Mechanism of Nickel(II)-Catalyzed C(2)-H Alkynylation of Indoles with Alkynyl Bromide

Article abstract of DOI:10.1021/acs.organomet.8b00177

The nickel system (THF)₂NiBr₂/phen has recently been shown as an efficient catalyst for the C-H bond alkynylation of diverse heteroarenes with (triisopropylsilyl)alkynyl bromide via monodentate chelation assistance. Herein, we report an extensive mechanistic investigation for the direct alkynylation of indoles involving the well-defined nickel catalyst, which features a coordinative insertion pathway of alkynyl bromide with the Ni(II) catalyst. Catalytic relevant nickel complexes, (phen)NiCl₂ (5), (phen)₂NiCl₂ (6) and [(phen)₃Ni]·NiCl₄ (7) were isolated, and the complexes 6 and 7 were structurally characterized. Well-defined complexes were as competent as the in situ generated catalyst system (THF)₂NiBr₂/phen for the alkynylation of indoles. Various controlled studies and reactivity experiments were performed to understand the probable pathway for the alkynylation reaction. Kinetics analysis highlights that the complex (phen)NiX₂ acts as a precatalyst, and the involvement of substrate indole and LiO^tBu are essential for the generation of the active catalyst. Deuterium labeling and kinetic studies suggest that the process involving C-H cleavage and carbo-nickelation of indole is a crucial rate influencing step. Reactivity study of various alkynyl compounds with nickel-species highlights a migratory insertion route for the reaction. DFT calculations firmly support the experimental findings and suggest the coordinative insertion pathway of alkynyl bromide rather than oxidative addition toward the nickel(II) center.

Full text of DOI:10.1021/acs.organomet.8b00177

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Mechanism of Nickel(II)-Catalyzed C(2)−H Alkynylation of Indoles
with Alkynyl Bromide
Shrikant M. Khake,†,∥ Shailja Jain,‡ Ulhas N. Patel,†,∥ Rajesh G. Gonnade,§ Kumar Vanka,‡
and Benudhar Punji*,†,∥
‡
†Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, Physical and Materials Chemistry Division, and
§Centre for Material Characterization, CSIR−National Chemical Laboratory (CSIR−NCL), Dr. Homi Bhabha Road, Pune 411
008, India
∥Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 020, India
S
* Supporting Information
ABSTRACT: The nickel system (THF)2NiBr2/phen has recently been shown
as an efficient catalyst for the C−H bond alkynylation of diverse heteroarenes
with (triisopropylsilyl)alkynyl bromide via monodentate chelation assistance.
Herein, we report an extensive mechanistic investigation for the direct alkynylation
of indoles involving the well-defined nickel catalyst, which features a coordinative
insertion pathway of alkynyl bromide with the Ni(II) catalyst. Catalytic relevant
nickel complexes, (phen)NiCl2 (5), (phen)2NiCl2 (6) and [(phen)3Ni]·NiCl4 (7)
were isolated, and the complexes 6 and 7 were structurally characterized. Well-
defined complexes were as competent as the in situ generated catalyst system
(THF)2NiBr2/phen for the alkynylation of indoles. Various controlled studies
and reactivity experiments were performed to understand the probable pathway
for the alkynylation reaction. Kinetics analysis highlights that the complex
(phen)NiX2 acts as a precatalyst, and the involvement of substrate indole and
LiOtBu are essential for the generation of the active catalyst. Deuterium labeling
and kinetic studies suggest that the process involving C−H cleavage and carbo-nickelation of indole is a crucial rate influencing
step. Reactivity study of various alkynyl compounds with nickel-species highlights a migratory insertion route for the reaction.
DFT calculations firmly support the experimental findings and suggest the coordinative insertion pathway of alkynyl bromide
rather than oxidative addition toward the nickel(II) center.
Although the nickel catalyzed C−H bond alkynylation of
arenes and heteroarenes are becoming more developed, detailed
mechanistic studies for this method are not well established.
Miura has proposed the initial oxidative addition of alkynyl
bromide to the nickel(0) species during the alkynylation of
azoles,6a,b analogous to the conventional Ni(0)-catalyzed cross-
coupling. The oxidative addition is followed by the trans-
metalation with lithiated azoles, and subsequent reductive elimi-
nation of product regenerates the Ni(0) catalyst. Overall, the
proposed catalytic process for the alkynylation of azoles follows
a Ni(0)/Ni(II) catalytic cycle.6a In contrast, Li6e and Balaraman6h
hypothesized that the alkynylation of benzamide proceeds via a
Ni(II)/Ni(IV) pathway. It is believed that the sigma donor
bidentate directing group stabilizes the nickel in higher oxida-
tion state in such cases. On the other hand, a Ni(I)/Ni(III)
redox pathway for the similar alkynylation reaction has been
proposed.6g,i All these nickel-catalyzed alkynylation mecha-
nistic proposals, i.e., Ni(0)/Ni(II), Ni(II)/Ni(IV) and Ni(I)/
Ni(III) have been suggested with limited experimental evi-
dence. Recently, we have reported a Ni(II)-catalyzed regioselective
INTRODUCTION
■
Indoles and their derivatives are key structural motifs in natural
products, bioactive compounds, marketed drugs, and agro-
chemicals.1 Therefore, there exists a strong demand for the
efficient synthesis and functionalization of indole derivatives.
Particularly, the regioselective alkynylation of indoles via direct
C−H bond activation leading to the alkynylated indoles is
significant, because of the possibilities of diverse postfunction-
alization of the latter compound.2 Various transition-metal
catalysts have been known for the C−H bond alkynylation of
different arenes and heteroarenes, including indoles.3 Specif-
ically, the earth-abundant and inexpensive 3d metals, such as
Fe,4 Co,5 Ni,6 Cu7 have been successfully employed for the
alkynylation of activated azoles and benzamides, and been
found to be more beneficial. Shi8 and Ackermann9 have indi-
vidually shown the C-2 alkynylation of indoles by cobalt catal-
ysis employing different alkynyl coupling partners. Similarly,
Ackermann has demonstrated a versatile approach for the
manganese-catalyzed C-2 alkynylation of indoles under mild
conditions.10 Recently, we have demonstrated the alkynylation
of indoles and imidazoles with alkynyl bromide using a nickel
catalyst, wherein a number of sensitive functional groups are
tolerated.11
Received: March 26, 2018
© XXXX American Chemical Society
A
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alkynylation of indoles and speculated a probable reaction
pathway.11 Herein, we have provided detailed mechanistic
insight for the nickel-catalyzed alkynylation of indoles with
alkynyl bromide, which proceeds through the coordinative
insertion of the alkynyl functionality without undergoing a
redox process. Synthesis and characterization of catalytically
relevant nickel complexes, detailed kinetic investigations and
controlled reactivity studies have been carried out to obtain
more insights. DFT calculations were performed to support the
experimental results and to find out the energetically feasible
intermediates. An updated and improved mechanistic cycle has
been proposed considering all the experimental findings and
DFT energy calculations.
Scheme 2. Synthesis of Different (phen)nNiCl2 Complexes
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Nickel Complexes.
Recently, we have developed a nickel-catalyzed method for the
alkynylation of indoles with (triisopropylsilyl)alkynyl bromide,
wherein an in situ generated catalyst system (THF)2NiBr2/phen
[phen = 1,10-phenanthroline] was employed (Scheme 1).11
Scheme 1. Nickel-Catalyzed Alkynylation of 2-Pyridinyl
Indole
and 7 were elucidated by single crystal X-ray diffraction study.
The complexes 5,12 613 and 714 have previously been isolated
by different approaches and were analyzed only by elemental
analyses.
All the three nickel complexes 5−7 are NMR inactive and
1
hence could not be characterized by H and 13C NMR spec-
troscopy. However, the complexes were crystallized in ana-
lytically pure form and characterized by elemental analyses.
Furthermore, the molecular structures of two complexes were
elucidated by X-ray diffraction studies. The ORTEP diagrams
of 6 and 7 are shown in Figures 1 and 2, respectively. Selected
Further to this, we have found that the well-defined com-
plex [(phen)3Ni·NiBr4] (4), obtained from the reaction of
(THF)2NiBr2 and phen, efficiently catalyzes the reaction under
optimized conditions. It is assumed that the complex [(phen)3Ni·
NiBr4] (4) remains in equilibrium with (phen)2NiBr2 and
(phen)NiBr2 during the reaction and one of the later species
acts as a catalyst for the alkynylation reaction. Notably, even
with the different stoichiometric reactions of phen and
(THF)2NiBr2, the metalation reaction always afforded the
mixture of (phen)2NiBr2 and (phen)NiBr2, i.e., the complex
composition [(phen)3Ni·NiBr4] (4), as evident from the
elemental analysis. Unfortunately, the selective isolation of the
species (phen)2NiBr2 or (phen)NiBr2 was not successful. To
synthesize and identify the differently coordinated nickel
complexes, i.e., (phen)nNiX2 (n = 1 or 2), we have performed
various controlled experiments employing the nickel precur-
sor, (DME)NiCl2. Thus, the reaction of (DME)NiCl2 with
1.2 equiv of 1,10-phenanthroline in THF afforded complex
(phen)NiCl2 (5) in 91% yield along with 7% of (phen)2NiCl2
(6) (Scheme 2). However, the reaction of (DME)NiCl2 with
2.0 equiv of 1,10-phenanthroline yielded (phen)1.2NiCl2
{mixture of (phen)NiCl2 and (phen)2NiCl2} in 90% yield
and a trace amount of [(phen)3Ni]·NiCl4 (7). The composi-
tion of all the compounds 5, 6, and 7 was analyzed by ele-
mental analysis. Furthermore, the structures of complexes 6
Figure 1. Thermal ellipsoid plot of (phen)2NiCl2 (6). All hydrogen
atoms are omitted for clarity.
bond lengths and bond angles are shown in Table 1. The
geometry around the nickel center in the complex 6 is
distorted octahedral, wherein the nickel is coordinated by two
phenanthroline ligands, and the fifth and sixth coordination
sides are occupied by the −Cl ligand. Two phenanthroline rings
are almost perpendicular to each other with N(2)−Ni−N(4)
and N(1)−Ni−N(3) angles around 85° and 174°, respectively.
The bite angle of the phenanthroline ligand is approximately
79°. The Ni−N bond lengths are in the range of 2.08−2.10 Å,
B
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Scheme 3. Alkynylation Employing Different Nickel-
Catalysts
Figure 2. Thermal ellipsoid plot of [(phen)3Ni]·NiCl4 (7). All hydro-
a Teflon screw cap tube was charged with catalyst 4 (0.0044 g,
0.009 mmol, 0.009 M), alkynyl bromide 2 (0.45 mmol, 0.45 M),
LiOtBu (0.60 mmol), mesitylene (0.22 mmol, 0.22 M, internal
standard) and 1-(pyridin-2-yl)-1H-indole 1 (0.058 g, 0.30 mmol,
0.30 M), and toluene (0.97 mL) was added to make the total
volume to 1.0 mL. The tube containing the reaction mixture was
heated at 150 °C in a preheated oil bath and progress of the
alkynylation was monitored by gas chromatography (GC) at
regular intervals. The data was collected after the exclusion of
the induction period (30−60 min). The final data was
obtained by averaging the results of two independent experi-
ments for the reaction. The rate of the reaction was then calcu-
lated by plotting concentration of product versus time (min),
wherein the slope represents the reaction rate. Similarly, the
rate of alkynylation was measured using different initial concen-
trations (0.6, 0.9, 1.2 M) of indole 1 (see Table S1 and Figure S1
in the Supporting Information for details). As shown in Figure S1
in the Supporting Information, the rate of the alkynylation
reaction increases upon the increased initial concentrations of 1.
A slope of 1.15 was obtained from the plot of log(rate) versus
log(conc. 1), suggesting a fractional and complex rate order on
substrate 1 (Figure 3). This finding highlights a significant and
gen atoms are omitted for clarity.
Table 1. Selected Bond Lengths (Å) and Bond Angles (°)
for Complexes 6 and 7
bond length (Å)
Complex 6
bond angles (deg)
Ni(2)−Cl(1)
Ni(1)−N(2)
Ni(1)−N(4)
Ni(1)−N(1)
Complex 7
2.2678(6)
2.0658(6)
2.0739(6)
2.0978(6)
N(2)−Ni(1)−N(1)
80.24(2)
78.78(3)
171.75(2)
108.81(6)
N(4)−Ni(1)−N(3)
N(2)−Ni(1)−N(4)
Cl(1)−Ni(2)−Cl(4)
Ni(1)−Cl(1)
Ni(1)−N(2)
Ni(1)−N(4)
Ni(1)−N(6)
2.418(6)
2.10(6)
2.07 (6)
2.09(6)
N(2)−Ni(1)−Cl(1)
N(4)−Ni(1)−Cl(2)
N(2)−Ni(1)−N(4)
Cl(1)−Ni(1)−Cl(2)
172.5(2)
79.5(3)
85.2(2)
98.11(6)
and both the Ni−Cl bond lengths are around 2.41 Å. The
molecular structure of complex 7 has two different nickel cen-
ters; one is coordinated through three phenanthroline ligands
in an octahedral fashion, and the other nickel center is NiCl4
with a tetrahedral geometry. All three phenanthroline rings are
almost perpendicular to each other with the trans N−Ni(1)−N
bond angles in the range of 168.5−170.3°. The N−Ni(1)−N
bite angles of phenanthroline moieties are in between 79.2°
and 80.1°. All the six Ni(1)−N bond lengths are in the range
of 2.07 to 2.10 Å. The Cl−Ni(2)−Cl bond angles are in the
range of 106.28(7)° to 114.54(7)°, which indicates the
distorted tetrahedral geometry around the nickel.
Alkynylation of Indole Using Isolated Nickel Com-
plexes. To know the competency of isolated nickel complexes
as catalysts for the alkynylation of indoles, the complexes
(phen)NiCl2 (5), (phen)2NiCl2 (6) and [(phen)3Ni]·NiCl4 or
[(phen)1.5NiCl2] (7) were employed for the alkynylation of
indoles with alkynyl bromide under the standard catalytic
conditions. All three complexes 5−7 were as competent as the
in situ generated catalyst (THF)2NiBr2/phen or the catalyst
[(phen)3Ni]·NiBr4 (4) for the alkynylation reaction (Scheme 3).
Hence, complex 4 or (THF)2NiBr2/phen was employed as a
catalyst for the mechanistic study of the alkynylation reaction.
Kinetics Analysis of the Alkynylation Reaction. In order
to know the effect of reaction components on the alkynylation,
the rate orders of the alkynylation reaction with various reac-
tion components were determined by the initial rate method.
First, the rate order of the alkynylation reaction on substrate
(pyridin-2-yl)-1H-indole (1) was determined by measuring the
initial rates of the alkynylation at different initial concentra-
tions of 1. In a standard kinetic experiment (rate measurement),
Figure 3. Plot of log(rate) vs log(conc. 1).
diverse role of substrate 1 in the alkynylation. The rate of the
alkynylation reaction was almost similar to different initial con-
centrations of alkynyl bromide, highlighting a zeroeth order
behavior with respect to the concentration of alkynyl bro-
mide (Figure S2 in the Supporting Information). Similarly, the
rate of the alkynylation was independent of the concentration
of LiOtBu and was zeroeth order with respect to LiOtBu
C
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(Figure S3 in the Supporting Information). Next, the reaction
rate was determined with different loadings of catalyst 4. A slope
of 0.46 was obtained from the plot of log(rate) versus
log(conc. cat 4), suggesting that the reaction is fractional order
with catalyst 4 (Figure S4 in the Supporting Information).
In consideration of the involvement of catalyst 4 in multiple
steps during the alkynylation, the observed fractional rate order
appears to be logical. Such a scenario highlights that more than
one step has comparable energy barriers during the multisteps
involvement of the nickel catalyst. This is also consistent with
the DFT energy calculations (vide infra for discussion). Notably,
upon increasing the concentrations of catalyst 4, indole 1 or
LiOtBu, the induction periods were drastically reduced (see
Figures S1, S3 and S4 in the Supporting Information for
details), which strongly supports our previous observation that
the active catalyst generation involves precatalyst 4, substrate 1
and LiOtBu, and that the C−H nickelation could be very
crucial.11
Scheme 4. Reactivity of (THF)2NiBr2/phen with (Pyridin-2-
yl)-1H-indole (1)
It is interesting to note that the electronics on the 2-py-indole
substrate has no influence on the rate of the alkynylation reac-
tion,11 thus, ruling out an electrophilic type C−H activation.
Furthermore, the rate of alkynylation was measured employing
the 3,4,7,8-tetramethyl-phenanthroline/(THF)2NiBr2 catalyst
system (see Figure S6 in the Supporting Information). The reac-
tion rate was found to be much slower (1.7 × 10−4 M min−1)
compared to the rate employing the (THF)2NiBr2/phen system
(1.9 × 10−3 M min−1). This indicates that the C−H nickelation
could be a function of the electrophilicity on the nickel center
and that the electrophilic nickel center favors the alkynylation
reaction.
Our previous experimental findings suggested that the com-
plex 4 catalyzed alkynylation reaction does not involve a radical
manifold and the substrate indole is essential for the generation
of an active nickel catalyst.11 Furthermore, the kinetic isotope
effect (KIE) value was determined to be 3.6. The high KIE
value along with the positive and fractional rate order on
indole 1, strongly suggests that the C−H bond cleavage and
carbo-nickelation is one of the rate influencing steps in the
alkynylation reaction. This was further supported by the DFT
energy calculations (vide infra for discussion), wherein a high
barrier was observed for the C−H nickelation step comple-
menting the significant influence of indole substrate 1 on the
rate of the alkynylation. Although the observed zeroeth order
dependence on base is not consistent with the proposed turn-
over influencing step, we believe that the reaction is apparent
zero order dependence on LiOtBu under pseudo-first-order
conditions.
was observed. The hypothesized nickelacycle species could be
paramagnetic in nature. Interestingly, the same reaction in the
presence of alkynyl bromide 2 afforded the alkynylated product
3 in quantitative yield and did not produce the self-dimerized
product 8. We believe that the dimerized product 8 produced
via the intermediates A and E in the absence of the coupling
partner 2 (Scheme 4). However, in the presence of alkynyl
bromide 2, the presumed intermediate A led to the productive
alkynylation reaction resulting in the formation of 3. Several
attempts to isolate the probable nickelacycle species A were
unsuccessful, and the reaction always ended up with the
dimerized product 8 in the absence of alkynyl bromide 2.
Additionally, a reaction of indole 1 with alkynyl bromide 2
employing 50 mol % of (THF)2NiBr2/phen did not produce
the detectable dimerized product 8. All these results emphasize
that the intermediacy of Ni(0) as an active catalyst is very
unlikely. The feasibility of the intermediate species A and
further reaction with alkynyl bromide is demonstrated by DFT
calculations (vide infra for discussion). Considering the
positive and fractional rate order of alkynylation reaction
with substrate 1, we believe that both the intermediates A and
E generate concurrently (Scheme 4) and react with alkynyl
bromide to afford the desired alkynylated product. This probabil-
ity has been considered and investigated by DFT calculations.
Considering our inability to detect a dimagnetic nickel spe-
cies, we have considered an odd electron species as the active
catalyst and investigated a probable Ni(I)/Ni(III) process. It
should be noted that the standard alkynylation reaction in the
presence of radical inhibitors TEMPO or galvinoxyl is unaf-
fected and produced quantitative yield of alkynylated indole.11
Although TEMPO or galvinoxyl are known to quench organic
radicals, it has been shown that Ni(I) species can react with
TEMPO to generate TEMPO-bound Ni(II) species, which
would not allow a Ni(I)/Ni(III) process.15 These findings sug-
gest that the Ni(I) species does not exist during the reaction to
proceed the catalysis via a Ni(I)/Ni(III) pathway. This prob-
ability has also been verified by DFT calculations. The inability
to observe any diamagnetic nickel species is most likely due to
the tetrahedral geometry of the (phen)Ni(II) species, which
might be paramagnetic in behavior.12a
Controlled Reactivity Study. Experimental studies indi-
cated that neither the isolated complex [(phen)3Ni·NiBr4] (4)
nor a Ni(0)-species is the active catalyst during alkynylation
reaction, as the induction period was observed employing these
catalyst systems.11 Further, we have found that the generation
of the active catalyst involves the indole 1 and LiOtBu. Looking
at the reaction components, we have hypothesized that a
nickelacycle species, formed by the reaction of (THF)2NiBr2/
phen with indole 1, could be the active catalyst during the reac-
tion. In that regard, in order to detect the presumed nickelacycle
species, a stoichiometric reaction of (THF)2NiBr2/phen and 1 was
performed in the presence of LiOtBu in toluene-d8 (Scheme 4).
The reaction mixture was heated for 3 h and the 1H NMR analysis
1
was carried out. The H NMR does not show any detectable
Probing Reactivity of Alkynyl-Species with Nickel. We
further probed the reactivity pattern of alkynyl bromide with
the nickel catalyst. To know the reactivity of the terminal
nickel containing species; instead the formation of self-coupled
dimerized product, 1,1′-di(pyridin-2-yl)-1H,1′H-2,2′-biindole (8)
D
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Figure 4. Free energy profile for the Ni(II)-catalyzed alkynylation of indoles. The free energy values are given in kcal/mol. 1 = 1-(pyridin-2-yl)-1H-
indole, 2 = (triisopropylsilyl)ethynyl bromide.
alkyne as well as an internal alkyne, the catalytic reactions were
performed employing (triisopropylsilyl)acetylene and bis-
(trimethylsilyl)acetylene as coupling partners under standard
catalytic conditions. Unfortunately, both the terminal as well as
internal alkynes were not capable of affording the alkynylated
indole. Hence, we have performed stoichiometric reactions to
identify any nickel vinylic species. Thus, the reaction of com-
plex 4 with indole 1 and (triisopropylsilyl)acetylene was carried
out in the presence of LiOtBu for 1 h, and MALDI-TOF
analysis was performed for the reaction mixture. MALDI shows
peak at m/z = 513.42, which correspond to the intermediate
(phen)Ni(2-py-indolyl)Br + H+ (A + H)+. Unfortunately, we
could not observe the nickel vinylic species. Notably, the
(triisopropylsilyl)ethynyl chloride reacted efficiently under
the standard catalytic conditions to afford the alkynylated
product in 83% yield. Furthermore, the rate of the alkynylation
reaction employing (triisopropylsilyl)ethynyl chloride is com-
parable with that observed using (triisopropylsilyl)ethynyl
bromide (2.4 × 10−3 M min−1 and 1.8 × 10−3 M min−1 with
alkynyl chloride and alkynyl bromide, respectively; see Figure
S5 in the Supporting Information). These observations suggest
that the reaction of alkynyl bromide with nickel is less likely to
occur via oxidative addition, because the rate of alkynylation is
expected to be slower with alkynyl chloride than with alkynyl
bromide if the reaction proceeds via the oxidative addition
approach. This supports our assumption that the reaction of
alkynyl-species with nickel most likely occurs via a migratory
insertion pathway. This finding is further supported by DFT
calculations.
Quantum Chemical Calculations. Full quantum chem-
ical calculations were performed with density functional theory
(DFT) at the PBE/TZVP level of theory in order to under-
stand the mechanism of the Ni(II)-catalyzed C−H bond
alkynylation of indole. The reaction first proceeds through
C−H bond activation of substrate 1 with (phen)NiBr2 to form
a five-coordinated nickelacycle intermediate A via the six-
membered transition state TS-1 (Figure 4). The energy barrier
for this process is found to be 22.2 kcal/mol. Upon checking
the possible coordination of indole 1 to the nickel catalyst as a
separate step, the substrate indole 1 drifted away from the
Ni(II) center in all the geometries optimized. Hence, the coor-
dination of indole to the Ni(II) catalyst as an independent step
is unlikely. DFT calculations show that the five coordinated
nickelacycle intermediate A has energy −12.2 kcal/mol, which
appears to be thermodynamically stable. A cationic four-
coordinate nickel species (phen)Ni(2-py indolyl)]+Br− is
E
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Figure 5. Free energy profile for the activation of the C−H bond by the Ni(II) catalyst. The values are given in kcal/mol.
thermodynamically unstable by 5.7 kcal/mol with respect to
species A (see Figure S8 in the Supporting Information) and is
therefore unlikely to be formed. Next, the approach of
substrate 2 to intermediate A would lead to the formation of
B by the π-coordination of 2 to the Ni(II) center. The forma-
tion of B occurs through TS-2, with the breaking of pyridinyl
nitrogen−nickel bond and the formation of the nickel−alkynyl
bromide π-bond concurrently. The energy barrier for this step
is 17.1 kcal/mol. The reaction of intermediate B has two possi-
bilities: either it can convert (i) into intermediate C or (ii) into
intermediate D by oxidative addition. The intermediate B can
convert to C′ via the three-membered transition state TS-3,
with the breaking of the Ni−C bond and the formation of
C−C bond occurring simultaneously. The intermediate C can
generate from C′ via the transition state TS-4 with a barrier of
4.8 kcal/mol. The formation of the final coupled product 3
takes place from intermediate C via a four-membered transi-
tion state TS-5, with the breaking of the Ni−C and C−Br
bonds and the formation of the Ni−Br bond with the sur-
mounting energy barrier of 4.2 kcal/mol. The observed free
energy profile, particularly the high barrier for the C−H
nickelation process, is consistent with the experimental find-
ings, wherein a significant influence of the substrate indole
1 on the reaction rate as well as a high kinetic isotope effect
(kH/kD = 3.6)11 was observed.
We further investigated the alternative reaction possibility of
the involvement of alkynyl bromide during the alkynylation.
The intermediate B might convert into D via the oxidative addi-
tion of alkynyl bromide through the three-membered transition
state TS-3′. For this step, the energy barrier is 33.0 kcal/mol.
The formation of product 3 from D takes place via TS-4′. The
calculations suggest that the formation of C has a lower barrier
than the formation of D, and hence the coordinative inser-
tion path would be more favorable than the oxidative addition
path (Figure 4). This observation is also consistent with the
experimental findings that the alkynyl chloride reacted slightly
faster than the alkynyl bromide during the alkynylation reac-
tion. To better understand the orientation of the bromide with
regards to the Ni and SiiPr3 groups, the 3-D pictures of TS-3,
C, TS-4, C′ and TS-5 have also been provided in Figure 4.
Further, we have probed the possible formation of Ni(I)
during the catalytic reaction by DFT calculations. We have
performed DFT calculations in the presence as well as in the
absence of LiOtBu. From the calculations, it was observed that
the formation of the Ni(I) species is energetically unfavorable
(see Figure S7 in the Supporting Information for details). These
calculations suggest that the formation of the paramagnetic
Ni(I) species is unlikely to proceed the catalytic reaction via a
Ni(I)/Ni(III) process, which is in agreement with the experi-
mental observations.
Since indole 1 significantly influences the rate of the
alkynylation reaction, and the self-coupled product 8 was
observed in the controlled reaction, we believe that the indole
is involved in the generation of the active catalyst, which would
then initiate the catalytic process. In this regard, we have inves-
tigated one more possibility for C−H activation on indole by
the Ni(II) catalyst (Figure 5). In this proposal, the C−H acti-
vation of indole 1 occurs at the presumed active nickel spe-
cies A, leading to the formation of intermediate E. The energy
barrier for this process is 15.5 kcal/mol. The reaction of E with
the alkynyl bromide 2 resulted in the formation of the interme-
diate G via the coordinative insertion path with a barrier of
21.9 kcal/mol. Though the C−H activation of indole 1 at
species A is more facile than the same at (phen)NiBr2, the
overall barrier for the formation of the alkyne inserted species
G is reasonably high (28.4 kcal/mol). Hence, C−H activation
and alkyne insertion by this approach could be a minor path.
We have also checked the oxidative addition pathway of 2 with
intermediate E, but here, the resulted intermediate H was
found to be less stable than intermediate G by 7.2 kcal/mol
F
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Article
(ΔE) (Scheme 5). Since the coordinative insertion of the alkynyl
bromide 2 with intermediate A is lower in barrier (22.2 kcal/mol,
influencing step to form the active nickelacylce species A. The
coordination of alkynyl bromide 2 with intermediate A will
generate the nickel complex B (Figure 6, Path I). Migratory
insertion of alkynyl bromide in the Ni(II)−C bond would
produce the complex C. The DFT calculations support the for-
mation of complex C. Complex C upon β-bromide elimination
would afford the alkynylated product 3 and regenerate the
Ni(II) catalyst.9 DFT studies suggest that the alkynylation
would follow the coordinative insertion pathway rather than
the oxidative addition of alkynyl bromide to complex A, and
are consistent with the experimental findings. The induction
period might be necessary for the generation of species A,
because such an induction period was absent when the mixture
of catalyst 4, indole 1 and LiOtBu was heated before the
addition of alkynyl bromide.
Scheme 5. Electronic Energy for the Intermediate G and
Intermediate H
Alternatively, as a minor path, the complex A can act as an
active catalyst and facilitate the C−H activation on indole 1 to
generate species E (Figure 6, Path II). Coordinative insertion
of alkynyl bromide 2 to the intermediate E would afford
species G. The complex G, upon β-bromide elimination would
produce the alkynylated product 3 and regenerate the active
catalyst A. Though there exist a number of reports on the
C−H bond alkynylation reaction, most of them have proposed
an oxidative addition pathway for the reaction of alkynyl bro-
mide with Ni(II), with limited experimental inputs. However,
here we have explicitly demonstrated that the reaction of
alkynyl bromide with the Ni(II) species proceeds via the coor-
dinative insertion approach.
Figure 4) than the overall barrier for the formation of G via
species E (28.4 kcal/mol, Figure 5), we assume that the spe-
cies A would be the crucial intermediate during the alkynylation,
and alkynyl bromide 2 would react in a facile manner with A
via the coordinative insertion pathway. However, alkynylation
through a minor pathway via the coordinative insertion of 2
with intermediate E can also occur.
Probable Catalytic Cycle. On the basis of the experi-
mental results and DFT calculations, and our earlier observa-
tions,11 we have depicted more authentic catalytic cycles for
the nickel-catalyzed alkynylation of indole with alkynyl bromide
(Figure 6). The (phen)NiBr2 species enters the catalytic cycle
and reacts with 1-(pyridin-2-yl)-1H-indole (1) in the rate
CONCLUSION
■
We have uncovered in detail the mechanism for the nickel-
catalyzed alkynylation of indole with alkynyl bromide. Some
catalytically competent nickel-complexes were synthesized and
structurally characterized. Kinetics, controlled reactivity stud-
ies, and DFT energy calculations highlight that the alkynylation
of indole follows a coordinative insertion path of alkynyl
Figure 6. Plausible updated catalytic cycles for nickel-catalyzed alkynylation reaction.
G
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Article
[(phen)3Ni]NiCl4 (7): C, 54.06; H, 3.02; N, 10.51. Found: C, 54.31;
H, 3.09; N, 10.67.
bromide involving the rate influencing C−H activation on
indole. The fractional positive rate order of the alkynylation
reaction with indole substrate and the involvement of indole
in the formation of the active catalyst have provided clear
mechanistic insights. The C−H activation of indole at the
nickelacycle species (phen)Ni(2-py indolyl)Br (A) appears to
be more facile than the same at the (phen)NiBr2 center;
however, the overall process for the alkynylation via the former
approach seems less likely. Considering all the experimental
findings and DFT calculations, we have drawn two catalytic
cycles for the nickel-catalyzed alkynylation of indole with
alkynyl bromide that proceed through the coordinative inser-
tion of alkynyl bromide into the Ni(II)−C bond and do not
involve a redox pathway.
General Procedure for Kinetic Experiment. To a Teflon-screw
capped tube equipped with magnetic stir bar was introduced catalyst 4
(0.0044 g, 0.009 mmol), LiOtBu (0.048 g, 0.60 mmol), alkynyl
bromide 2 (0.117 g, 0.45 mmol) and 1-(pyridin-2-yl)-1H-indole 1
(0.058 g, 0.304 mmol, 0.30 M), and toluene (required amount) was
added to make the total volume 1.0 mL. To the reaction mixture
mesitylene (0.030 mL, 0.215 mmol) was added as an internal
standard. The reaction mixture was then stirred at 150 °C in a
preheated oil bath. At regular intervals, the reaction vessel was cooled
to ambient temperature, introduced to the glovebox and an aliquot of
the sample was withdrawn to the GC vial. The sample was diluted
with toluene/acetone and subjected to GC analysis. The concen-
tration of the product 3 obtained in each sample was determined with
respect to the internal standard mesitylene. The data of the con-
centration of the product vs time (min) plot was drawn with Origin
Pro 8. For the reaction rate, the data were fitted linear (excluding
induction period) with Origin Pro 8, and the rate was determined by
initial rate method with different time intervals. The slope of the linear
fitting represents the reaction rate. The order of the reaction was then
determined by plotting the log(rate) vs log(conc. component) for a
particular component.
Computational Details. All the calculations in this study have
been performed with density functional theory (DFT), with the aid of
the Turbomole 7.1 suite of programs,19 using the PBE functional.20
The TZVP21 basis set has been employed. The resolution of identity
(RI),22 along with the multipole accelerated resolution of identity
(marij)23 approximations have been employed for an accurate and
efficient treatment of the electronic Coulomb term in the DFT
calculations. Solvent correction was incorporated with optimization
calculations using the COSMO model,24 with toluene (ε = 2.38) as
the solvent. The values reported are ΔG values, with zero-point
energy corrections, internal energy and entropic contributions
included through frequency calculations on the optimized minima
with the temperature taken to be 298.15 K. Harmonic frequency
calculations were performed for all stationary points to confirm them
as local minima or transition state structures. For all the Ni(II) and
Ni(IV) species considered, the DFT studies have been performed for
the singlet state, whereas for Ni(I) and Ni(III) the DFT studies have
been performed for the doublet spin state.
EXPERIMENTAL SECTION
■
General Experimental Considerations. All manipulations were
conducted under an argon atmosphere either in a glovebox or using
standard Schlenk techniques in predried glasswares. The catalytic
reactions were performed in flame-dried reaction vessels with Teflon
screw cap. Solvents were dried over Na/benzophenone or CaH2 and
distilled prier to use. Liquid reagents were flushed with argon before
use. The compounds (THF)2NiBr2,16 (2-pyridinyl)-indole17 were
synthesized according to the previously described procedures. Alkynyl
bromide (2) was synthesized according to literature procedures.18 All
other chemicals were obtained from commercial sources and were
used without further purification. High-resolution mass spectroscopy
(HRMS) mass spectra were recorded on a Thermo Scientific Q-Exactive,
Accela 1250 pump. Melting point was measured on Buchi 540
̈
capillary melting point apparatus; values are uncorrected. NMR (1H
and 13C) spectra were recorded at 400 or 500 (1H), 100 or 125 {13C,
DEPT (distortionless enhancement by polarization transfer)},
respectively on Bruker AV 400 and AV 500 spectrometers in
CDCl3 solutions, if not otherwise specified; chemical shifts (δ) are
given in ppm. The 1H and 13C NMR spectra are referenced to residual
solvent signals (CDCl3: δ H = 7.26 ppm, δ C = 77.2 ppm).
Procedure for Synthesis of (phen)nNiCl2 Complexes. (phen)-
NiCl2 (5) and (phen)2NiCl2 (6). A Schlenk flask was charged with
(DME)NiCl2 (0.30 g, 1.365 mmol) and 1,10-phenanthroline (0.295 g,
1.638 mmol), and THF (15 mL) was added to it. The reaction
mixture was stirred at room temperature for 12 h, during which a light
blue precipitate was formed. The reaction mixture was filtered, and
the light blue solid was washed with THF (30 mL) to remove
unreacted 1,10-phenanthroline. The blue solid was further washed
with CH3CN (4 × 15 mL), and the solid was dried under vacuum to
obtain an analytical pure compound of (phen)NiCl2 (5). The
combined acetonitrile solution was concentrated and kept at low
temperature to obtain a crystalline compound of (phen)2NiCl2 (6).
Yield: 0.38 g, 91% (5) and 0.05 g, 7% (6). Anal. Calcd for
C12H8Cl2N2Ni (5): C, 46.52; H, 2.60; N, 9.04. Found: C, 46.91; H,
2.67; N, 9.05. Anal. Calcd for C24H16Cl2N4Ni (6): C, 58.83; H, 3.29;
N, 11.43. Found: C, 59.01; H, 3.35; N, 11.65.
(phen)nNiCl2 and [(phen)3Ni]NiCl4 (7). A Schlenk flask was charged
with (DME)NiCl2 (0.50 g, 2.275 mmol) and 1,10-phenanthroline
(1.03 g, 5.689 mmol), and THF (20 mL) was added to it. The
reaction mixture was stirred at room temperature for 12 h, during
which a light green precipitate was formed. The reaction mixture was
filtered, and the light green solid was washed with THF (30 mL) to
remove unreacted 1,10-phenanthroline. The light green solid
was further washed with CH3CN (4 × 15 mL), and the solid was
dried under vacuum to obtain a mixture of compounds
(phen)1.2NiCl2 [mixture of (phen)NiCl2 and (phen)2NiCl2]. The
combined acetronitrile solution was concentrated and kept at low
temperature to obtain a crystalline compound of [(phen)3Ni]NiCl4
(7). Yield: 0.71 g, 90% for (phen)1.2NiCl2 and 0.055 g, 6% for
[(phen)3Ni]NiCl4 (or (phen)1.5NiCl2; 7). Anal. Calcd for
C14.4H9.6Cl2N2.4Ni [(phen)1.2NiCl2]: C, 50.01; H, 2.80; N, 9.72.
Found: C, 50.40; H, 2.87; N, 9.85. Anal. Calcd for C18H12Cl2N3Ni
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.organomet.8b00177.
■
S
Detailed experimental procedures, analytical data for
compounds, kinetic plots (PDF)
Additional data (XYZ)
Accession Codes
CCDC 1832266−1832267 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*Tel: + 91 20 2590 2733. Fax: + 91 20 2590 2621. E-mail:
b.punji@ncl.res.in.
■
ORCID
Rajesh G. Gonnade: 0000-0002-2841-0197
Kumar Vanka: 0000-0001-7301-7573
Benudhar Punji: 0000-0002-9257-5236
H
DOI: 10.1021/acs.organomet.8b00177
Organometallics XXXX, XXX, XXX−XXX

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Article
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to the SERB, New Delhi, India (EMR/2016/
000989) for financial support. SMK thanks CSIR−New Delhi
for the research fellowship. KV and SJ acknowledge “MSM”
(CSC0129) and DST (EMR/2014/000013) for funding. We
thank one of the reviewers for suggesting very crucial
mechanistic experiments.
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