2.2
0.3
0.0
0.0
-5
INT1-H
O
8-AQ-
+DPA
INT3a-Z
-7.7
N
Li
+Ni(cod)2
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Ni
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H
F
Ph
-10
-15
-20
-25
O
N
INT2
O
Ph
N
Ni
N
Ni
N
Li
N
DPA
+LiF
INT2
N
INT1-H
INT3-Z
-21.4
F
INT2-F
-23.9
8-AQ-
Ph
Ph
-22.9
INT3a-Z
Figure 3. Gibbs Energy profiles for the C-F (pink) versus C-H activation (black) through INT2-F and INT2-H, respectively,
followed by the first DPA insertion at INT2-F to form INT3-Z. The reaction was modeled by DFT at
M06L/Def2TZVP//M06L/Def2SVP level of theory; energies given in kcal/mol.
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The role of Li+ is remarkable since it facilitates the C-F
dihedral angle between the atoms directly bonded to the
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oxidative addition, stabilizes the fluoride-Ni(II) species and is
ready to extrude LiF (see TSCF in Figure 4), which formation is
one of the driving forces of the reaction. Actually, the reaction
does not proceed using tBuOK (potassium salt) as base. After
the C-F oxidative addition step and extrusion of LiF, the first
alkyne insertion (diphenyl acetylene -DPA- was modelled)
follows to form INT3-Z, with a barrier of 24.2 kcal/mol (Figure
3) (DFT studies clearly indicate that INT3-Z isomer is
thermodynamically favored compared to INT3-E, see below
and Figures 5-6).
metal), showed that the E-isomer is significantly less distorted
from the square-planarity (dihedral angle 23.3º) than the Z-
isomer (50.2º), thereby explaining the thermodynamic
stability of INT4-E compared to INT4-Z (Figure 6).
G
(kcal/mol)
9
34.8
TS-ERE
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N
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RedEli
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INT3-E-DPA
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Ph
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Ni
TSRE-DPA
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11.9
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INT3-Z-DPA
RedEli
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INT3-E
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+
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0.0
-5
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RedEliDPA
Ph
INT3-Z
Ph
Ph
Ph
Ph
INT4-Z
-8.1
O
-10
-15
-20
INT4-Z
N
Ni
O
N
Figure 4. Optimized geometries of TSCF and TSCH
.
N
Ph
R
Ph
-19.3
N
Ni
INT3-Z
INT4-E
H
R
At this point, chemo-divergent behaviour can occur: i) the
INT3-Z can either undergo reductive elimination to form the
alkyne mono-annulation product 3 or ii) a second alkyne
insertion into a Ni–C bond proceeds towards INT4-Z. When
the latter is formed, this can either isomerize to form the
INT4-E (equivalent to the isolated crystal structure INT4-E-
H), which is more stable than INT4-Z (see below), or it can
further react towards the synthesis of the homologation
product. The experimental results suggest that additional
presence of 8-AQ-motifs either in the substrate or the
products, facilitate the activation of the meta C–H bond by
stabilizing the nickel(II) center to give the final homologation
product (INT5 and INT6). The presence of EWG on the alkyne
triggers the chemo-divergent transformation of INT3-Z to
the alkyne mono-annulation product, instead of the aromatic
homologation product.
R
R
INT4-E
Figure 5. Gibbs Energy profiles for the transition from the
monoalkyne intermediates (INT3-E or INT3-Z) to the double
inserted alkyne compounds INT4-E (in blue) or INT4-Z (in
pink), as well as the pathways for the intramolecular alkyne
mono-annulation from INT3-E (in green) and the annulation
from INT3-Z with a second DPA coordinated to the metal (in
red). The reaction was modeled by DFT at
M06L/Def2TZVP//M06L/Def2SVP level of theory; energies
given in kcal/mol.
The insertion of the first alkyne may lead to two different
INT3 isomers, INT3-Z and INT3-E (Figure 5), which are
differentiated by the stereochemistry of the C-C double bond
from the first inserted alkyne in Z (INT3-Z) or in E
conformation (INT3-E).51 The latter is 6.0 kcal/mol less stable
than the former. The formation of INT4-E (-19.3 kcal/mol),
which has exactly the same geometry as the crystal structure
of INT4-E-H depicted in Figure 1, requires overcoming TS-
E3-4 (33.4 kcal/mol). However, we found a far more kinetically
favourable mechanism involving the first inserted alkyne in a
Z conformation, which transition state Gibbs energy (TS-Z3-
4) is 21.5 kcal/mol lower than TS-E3-4 (Figure 5). Importantly,
the product obtained INT4-Z (-8.1 kcal/mol) is 11.2 kcal/mol
less stable than INT4-E. The experimental crystallization of
INT4-E-H was mirrored by its strong thermodynamic stability
found in the calculations, which is the driving force of a
multistep isomerization of INT4-Z upon isolation as solid. In
addition, detailed analysis of geometry of the Ni(II) center for
optimized INT4-Z and INT4-E structures (by checking the
Figure 6. Optimized geometries of a) INT4-Z and b) INT4-E.
The enlarged section highlights the distortion of the square
planarity on the complex by measuring the dihedral angle
N1N2C3C4. Atom-color code: C grey, N blue, O red, Ni green
(Hydrogen atoms have been omitted for clarity).
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The small energy barriers for the C-F oxidative addition, first
Detailed spectroscopic characterization of all compounds is
1
2
3
4
5
6
alkyne insertion and second alkyne insertion (< 24 kcal/mol),
together with the isolation of the double-alkyne-inserted
nickelocyclic intermediate species, are in agreement with the
rate-determining step being later than the insertion of the
second alkyne.
included, optimization details, experimental details of
catalytic reactions, experimental details of stoichiometric
reactions for the formation of INT4-E-H and INT4-E-Me and
also computational details. Crystallographic data for INT4-E-
H (CCDC-1891021) is provided.
Regarding the computed pathway leading to the alkyne
mono-annulation products (Figure 5), the most kinetically
favourable pathway involves a second molecule of acetylene
coordinated to INT3-Z. It evolves through a reductive
elimination transition state, TS-ZRE-DPA (13.11 kcal/mol),
which is only slightly above of TS-Z3-4 by 1.2 kcal/mol (Figure
7). This small Gibbs energy difference agrees with the
experimental formation both aromatic homologation and
alkyne mono-annulation products, being the former one
preferred. When p-CF3-substituted alkyne is used, the Gibbs
energy difference between the transition state of the second
alkyne insertion, CF3-TS-Z3-4 (13.4 kcal/mol) and the
intramolecular reductive elimination, CF3-TS-ZRE-DPA (14.0
kcal/mol) is reduced to 0.6 kcal/mol, in agreement with the
experimental trend observed when EWG are present (see
Figure S21).
7
8
9
AUTHOR INFORMATION
Corresponding Author
*lutz.Ackermann@chemie.uni-goettingen.de
*xavi.ribas@udg.edu
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Notes
The authors declare no competing financial interest.
Crystallographic data for INT4-E-H (CCDC-1891021) can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENT
This work was financially supported by grants from the
European Research Council (ERC-2011-StG-277801 to XR),
the DFG (Gottfried-Wilhelm-Leibniz award to LA), MICINN
(CTQ2016-77989-P to XR), and Generalitat de Catalunya
(2017SGR264). XR is thankful for an ICREA Acadèmia award.
We thank COST Action CHAOS (CA15106) and Dr. L. Gómez
and STR from UdG for technical support.
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The possibility that a second AQ-containing substrate
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50.
Marenich, A. V.; Cramer, C. J.; Truhlar, D. G., Universal
solvation model based on solute electron density and on a
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