Mechanistic Interrogation of Alkyne Hydroarylations Catalyzed by Highly Reduced, Single-Component Cobalt Complexes

Article abstract of DOI:10.1021/jacs.0c04072

Highly reactive catalysts for ortho-hydroarylations of alkynes have previously been reported to result from activation of CoBr2 by Grignard reagents, but the operative mechanism and identity of the active cobalt species have been undefined. A mechanistic analysis of a related system, involving hydroarylations of a (N-aryl)aryl ethanimine with diphenylacetylene, was performed using isolable reduced Co complexes. Studies of the stoichiometric reaction of Co(I) or Co(II) precursors with CyMgCl implicated catalyst initiation via a β-H elimination/deprotonation pathway. The resulting single-component Co(-I) complex is proposed as the direct pre-catalyst. Michaelis-Menten enzyme kinetic studies provide mechanistic details regarding the catalytic dependence on substrate. The (N-aryl)aryl ethanimine substrate exhibited saturation-like behavior, whereas alkyne demonstrated a complex dependency; rate inhibition and promotion depend on the relative concentration of alkyne to imine. Activation of the aryl C-H bond occurred only in the presence of coordinated alkyne, which suggests operation of a concerted metalation-deprotonation (CMD) mechanism. Small primary isotope effects are consistent with a rate-determining C-H cleavage. Off-cycle olefin isomerization catalyzed by the same Co(-I) active species appears to be responsible for the observed Z-selectivity.

Full text of DOI:10.1021/jacs.0c04072

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Article
Mechanistic Interrogation of Alkyne Hydroarylations Catalyzed
by Highly Reduced, Single-Component Cobalt Complexes
Benjamin A. Suslick, and T. Don Tilley
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04072 • Publication Date (Web): 26 May 2020
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Journal of the American Chemical Society
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Mechanistic Interrogation of Alkyne Hydroarylations Catalyzed by
Highly Reduced, Single-Component Cobalt Complexes
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Benjamin A. Suslick and T. Don Tilley*
Department of Chemistry, University of California, Berkeley, California 94720, United States
Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
Supporting Information Placeholder
ABSTRACT: Highly reactive catalysts for ortho-hydroarylations of alkynes have previously been reported to result from activation of
CoBr2 by Grignard reagents, but the operative mechanism and identity of the active cobalt species have been undefined. A mecha-
nistic analysis of a related system, involving hydroarylations of a (N-aryl)aryl ethanimine with diphenylacetylene, was performed
using isolable reduced Co complexes. Studies of the stoichiometric reaction of Co(I) or Co(II) precursors with CyMgCl implicated
catalyst initiation via a β-H elimination/deprotonation pathway. The resulting single-component Co(-I) complex is proposed as the
direct precatalyst. Michaelis-Menten enzyme kinetic studies provide mechanistic details regarding the catalytic dependence on
substrate. The (N-aryl)aryl ethanimine substrate exhibited saturation-like behavior whereas alkyne demonstrated a complex de-
pendency; rate inhibition and promotion depends on the relative alkyne to imine concentration. Activation of the aryl C–H bond
occurred only in the presence of coordinated alkyne, which suggests operation of a concerted metalation-deprotonation (CMD)
mechanism. Small primary isotope effects are consistent with a rate-determining C–H cleavage. Off-cycle olefin isomerization cat-
alyzed by the same Co(-I) active species appears to be responsible for the observed Z-selectivity.
metal complexes to participate in C–H activation chemis-
INTRODUCTION
try.36,44-54 Two distinct classes of Co precatalysts have been dis-
Chelation-assisted C–H activations allow selective function-
alization of unreactive C–H bonds, thereby accessing atom-
economical, late-stage molecular modifications without the in-
stallation of wasteful cross-coupling partners.1-9 In this context,
hydroarylation has emerged as an attractive method to form
C–C bonds via the addition of activated aryl C–H bonds across
olefins or alkynes. In the past two decades, catalyst develop-
ment for such reactions has been aided by mechanistic inves-
tigations.2,8-10 The first report of olefin hydroarylation from the
Murai group11,12 described RuH2(CO)(PPh3)3 as the precatalyst
and more recent advances in hydroarylations are based on
precatalysts bearing a metal center with a square-planar, d8 or
octahedral d6 configuration (e.g., Rh(I),13-18 Ir(I)19-28 Pd(II),29 and
Pt(II)30-32). Significantly, mechanistic studies with these second-
and third-row transition metal catalysts implicate a rate-limit-
ing C–H addition.30-33 By comparison, far fewer first-row transi-
tion metal hydroarylation catalysts have been identified, de-
spite recent efforts to exploit the high abundance and low
costs34 of Fe,35 Co,3,36 and Ni.37-42 Future catalyst designs should
rely on mechanistic information that is largely nonexistent, and
notably, first-row metals often engage in mechanisms that are
distinctly different from those of heavier transition metals.2,5,43
covered, based on either high- or low-valent cobalt. For well-
defined, high-valent Co(III) complexes, DFT calculations sug-
gest that a redox-neutral C–H activation step is plausible.44-
46,55,56 Additionally, the isolation of cyclometallated intermedi-
ates implicate the operation of an alkyne insertion step in the
catalytic cycle.45,55 In comparison, mechanisms for low-valent
Co catalysis remain elusive.
Low-valent cobalt catalysts for the hydroarylation of alkynes
have been generated in situ and have been extensively studied
by the Yoshikai group.36,47-53 The uncharacterized, active cata-
lytic species is generated by treatment of CoBr2 with certain
Grignard reagents (e.g., tBuCH2MgBr andMe3SiCH2MgBr) in the
presence of added ligands and substrates. Additionally, the re-
sultant hydroarylation products form as a mixture of E- and Z-
olefins and this aspect of the mechanism is also not under-
stood.
Several plausible catalytic cycles have been proposed for the
catalytic hydroarylation of (N-aryl)aryl ethanimines with inter-
nal alkynes;36 however, specific details about the nature of the
catalytic intermediates (e.g., oxidation states, ligand sphere,
etc.) or the initiation pathway have remained unclear. The Gri-
gnard reagent has been proposed to reduce the Co(II) precat-
alyst to a Co(I) or Co(0) active species, possibly via a radical-
based, one-electron reductive coupling.2,3 While metal-hydride
Recent developments in Co-catalyzed ortho-hydroarylations
illustrate the potential for highly active first-row transition
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n
complexes are implicated as key intermediates, such species
CyMgCl, or Bu2Mg) successfully activated Co-Cl towards pro-
1
2
3
4
have yet to be observed. The work described here addresses
the mechanism of alkyne hydroarylation by low-valent cobalt,
with reactivity studies that provide insight into the nature of
the catalytically active species, the catalytic cycle, and the con-
current olefin isomerization.
ductive catalysis.
Table 1. Effects of Organometallic Activator Identity.
5
6
7
RESULTS AND DISCUSSION
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9
Conditions for Catalytic Hydroarylation. Investigations be-
gan with examination of a particular “one-pot” transformation
closely related to those described by Yoshikai and coworkers36
involving hydroarylation of diphenylacetylene by an (N-
aryl)aryl ethanimine, with a CoCl2/RMgCl (R = -CH2CMe3, -
CH2SiMe3)/P(3-Cl-C6H4)/pyridine catalyst system. For these re-
actions, reported yields range from 60-95% and strongly favor
the E-isomer as the product (Z/E ratio of ca. 0.1-0.2). The reac-
tion chosen for study also utilized an in situ-generated catalyst
from a CoCl2/CyMgCl/PPh3 mixture. In this case, the hydroary-
lation of 1a was found to proceed in 33% yield, but surprisingly
with Z-selectivity and a relatively high Z/E ratio of 5.7 after hy-
drolysis (eq 1). It is worth noting that Z-selective catalysis has
also been observed by the Petit group57 using Co(I)-PMe3
precatalysts and microwave conditions.
M–R
–
nBuLi
1H NMR Yield (%) a
Z/E a
–
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0
5
4.4
–
PhLi
< 2
12
< 2
32
33
33
84
55
10
41
5
MesLi
33
MeMgCl
EtMgCl
H2C=CHMgBr b
CyMgCl
CyMgCl b
nBu2Mg
Mes2Mg
Bn2Mg
Ph2Zn
–
5.1
27
> 100
> 100
> 100
14
5.2
23
a As measured by H NMR spectroscopy of the crude reaction
mixture vs Si(SiMe3)4 as an internal standard. b An equivalent of
pyridine was added.
1
Previous reports of such reactions speculated that the re-
ducing conditions likely give rise to a low-valent catalytically
active species formed by the reduction of Co(II) precursors by
the Grignard reagent.2,3,36,47 To more thoroughly probe the na-
ture of the active catalyst, the well-defined Co(I) complex
(PPh3)3CoCl58 (Co-Cl) was investigated as a catalyst precursor.
Complex Co-Cl is not a competent single-component hydroary-
lation catalyst (Table 1); however, treatment of Co-Cl with two
equivs of CyMgCl produced a catalytic species giving yields sim-
ilar to those observed with CoCl2/PPh3 in the presence of acti-
vators (eq 1). Since previous reports have indicated a dramatic
effect associated with the nature of the Grignard reagent,36,47
catalysis with Co-Cl was examined with a range of organome-
tallic activators (Table 1). The best results were obtained with
CyMgCl, and in general it appears that β-hydrogens in the alkyl
group of the magnesium reagent lead to better results.
Optimization of catalytic conditions with Co-Cl and CyMgCl
revealed several insights. First, Yoshikai and coworkers36 ob-
served that addition of an equivalent of pyridine greatly im-
proved yields (a two-fold increase in some cases). Similarly, ad-
dition of 1 equiv of pyridine (relative to substrates) to a cata-
1
lytic mixture derived from Co-Cl/CyMgCl improved H NMR
yields from 33 to 84% (Supporting Information, Table S4). Also,
catalytic efficiencies modestly improved with addition of 5%
v/v TMEDA or 1,4-dioxane, to 45 and 42%, respectively (Table
S4). The possible role of adventitious acid in this catalysis (e.g.,
to facilitate a Friedel-Crafts processes) was addressed by addi-
tion of one equivalent (relative to Co) of a proton scavenger.
Thus, the non-coordinating base 2,6-di-tert-butyl-4-methylpyr-
idine was added in lieu of pyridine to the catalytic mixture. This
experiment illustrates that the catalytic yield is unaffected by
the presence of this compound (Table S4). The addition of
these weakly Lewis basic additives (i.e., Py, TMEDA, 1,4-diox-
ane) likely aids in the separation of the Li+ or Mg2+ counterions
from the anionic metal center via the formation of a crowned
complex, thereby increasing the nucleophilicity at Co. How-
ever, stoichiometric addition (relative to Co) of strongly coor-
dinating N-heterocyclic carbene ligands (e.g., IMes or IPr) in
the presence or absence of pyridine resulted in complete cat-
alytic inhibition (Table S4). Inhibition of catalysis also occurred
in coordinating solvents (e.g., Py or MeCN). On the other hand,
ethereal solvents (THF, 2-methyl-THF, dioxane, Et2O) resulted
In general, organomagnesium reagents were observed to
out-perform more reactive organolithium reagents. In some
cases, no catalysis resulted from treatment of Co-Cl with an or-
ganolithium. In contrast to results reported by the Yoshikai
group36,47-53 where E-products are favored (vide supra), the Z-
isomer (formally a trans-insertion product) is the major species
with all the activators tested. Additionally, the degree of Z-se-
lectivity was found to vary with the organometallic activator
employed. Activators bearing β-CH2 fragments (e.g., EtMgCl,
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in the highest catalytic conversions (Supporting Information, The organic byproducts created by treatment of complexes
1
2
3
4
5
6
7
8
Table S5). The CyMgCl/Co-Cl ratio (in THF with pyridine) was
found to impact both conversion and selectivity in catalysis
(Supporting Information, Table S6). While at least two equiva-
lents of CyMgCl relative to Co were required for reasonable
conversion, an excess of ca. 5 equiv of CyMgCl greatly reduced
activity by adventitious substrate degradation via nucleophilic
attack. Finally, the concentration of the substrate influenced
the overall conversion (Supporting Information, Table S7); di-
lute catalytic conditions provided the highest yielding in situ
catalyst, and yields decreased as a function of substrate con-
centration (e.g., 83% for 0.05 M vs. 66% for 1.0 M, as measured
by 1H NMR spectroscopy).
Co-Cl and Co-H (as well as CoCl2/3PPh3) with CyMgCl were
quantified by 1H NMR spectroscopy (Table 2). With two equiv-
alents of CyMgCl, equimolar amounts of cyclohexene and cy-
clohexane were observed for both CoCl2 (with PPh3) and Co-Cl.
An excess of CyMgCl with Co-Cl did not result in the evolution
of additional cyclohexane or cyclohexene. In contrast, stoichi-
ometric treatment of Co-H with CyMgCl afforded only a single
equivalent of cyclohexane.
9
Upon first inspection, it is perhaps surprising that deproto-
nation of Co-H occurs given the ancillary ligand environment,
since cobalt hydride complexes bearing only σ-donating phos-
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MeCN
phine co-ligands display hydridic character (e.g., pKa
Formation and Identity of Catalytically Active Species. The
activation of cobalt by the organomagnesium reagent would
seem to occur via formation of a reactive alkyl complex of the
type (PPh3)3CoR. Interestingly, treatment of Co-Cl with 1 equiv
of CyMgCl (eq 2) cleanly produced cyclohexene and the dia-
magnetic hydride (PPh3)3Co(N2)H (Co-H), first reported by
Sacco and Rossi59,60 in 1967.
[HCo(dppe)2] = 38.1). The introduction of π-acidic ligands con-
siderably reduces the pKa value (e.g., pKaMeCN [HCo(CO)4] = 8.3;
[HCo(CO)3(PPh3)] = 15.4).62,63 Given the slight π-acidic behavior
of end-on N2 ligands, it seems plausible that Co-H is deproto-
THF
nated with a strong base such as a RMgX or R2Mg (e.g., pKa
[EtMgCl] = 30.1; pKaTHF [Et2Mg] = 30.5).64 Indeed, stoichiometric
treatment of Co-H with MeLi, nBuLi, Bn2Mg, or CyMgCl gener-
ated an equivalent of the corresponding alkane (i.e., MeH,
1
nBuH, toluene, and CyH, respectively) as determined by H
NMR spectroscopy in benzene-d6. Gram-scale deprotonation
of Co-H with nBuLi or nBu2Mg in THF (eqs 3 and 4) afforded Co(-
I) complexes of the type [(PPh3)3Co(N2)]nM (M = Li(THF)3, n = 1,
Co-Li; M = Mg(THF)4, n = 2, Co2-Mg) as reported by Yamamoto
and coworkers.65
It has been previously reported by Kisch and coworkers61
that Co-H catalyzes the hydroarylation of diphenylacetylene
with diaryl-substituted diazo compounds as a neat melt at 85
°C. However, in our hands, 10 mol% of complex Co-H did not
promote catalysis with diphenylacetylene and 1a in a solution
of THF and pyridine heated to 65 °C for 1 d. However, the ad-
dition of an equiv (relative to Co) of CyMgCl or a similarly
n
strong base (e.g., BuLi, LDA) gave catalysis (Supporting Infor-
mation, Table S8). Activation of the cobalt hydride species un-
der the latter conditions suggests that the active catalyst re-
sults from deprotonation.
Complexes Co-Li and Co2-Mg exhibit red-shifted N2 stretch-
ing modes at 1898 and 1860 cm-1, respectively (for compari-
son, νN-N (Co-H) = 2092 cm-1; KBr). Co-Li exhibited a broad
7Li{1H} NMR resonance at -3.8 ppm in benzene-d6, which is con-
sistent with solvent-separated ion pairs.66-68 Hydrolysis of Co-
Li resulted in liberation of three equivalents of both THF and
PPh3 as determined by 1H NMR spectroscopy versus Si(SiMe3)4
as an internal standard, which is in agreement with the solid-
state composition of Co-Li as determined by elemental analy-
sis. However, both complexes appear to exhibit ligand dissoci-
ation in benzene-d6, as indicated by the existence of a 31P{1H}
NMR resonance at -5.24 ppm (unbound PPh3), along with
those for Co-Li (48.14) or Co2-Mg(48.26).
Table 2. Quantification of Cyclohexene and Cyclohexane from
Activation of Cobalt Species.
[Co]
CyMgCl
(equiv)
Cyclohexene
(equiv) a
Cyclohexane
(equiv) a
1
2
4
1
2
4
1
0.7
1
0.3
1
CoCl2 /
3PPh3
2
2
For comparative purposes, a structural analogue to Co2-Mg
was prepared according to the procedure described by Long
and coworkers.69 Treatment of CoCl2 with Zn and the triden-
tate ligand triphos, MeC(CH2PPh2)3, afforded the intermediate
species [(triphos)CoCl], which upon further reduction with Mg
afforded Co'2-Mg (eq 5). This complex exhibits a similarly red-
shifted N2 stretch at 1846 cm-1 (KBr). Complex Co'2-Mg gives
rise to a single 31P{1H} NMR resonance at 31.20 ppm.
0.7
1
0.3
1
Co-Cl
Co-H
1
1
0
1
a Volatile organic products were separated from [Co] via vac-
uum transfer and quantified by 1H NMR spectroscopy vs p-xylene
as an internal standard.
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by enhanced Li or Mg sequestration. While neither Co-Cl nor
1
2
3
4
5
6
7
8
Co-H are single-component catalysts, competent catalysis oc-
curs after addition of CyMgCl (1 and 2 equiv, respectively). In
contrast to the Co(I) precursors, the Co(-I) species Co-Li and
Co2-Mg catalytically coupled (N-aryl)aryl ethanimine 1a and
diphenylacetylene without the addition of Grignard. Addition-
ally, catalytic yields observed for Co-Li and Co2-Mg are compa-
rable to those obtained using CoCl2/3PPh3, Co-Cl, or Co-H with
a corresponding quantity of CyMgCl, which implicates
[(PPh3)3Co(N2)]- as the catalytically active Co fragment. Inter-
estingly, Z-2a was the major isomer observed regardless of
precatalyst, which suggests that a common species capable of
E- to Z-olefin isomerization exists as a result of activation with
CyMgCl.
While complexes of Co(-I) are relatively uncommon, a recent
report by Deng and coworkers70 describes the Co(-I) dinitrogen
complex [(ICy)2Co(N2)2][K(18-c-6)] in the context of nitrogen
fixation. DFT calculations indicate that the formally d10 Co cen-
ter engages in extensive back-bonding into the N2 π* orbital,
which may activate the N2 ligand of this complex for function-
alization. An example of such reactivity is borne out in the cat-
alytic silylation of N2 to N(SiMe3)3 in the presence of excess KC8
and Me3SiCl.70 Long and coworkers69 described similar N2 func-
tionalization chemistry with Co'2-Mg; stoichiometric treatment
of this complex with Me3SiCl afforded the silyldiazenido com-
plex, [(triphos)Co(N2SiMe3)], likely as a result of N2 activation
by the electron rich metal center. Given this notable reactivity
toward N2, investigations into interactions of highly-reduced
Co complexes with unsaturated substrates (i.e., olefins and al-
kynes) are of interest, particularly in the context of hydroary-
lations.
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60
Unlike the PPh3-ligated complexes, the triphos analogue
Co'2-Mg did not catalyze hydroarylation. Stoichiometric reac-
tions with either diphenylacetylene or 1a did not consume the
organic substrate and instead afforded a common, unknown
paramagnetic species consistent with broadened 1H NMR res-
onances at δ 15.10 (br s, 18H), -1.17 (br s, 6H), -2.54 (br s, 2H)
in benzene-d6 (see Supporting Information, Figures S4 and S5).
The lack of reactivity with alkyne or aryl-imine observed with
Co'2-Mg implies that a catalytic intermediate with fewer than
three ancillary phosphine ligands is required for catalysis.
While hydroarylations reported by the Yoshikai group36 have
focused on Mg-containing activators, Co-Li proved to be more
convenient for mechanistic investigations. The charge match-
ing of the Co(-I) fragment and Li+ is expected to result in more
facile ion dissociation events as compared to Co2-Mg. All sub-
sequent mechanistic studies, therefore, employed Co-Li as the
catalyst.
Table 3. Activity Comparison of Added Catalysts.
Table 4. Arene Functional Group Tolerance.
[Co]
CyMgCl
(equiv)
1H NMR Yield (%) a
Z/E a
CoCl2 /
3PPh3
4
41
40
0
2
0
1
0
0
0
0
–
59
–
Co-Cl
Co-H
45
0
44
58 (50) b
64 (48) b
0
65
> 100
44
–
Imine
1b
[Co]
Yield (%) a,b
Conv. (%)
Z/E a
a,c
Co-Li
Co2-Mg c,d
Co'2-Mg c,d
CoCl2/3PPh3/
4CyMgCl
30
36 (33)
11
68
36
36
8.8
8.0
Co-Li
a Determined by comparison to a known quantity of Si(SiMe3)4
as an internal standard. b Isolated yield given in parenthesis. c 0.5
equiv of complex was added. d 1,4-dioxane (5% v/v) was used in-
stead of TMEDA.
CoCl2/3PPh3/
4CyMgCl
> 100
1c
Co-Li
Co-Li
Co-Li
86 (70)
43 (29)
47 (27)
86
43
47
6.7
15
20
1d
1e
Table 3 compares the catalytic hydroarylation activity of co-
balt complexes Co-Cl, Co-H, Co-Li, Co2-Mg, and Co'2-Mg with
those of a catalyst generated in situ as described above in eq
1. TMEDA or 1,4-dixoane were employed as co-solvents in
place of pyridine since higher catalytic activities for the anionic
complexes were observed under those conditions, presumably
a 1H NMR yield and Z/E ratios were determined by comparison
b
to a known quantity of Si(SiMe3)4 as an internal standard. Iso-
lated yield given in parenthesis. c Conversion was determined from
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the quantity of substituted acetophenone derived from hydrolysis
of unreacted imine substrate.
Substrate Binding and Implications for the Catalytic Cycle.
1
2
3
4
5
6
7
8
To probe interactions of the alkyne substrate with the cobalt
center, Co-Li was treated with an excess of the alkyne bis(para-
tolyl)acetylene (p-TolCCp-Tol; Figure 1). For varying quantities
of added alkyne, the ratio of free to bound alkyne was quanti-
fied vs. an internal standard after equilibration. The existence
of multiple distinct tolyl-CH3 resonances suggests the presence
of a mixture of several alkyne-ligated complexes. On the basis
of the initial concentration of Co-Li, an average number of
bound alkynes per Co (x) was determined for various [p-
TolCCp-Tol]0/[Co-Li]0 ratios and temperatures, and the results
are plotted in Figure 1. The addition of alkyne results in dis-
placement of ligated PPh3, and under catalytic conditions (ca.
10 equivs relative to Co) ~2 alkynes per Co are consumed,
which corresponds to displacement of the N2 ligand and one
PPh3. Surprisingly, this ratio appears to be temperature invari-
ant.
Comparisons of the functional group tolerance of the single-
source catalyst Co-Li vs. the in situ CoCl2/3PPh3/CyMgCl cata-
lyst were made for several substrates as shown in Table 4.
These results illustrate a potential advantage to “Grignard-
free” hydroarylations. Electrophilic groups (e.g., esters, ke-
tones, aldehydes) are often not compatible with nucleophilic
organomagnesium reagents that can undergo rapid, compet-
ing reactions with the substrate. This problem may be circum-
vented to some extent by addition of the Grignard to the cata-
lyst mixture prior to introduction of the substrate, but in situ
catalyst generations of this type often employ a slight excess
of activator. Note that the Yoshikai group52 has developed “Gri-
gnard-free” catalysis by use of Mg turnings as the terminal re-
ductant, but these reducing conditions may also lead to unde-
sired reactions of various functional groups (e.g., halides).
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Significantly, with complex Co-Li as the catalyst, substrates
bearing an ester (1b) or a nitrile (1c) group are tolerated in
modest yields; only the desired product was observed. In con-
trast, the in situ reactions did not cleanly catalyze hydroaryla-
tion since products derived from nucleophilic addition of
CyMgCl to the carbonyl or nitrile fragments were produced, as
observed by 1H NMR spectroscopy. The existence of such spe-
cies requires more difficult purification procedures. Moderate
catalytic conversion occurred with substrates bearing elec-
tron-withdrawing CF3 (1d) or donating OMe (1e) functionali-
ties. These data suggest that complex Co-Li may be useful for
substrates that are not tolerated by the catalysts generated in
situ despite being mildly acid-sensitive.
Given the observations described above, it appears that cat-
alyst generation occurs by treatment of precatalyst Co-Cl with
an organometallic transmetalation reagent bearing a β–H sub-
stituent (e.g., EtMgCl, CyMgCl, etc; Scheme 1). The resultant
Co–R complex (A) undergoes rapid β–H elimination under an
N2 atmosphere to generate (PPh3)3Co(N2)H (Co-H) and an
equivalent of olefin (e.g., ethylene, cyclohexene, etc.). Depro-
tonation by the basic organometallic activator then results in
formation of stoichiometric alkane (e.g., ethane or cyclohex-
ane) and the active Co(-I) anion. Indeed, similar activation
pathways have been reported by Koszinowski and coworkers71
in the context of Co-catalyzed Heck-type reactions.
Figure 1. Average bound alkynes per Co as a function of alkyne
equivalents. Reaction conditions: [Co-Li]0 = 13 mM; [bis(p-
tolyl)acetylene]0 = 19, 44, 90, 135, and 190 mM. Average bound
1
alkyne per Co measured by H NMR spectroscopy in benzene-d6
versus Si(SiMe3)4 as an internal standard with the NMR probe tem-
perature calibrated and set to 338 K.
While similar ligand substitution behavior was observed
with (N-aryl)aryl ethanimine, productive C–H activation did not
occur. Thus, stoichiometric treatment of Co-Li with imine 1a in
benzene-d6 at 65 °C did not result in the generation of a new
Scheme 1. Proposed Catalyst Activation Mechanism.
1
cyclometallated species after 2 d; instead, only broadened H
NMR resonances for 1a, likely the result of rapid ligand ex-
change with PPh3, were observed.
Reactant Order and Catalytic Kinetics. The reaction profile
with complex Co-Li as catalyst was monitored by 1H NMR spec-
troscopy at 65 °C (Figure 2). Initial time points reveal that the
E-isomer is the kinetic product; conversion to Z-3a occurred
only after the formation of E-3a. These data are consistent with
an off-cycle isomerization process to generate the Z-isomer as
the thermodynamic product.
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slope was determined as the standard error of the linear regres-
sion (R2 = 0.92, Sx = 1.6 x 10-4 s-1). Error bars were determined from
the standard deviation of triplicate experiments B: log-log plot de-
piction of the first-order dependence of [Co-Li]0 on the initial rate
(slope ~ 1). Error determined as the standard error of the linear
regression (R2 = 0.91, Sx = 0.2).
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Figure 2. Representative initial reaction kinetic profile of the hy-
droarylation of 1a ([1a]0 = 67 mM) with diphenylacetylene ([al-
kyne]0 = 67 mM) catalyzed by Co-Li ([Co-Li]0 = 2 mM, 3 mol%). Re-
action was monitored by 1H NMR spectroscopy in benzene-d6 ver-
sus Si(SiMe3)4 as an internal standard with the NMR probe tem-
perature calibrated and set to 339 K. See Supporting Information,
Figure S18 for additional representative reaction profiles.
Figure 4. A: Dependence of [Co2-Mg]0 on the hydroarylation of 1a
([1a]0 = 67 mM) with diphenylacetylene ([alkyne]0 = 67 mM). Initial
rates (kinitial) were determined by H NMR spectroscopy in ben-
zene-d6 vs Si(SiMe3)4 as an internal standard with the NMR probe
temperature calibrated and set to 339 K. The dashed line is a linear
fit of the data with a slope of kobs = 3.0(3) x 10-5 s-1. Error deter-
mined as the standard error of the linear regression (R2 = 0.95, Sx
= 0.3 x 10-5 s-1). B: log-log depiction of the first-order dependence
of [Co2-Mg]0 on the initial rate (slope ca. 1.1). Error determined as
the standard error of the linear regression (R2 = 0.98, Sx = 0.06).
With Co-Li as the catalyst, an initial catalytic rate constant
was calculated at 338 K to be kobs = 9(2) x 10-4 s-1 (Figure 3A)
with a first-order dependence on [Co-Li]0 (Figure 3B). No ob-
servable difference in initial rate occurred when 12-crown-4
was added to the catalytic mixture. This result would seem to
rule out participation of the Li counterion as a Lewis-acid in the
catalysis. Significantly slower catalysis occurred with the bime-
tallic complex Co2-Mg (Figure 4A), with a calculated catalytic
rate constant of kobs = 3.0(3) x 10-5 s-1 as measured at 339 K,
which implicates slow decoordination of the active L3Co-1 frag-
ment from the Mg2+ counterion. Surprisingly, a first-order de-
pendence on [Co2-Mg]0 (Figure 4B) suggests that only a single
catalytically active Co fragment exists along with an inert
[L3Co(N2)]Mg+ counterion, which implicates Li+ as the better
dissociating counter cation.
1
Each of the substrates displayed saturation-type kinetics,
with pseudo-first order dependencies at low substrate concen-
trations. Given these results, a Michaelis-Menten analysis was
used to further examine the catalytic mechanism. Typically,
such studies are performed to elucidate the origin of satura-
tion behavior, using various models for enzyme inhibition.72,73
By presenting the data in a Lineweaver-Burk double-reciprocal
plot, two key mechanistic features can be extracted from a lin-
ear fit, namely the maximum achievable rate (νmax = 1/inter-
cepty) and a modified binding constant (KM = -1/interceptx).
Three main classes of enzymatic inhibition mechanisms exist,
which result from competitive (KM increases), uncompetitive
(both Vmax and KM decrease), and non-competitive (νmax de-
creases) binding of the inhibitor.73
With these mechanistic factors in mind, an enzymatic-like ki-
netic analysis was applied to the cobalt-catalyzed hydroaryla-
tions described herein. The hydroarylations of diphenylacety-
lene with 1a at various initial substrate concentrations were
monitored by 1H NMR spectroscopy in benzene-d6 at 338 K us-
ing complex Co-Li as the catalyst (7 mM; Figure 5). The initial
catalytic rate constants (kinitial) were determined for each of
these catalytic reactions (i.e., at each [alkyne]0 and [1a]0); at a
fixed alkyne concentration, saturation-like imine dependence
was observed and is reflected in a linear fit in the main double
reciprocal plot. A series of such linear fits was generated at a
variety of initial alkyne concentrations (see Supporting Infor-
mation, Tables S13-S15). Each fit passed through the same y-
Figure 3. A: Dependence of [Co-Li]0 on the hydroarylation of 1a
([1a]0 = 67 mM) with diphenylacetylene ([alkyne]0 = 67 mM). Initial
1
rates (kinitial) were determined by H NMR spectroscopy in ben-
zene-d6 vs Si(SiMe3)4 as an internal standard with the NMR probe
temperature calibrated and set to 338 K. The dashed line is a linear
fit of the data with a slope of kobs = 9(2) x 10-4 s-1. Error of the fit
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intercept from which an average νmax was calculated to be
1.2(2) x 10-5 M s-1. Interestingly, the slope of each fit (KM/νmax
depends on the initial alkyne concentration, as illustrated in
the expansion of Figure 5. This secondary Michaelis-Menten
plot was fit to a hyperbolic function which contains a linear and
an inverse dependence on alkyne concentration.
(where Kd and Kd’ are the dissociation constants for 1a and di-
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phenylacetylene, respectively; Ka’ is an off-cycle association
constant). The observed alkyne kinetics result from the role of
1a both as a substrate and a competitive inhibitor. That is, two
discrete regimes exist: at low concentrations, the presence of
alkyne increases the reaction rate, whereas high alkyne con-
centrations result in competitive inhibition, which is consistent
with the formation of inactive bis(alkyne) off-cycle species. In-
deed, precedent exists for such substrate inhibition, as ob-
served in related Ir28 and Ru75 olefin hydroarylation systems.
A model of the catalytic rate law was derived to account for
the hyperbolic fit and the full derivation is described in the Sup-
porting Information.74 This Michaelis-Menten model (eq 6) re-
lates the observed rate (ν) to a function of the catalytic rate
(where νmax = kcat[Co-Li]0) and substrate binding equilibria
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Figure 5. Lineweaver-Burk (double-reciprocal) plot of the hydroarylation of diphenylacetylene and 1a catalyzed by Co-Li (7 mM). Initial
rates (kinitial) were determined by 1H NMR spectroscopy in benzene-d6 with Si(SiMe3)4 as an internal standard with the NMR spectrometer
probe calibrated and set to 338 K. Each experiment within a data set was performed at identical [diphenylacetylene]0 as follows: 34 mM
( ), 49 mM ( ), 71 mM (●), 102 mM ( ), 138 mM (■), 210 mM (▲), and 280 mM (●). The colored dashed lines are the linear fits for each
corresponding data set. Each fit has the same y-intercept which corresponds to a Vmax = 1.2(2) x 10-5 M s-1. Error determined as the standard
deviation of the average of y-intercepts from all 7 data sets. Inset: Plot of the slope of the linear fits from the main plot versus [diphenyla-
cetylene]0. The black dashed line represents a hyperbolic fit of the data.
Given the lability of the ancillary phosphine ligands under
catalytic conditions, the influence of added PAr3 on catalysis
with Co-Li was investigated (Figure 6) with PPh3, PMes3 and
P(C6F5)3. Surprisingly, additional PPh3 promoted catalytic activ-
ity until saturation at ca. 50 equivs relative to Co-Li. A similar
rate enhancement occurred with added PMes3, which gave sat-
uration-like behavior at ca. 10 equivs relative to Co-Li. In con-
trast, the perfluorinated analogue, P(C6F5)3, displayed a com-
plex rate dependency; a modest rate increase was only ob-
served at ca. 1-3 equiv of added P(C6F5)3 relative to Co. It may
be possible that added phosphine promotes the reaction rate
either by stabilization of the active catalytic species or by
changing the operative mechanism. Similar saturation behav-
ior for ancillary ligands has been observed by Yoshikai and
coworkers.36 It is of note that C–H activation of the ortho-aryl
Monitored catalysis by time-resolved 31P{1H} NMR spectros-
copy probed the speciation of PPh3 (Figure 7). Given the rela-
tively low [PPh3] under catalytic conditions, a high-field NMR
spectrometer equipped with a liquid N2 cryoprobe broadband
channel was used to facilitate direct observation of potential
phosphorus-containing intermediates. Two new resonances
were observed over the course of the catalysis (in addition to
free PPh3); the first at 69.27 ppm is attributed to a new, Co-
bound PPh3 ligand, given the similar shift for Co-Li (48.14 ppm).
A second resonance at 9.90 ppm exists in a range similar to
that of a phosphonium-ylide, which typically exhibits reso-
nances between 5 to 20 ppm.76 However, it is unclear whether
this species might exist as a free “ylide” or is complexed by a
Co fragment.77-83
1
position of PPh3 does not occur (as determined by H NMR
spectroscopy), even at excess phosphine loadings.
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of p-anisidine, 4’-ethylacetophenone, and residual 1a. Deu-
1
teron incorporation into the ortho-C–H bond was not ob-
served; however, ca. 1.4 D was observed in the acetyl -C(O)CH3
fragment of 4’-acetophenone and in the iminyl -C(N)CH3 posi-
tion of 1a, which resulted from acid-catalyzed enol and
enamine tautomerization, respectively. To probe the interac-
tion of ortho-C–H bonds with the catalyst in the absence of al-
kyne, an equimolar mixture of 1a and Co-Li in THF was heated
to 65 °C for 2 h (Scheme 2B). Subsequent treatment with ben-
zoic acid-d (C6H5COOD) afforded 1a with D incorporation only
in the iminyl fragment. An analogous experiment with equimo-
lar quantities of 1a, Co-Li, and diphenylacetylene (Scheme 2C)
resulted in the formation of Z/E-2a and Z/E-3a. Interestingly,
only acid-catalyzed exchange into the acetyl or iminyl groups
occurred. That is, no ortho-H(D) exchange was observed. The
existence of these hydroarylation products as well as the lack
of ortho-deuterium incorporation in Scheme 2 suggest two
possibilities. First, the C–H bond activation event may require
the presence of alkyne to occur. Alternatively, the concentra-
tion of any intermediates derived from substrate deprotomet-
alation may not build up to an appreciable extent, thereby pre-
cluding interception by the added deuterium source.
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Figure 6. Dependence of added [PAr3]0 (PPh3, PMes3, or P(C6F5)3)
on the hydroarylation of 1a ([1a]0 = 67 mM) with diphenylacety-
lene ([alkyne]0 = 67 mM) catalyzed by Co-Li ([Co-Li]0 = 7 mM, 10
mol%). The reaction in benzene-d6 was monitored by 1H NMR
spectroscopy versus Si(SiMe3)4 as an internal standard with the
NMR probe temperature calibrated and set to 338 K. Error deter-
mined for reactions with added PPh3 as the standard deviation of
triplicate runs except at [PPh3]0 = 0.7 M, which was performed in
pentaplicate.
Scheme 2. Stoichiometric Deuteron-Quenching Reactions.
Figure 7. Time-resolved 31P{1H} NMR spectra (benzene-d6, 242.94
MHz) during the hydroarylation of 1a ([1a]0 = 67 mM) with diphe-
nylacetylene ([alkyne]0 = 67 mM) catalyzed by Co-Li ([Co-Li]0 = 7
mM, 10 mol%). Spectra were acquired on a 600 MHz NMR spec-
trometer equipped with a liquid N2 cryoprobe broadband channel
with the NMR probe temperature calibrated to 339 K. All spectra
over the course of the reaction are displayed atop one another as
a stack. Time points were acquired every 20 s as the average of 8
scans (d1 = 1s, d20 = 20 s, ns = 8). Inset: expansion of two new
peaks observed at 69.27 and 9.90 ppm, which grow in over the
course of the reaction. These peaks are attributed to a new bound
PPh3 complex and a phosphonium-ylide-like species, respectively.
Further investigation of catalysis with isotopically enriched
substrates probed the C–H activation step. Ortho-dideuterated
imine 1a-d2 was synthesized by selective deuteration of 4’-
ethylacetophenone with D2 and Crabtree’s catalyst followed
by condensation with p-anisidine (eq 7). In addition, ortho-
monodeuterated substrate 1f-d1 was synthesized from 2’-bro-
moacetophenone (eq 8).
Rate-Limiting C–H Activation and Isotope Effects. Deu-
teron-quenching experiments were utilized to probe the na-
ture of the C–H activation step (Scheme 2). In a control exper-
iment (Scheme 2A), a solution of imine 1a in chloroform-d was
treated with a slight excess of acetic acid-d4 to afford a mixture
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THF and TMEDA. The mixed products resulting from H(D)-
1
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3
4
crossover were not observed in this competition, which sup-
ports the C–H cleavage as a non-reversible step. Similarly, an
intramolecular KIE was calculated to be 3.6 using imine 1f-d1
bearing both an ortho-deuterium and ortho-proton (Scheme
3C).
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Scheme 3. Kinetic Isotope Effect Studies.
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Monitoring the hydroarylation of 1a-d2 with Co-Li as the cat-
alyst (14 mol%) by H NMR spectroscopy provided an isotope
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effect on both the catalytic rate as well as the rate of isomeri-
zation (Figure 8). The replacement of C–H for C–D greatly di-
minished the observed rate of Z-olefin formation and impli-
cates a C–H(D) cleavage step as being key to the isomerization.
2
Analysis of the Z/E-3a-d2 products by H NMR spectroscopy
confirmed deuterium incorporation into the vinylic position
(6.60 ppm and 7.06 ppm, respectively) and retention of deu-
terium at the ortho-aryl position (7.86 ppm).
Figure 8. Representative initial reaction kinetic profile of the hy-
droarylation of 1a-d2 ([1a-d2]0 = 72 mM) with diphenylacetylene
([alkyne]0 = 72 mM) catalyzed by Co-Li ([Co-Li]0 = 10 mM, 14
mol%). The reaction in benzene-d6 was monitored by 1H NMR
spectroscopy versus Si(SiMe3)4 as an internal standard with the
NMR probe temperature calibrated and set to 336 K.
In separate reactions performed at identical concentrations
of catalyst and substrates, the observed initial catalytic reac-
tion rate constants kH,obs and kD,obs were determined to be
8.5(5) x 10-6 M/s and 4.3(3) x 10-6 M/s, respectively (Scheme
3A). The calculated KIE (kH,obvs/kD,obs) of 2.0(3) is consistent with
a rate-determining C–H cleavage.84 Additional KIE experiments
with equimolar amounts of 1a and 1a-d2 are consistent with
this result; this intermolecular competition (Scheme 3B) re-
sulted in an isotopic distribution corresponding to a KIE of 3.5,
which is larger than that determined in the independent rate
experiments due to differing reaction conditions; namely, the
independent rates experiment employed benzene-d6 as sol-
vent, whereas the competition experiments used a mixture of
Substrate competition experiments further examined the
nature of the C–H transfer step. In three separate experiments,
equimolar amounts of electron rich and electron poor (N-
aryl)aryl ethanimine substrates were subjected to catalytic
conditions. The competition of 1a and 1b (eq 9) illustrates a
representative trend that electron-poor arenes (e.g., CO2Me)
are favored over electron-rich substrates (e.g., Et) in the catal-
ysis, which suggests that a proton-like transfer occurs in the C–
H bond activation event.85 Additional substrate competition
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experiments are given in the Supporting Information (Figures
Page 10 of 19
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Independent rate measurements for the hydroarylations of
the substituted (N-aryl)aryl ethanimines with Co-Li corrobo-
rated the competition experiments. The initial catalytic rates
determined for 1a, 1b, 1d, and 1e appear to correlate with the
σpara and σmeta parameters for the given substituent, as illus-
trated in the correlation plots (Figures 9A and 9C). The corre-
sponding Hammett plots (Figures 9B and 9D) were generated
by the normalization of the measured rates by the rate ob-
served for 1a (kX/kEt). The electronic effects imparted by the
substituent may affect any combination of three substrate-
centered transformations (i.e., imine pre-coordination and
decoordination, and C–H activation). The para-parameter in-
forms primarily on the imine coordination ability, whereas the
meta-parameter influences the lability of C–H cleavage. The
small, but positive slopes (ρ’para = 0.36(6) and ρ’meta = 0.6(2)) of
the normalized plot indicate that electron-withdrawing sub-
stituents may influence all of the aforementioned transfor-
mations. The weak correlation with the σpara parameter indi-
cates that electron-donating substituents dampen the ob-
served initial rate compared to withdrawing functionalities,
perhaps through prevention of competitive inhibition by addi-
tional imine donors. Interestingly, a stronger correlation exists
with the σmeta parameter, which suggests that the observed
rate of catalysis may relate to the pKa of the arene C–H bond.
However, the relatively small rate enhancements observed in
this series of substrates preclude the proposal of an unambig-
uous rationale.
Figure 9. A: para-Hammett parameter (σpara) versus the initial
rate of hydroarylation for 1a (Et), 1b (CO2Me), 1d (CF3), and 1e
(OMe). Catalytic conditions: (N-aryl)aryl ethanimine ([1]0 = 72
mM) with diphenylacetylene ([PhCCPh]0 = 72 mM) catalyzed by
Co-Li ([Co-Li]0 = 10 mM). The reactions in benzene-d6 were
monitored by 1H NMR spectroscopy versus Si(SiMe3)4 as an in-
ternal standard with the NMR probe temperature calibrated to
340 K. Error bars determined as the standard deviation of trip-
licate runs. B: Normalized Hammett plot, which depicts the
log(kX/kEt) as a function of the Hammett parameter σpara with a
slope of ρ’para = 0.36(6), with error determined as the standard
error of the linear regression (R2 = 0.95, Sx = 0.06). C: meta-
Hammett parameter (σmeta) versus the initial rate of hydroary-
lation. D: Normalized Hammett plot, which depicts the
log(kX/kEt) as a function of the Hammett parameter σmeta with
a slope of ρ’meta = 0.6(2), with error determined as the standard
deviation of the linear regression (R2 = 0.78, Sx = 0.22).
Proposed Mechanism for the Catalytic Cycle. Cumulatively,
the results described above allow postulation of a reasonable
mechanism for this catalysis (Scheme 4). The anionic complex
Co-Li appears to be a direct precursor to the active catalytic
species. Alkyne coordination occurs prior to the rate determin-
ing C–H activation step by displacement of PPh3 and N2 to gen-
erate the Co(alkyne) complex B which undergoes reversible
imine precoordination to form complex C. It is also possible
that multiple, non-productive alkyne ligation steps occur to
form off-cycle species such as D. This type of complex is appar-
ently not catalytically active based on the observed competi-
tive inhibition described in the Michaelis-Menten study (Figure
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5). Presumably, such complexes possess less activated alkyne An example of a first-row transition metal complex which
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ligands due to competitive π-backbonding.
undergoes phosphine assisted alkyne insertion was described
by Huggins and Bergman.78 In this report, (acac)Ni(PPh3)R com-
plexes were observed to react with internal alkynes of the type
R'CCR'' to afford (acac)Ni(CR'=CR''R)(PPh3) species with an un-
usual distribution of syn- and anti-insertion products. They
postulated that PPh3 played a role in both the insertion process
and off-cycle isomerizations by direct attack on Ni(alkyne) or
Ni(vinyl) intermediates. While analogous reactivity with mon-
ometallic cobalt complexes has yet to be described, a bimetal-
lic Co2(alkyne) complex undergoes an intramolecular rear-
rangement to generate a new P–Calkyne bond (eq 11) that is
reminiscent of a formal insertion (31P resonances observed at
31.3 and 4.7 ppm in dichloromethane).79 Phosphine-alkyne
couplings have also been reported for Mo,80 Re,81 Pd,82 and
Rh/Os heterobimetallic83 complexes.
In catalytically productive steps, complex C may undergo C–
H bond activation. One possible pathway (dashed) involves an
intramolecular aryl C–H oxidative addition (OA) in C to afford a
hydrido-Co(I) intermediate E; subsequent hydride insertion af-
fords a (C,N)-chelated complex F bearing a diphenylvinyl frag-
ment. Alternatively, a direct CMD-like mechanism may occur
through a transition state akin to TSC-F Reductive elimination
.
9
and substrate coordination afford the hydroarylation product
as the E-isomer and regenerates B. However, these two mech-
anisms do not explain the rate enhancement observed with
added PPh3.
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An alternative C–H bond activation route (bold) involves an
initial nucleophilic attack of exogeneous PPh3 onto the bound
alkyne in C to afford the zwitterionic intermediate G. This spe-
cies may be described by resonance structures involving
charge localization on the alkyne β-carbon (G1), the Co metal
center (G2), or across the entire alkyne. If addition of L to the
cobalt center occurs instead at C or G, the resultant coordina-
tively saturated 18 e- species would lack a requisite open coor-
dination site for the H transfer step to occur. This should lead
to a rate inhibition and not the observed rate enhancement.
We propose that PPh3 imparts Wittig-like character (and nu-
cleophilicity) to the Co-bound carbon, as illustrated by reso-
nance structure G1, and thereby accesses a more facile C–H
cleavage though a direct, H+ transfer to afford F (via TSG-F). In-
deed, concerted metalation deprotonation (CMD) mecha-
nisms have considerable theoretical precedence4,6,85-87 and
have been invoked in the context of hydroarylation, specifi-
cally towards relevant arene-to-alkyne or arene-to-olefin H-
transfer steps.39,40,57,88-90 Indeed, nucleophile assisted CMD
mechanisms are invoked in several C–H activation processes,
such as carboxylate-assisted thiophene activations with Pd85 or
intramolecular cyclometallations of Grubbs-type complexes.91
Indeed, precedent exists for phosphine addition to metal
bound alkyne complexes.77-83 One example reported by Chin
and coworkers77 demonstrated that such additions occur upon
exposure of [(CO)Ir(PPh3)4]+ to phenylacetylene (eq 10). The re-
sultant metalo-phosphonium-ylide complex exhibits a 31P NMR
resonance at 20.11 ppm (chloroform-d), which is similar to that
observed for the Co intermediate described above (9.90 ppm,
benzene-d6, Figure 7).
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Scheme 4. Proposed Mechanism for Alkyne Hydroarylation Catalyzed by Co-Li.a
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a Counter-cations have been omitted for clarity.
A related, low-valent cobalt system described by the Petit
group57 employed (PMe3)4Co as the precatalyst and microwave
conditions for alkyne hydroarylation. For this system, it was
postulated that multiple phosphine dissociations occur to gen-
erate a monophosphine Co(PMe3) intermediates. On the basis
of this assumption, computational studies indicated that a di-
rect, ligand-to-ligand hydride transfer (similar to TSC-F, Scheme
4) could account for the C–H activation event for this system.57
The barrier for this concerted H-transfer was calculated to be
ΔG‡ = 15.9 kcal mol-1 for the transition state corresponding to a
Co(0) center bearing imine, alkyne, and PMe3 ligands. How-
ever, the Petit57 mechanism does not include potential phos-
phine assistance.
tivation pathway. In this context, we favor the phosphine as-
sisted CMD-like mechanism (bottom) over the classical oxida-
tive bond cleavage path (top) or direct CMD path (middle).
Origin of Observed Olefin Z/E-Selectivity: Off-Cycle Isomeri-
zation. To investigate the off-cycle isomerization process, a se-
ries of disubstituted olefins was treated with catalytic quanti-
ties of complex Co-Li in the dark to avoid adventitious pho-
toisomerization (eqs 12 and 13). Quantitative isomerization
occurred after 20 h at 65 °C for mono- or diaryl substituted cis-
olefins (i.e., cis-stilbene and cis-β-methylstyrene, eq 12) to af-
ford the corresponding trans-olefin; surprisingly, complex Co-
Li was unreactive towards dialkyl olefins (i.e., cis-2-butene, eq
13). Upon stoichiometric addition of a hydrogen-atom source
(i.e, 9,10-dihydroanthracene, DHA), cis-2-butene was con-
verted to trans-2-butene with a half-life of ca. 5 h at 65 °C
(quantitative after 20 h). The reverse isomerization (i.e., trans-
to cis-) did not occur to an appreciable extent; after 20 h at 65
The CMD mechanism4,6,85-87 is now well recognized as an im-
portant class of bond activation steps, and it seems likely that
the hydroarylation catalysis with Co-Li involves such a C–H ac-
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Journal of the American Chemical Society
°C with added Co-Li, trans-stilbene remained stereometrically
pure.
diarylolefins without the addition of a reagent that might pro-
1
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3
4
duce a cobalt hydride species. However, it seems likely that a
Co–H species, formed under the reaction conditions, may be
responsible for the observed isomerization.
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9
The kinetic profiles of the isomerization process with cis-stil-
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bene (Figure 10A) and cis-β-methylstyrene (Figure 11A) as the
substrates were investigated by 1H NMR spectroscopy in ben-
zene-d6 at 22 °C. The dependence of the isomerization rate on
[olefin] revealed a first-order rate dependence for the case of
cis-stilbene (Figure 10B; kobs = 3.1(2) x 10-6 s-1), but an inverse
first-order dependence for cis-β-methylstyrene (Figure 11B;
kobs = 1.3(1) x 10-7 M-1 s-1). After ca. 3 days at 22 °C, near quan-
titative conversion (~ 95%) to the trans-isomer was observed
for both olefin substrates.
Figure 11. A: Representative kinetic profile of cis-β-methylstyrene
([cis-β-methylstyrene]0 = 120 mM) isomerization catalyzed by Co-
Li (10 mol%, [Co-Li]0 = 7 mM) as determined by 1H NMR spectros-
copy in benzene-d6 vs Si(SiMe3)4 as an internal standard with the
NMR probe temperature calibrated and set to 295 K. B: Depend-
ence of isomerization rate on [cis-β-methylstyrene]0. The dashed
line is a linear fit of the data with a slope of kobs = 1.3(1) x 10-7 M-1
s-1. Error determined as the standard error of the linear regression
(R2 = 0.96, Sx = 0.1 x 10-7 M-1 s-1).
These results point to a catalytic, off-cycle isomerization
event that accounts for the observed Z-selectivity in the hy-
droarylation process (Scheme 5). Initial coordination of cis-ole-
fin to complex Co-Li occurs to give intermediate H. A formal C–
H oxidative addition of the bound olefin of H could produce the
hydride species I bearing a cis-vinyl fragment. Cobalt-vinyl in-
termediates such as F (Scheme 4) and I (Scheme 5), may un-
dergo olefin isomerization in a manner similar to that postu-
lated by Huggins and Bergman78 for analogous trans-isomeri-
zation in vinylic complexes derived from cis-insertions of aryl-
substituted alkynes into a Ni–H bond. It was posited by these
authors78 that such Ni-based alkyne complexes exhibit charge
localization on the diaryl-vinyl ligand, thereby reducing the
double-bond character and allowing C–C bond rotation. In-
deed, a related group 9 species, [Cp*Rh(CPh=CHPh)(PMe3)]+,
undergoes this vinyl isomerization process through such a
mechanism.93
Figure 10. A: Representative kinetic profile of cis-stilbene ([cis-stil-
bene]0 = 95 mM) isomerization catalyzed by Co-Li (10 mol%, [Co-
1
Li]0 = 7 mM) as determined by H NMR spectroscopy in benzene-
d6 vs Si(SiMe3)4 as an internal standard with the NMR probe tem-
perature calibrated and set to 295 K. B: Dependence of isomeriza-
tion rate on [cis-stilbene]0. The dashed line is a linear fit of the data
with a slope of kobs = 3.1(2) x 10-6 s-1. Error determined as the
standard error of the linear regression (R2 = 0.98, Sx = 0.2 x 10-6 s-
1).
Cobalt-catalyzed olefin isomerizations have recently been
reported by Hilt and coworkers.92 Isomerization of terminal
olefins of the type H2C=CHCH2R into a mixture of E- and Z-in-
ternal olefins was observed upon treatment with a mixture of
CoBr2(PR3)2, Zn, ZnI2, and Ph2PH. Isomerization required the
use of Ph2PH, presumably because the key mechanistic step in-
volves reversible H-transfer to the olefin to generate the cobalt
intermediate L2Co(H3C–CHCH2R)(=PPh2). Free rotation about
the previously olefinic C–C bond in the resultant saturated al-
kyl fragment may occur, which results in formation of the ob-
served mixture of E- and Z-olefin products. In contrast to the
system described by Hilt,92 complex Co-Li isomerizes internal
Anionic character in the analogous Co–vinyl complex I
should concentrate negative charge on the benzylic β–C as in-
dicated in resonance structure J, which is stabilized in the pres-
ence of aryl substituents (e.g., R = Ph). This aryl-group reso-
nance stabilization of a carbanionic center would account for
the observation that cis-stilbene and cis-β-methylstyrene are
rapidly isomerized by Co-Li, whereas cis-2-butene is unreactive
under comparable conditions. A low-energy C–C bond rotation
in J would result in formation of a cobalt-bound trans-vinyl lig-
and (K). Reductive elimination and ligand substitution would
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Page 14 of 19
then liberate the observed trans-olefin and regenerate H. It is alkyne. This may be a result of an additional alkyne coordina-
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8
possible that PPh3 addition (akin to intermediate G proposed
above in Scheme 4) may play a role in the observed isomeriza-
tion process.
tion to formation of an off-cycle bis(alkyne) complex. Interest-
ingly, rate enhancements were observed with additional ancil-
lary ligand, which implicates PAr3 as a non-innocent reactant in
this system. The observed Z-selectivity occurs by an off-cycle
olefin isomerization catalyzed by Co-Li. Interestingly, only aryl-
substituted olefins (i.e., stilbene, β-methylstyrene) undergo
cis-to-trans isomerization, which may implicate free rotation
about the C–C bond within a metallo-carbanion intermediate.
It is plausible that a second olefin may bind to H to form the
bis(olefin) complex M, which may be catalytically incompetent.
It is likely that olefin size may suppress the formation of such
off-cycle species, which is consistent with observation of the
first-order dependence on cis-stilbene and inverse first-order
dependence on cis-β-methylstyrene.
9
These mechanistic insights should prove useful in the design
of new first row transition metal catalysts that utilize C–H acti-
vations and C–C bond hydroarylations. In particular, the iden-
tity of the active species and the mechanism of initiation pro-
vide insight into structural requirements for competent catal-
ysis. Highly reduced species exhibit catalytic activity, and such
species appear to be generated in situ when cobalt dihalide
species are activated with organometallic reagents (e.g,
RMgBr, RLi, AlR3, etc.). This information provides concepts for
developing first row-metal, single-component catalysts that
are storable in solid-state, which circumvents the need for
multiple, solution-state reagents.
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Scheme 5. Proposed Olefin Isomerization Mechanism. a
ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization data, kinetics data, and rate
law derivation are found in the Supporting Information and are
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: tdtilley@berkeley.edu
ORCID
a Counter-cations have been omitted for clarity.
Benjamin A. Suslick: 0000-0002-6499-3625
T. Don Tilley: 0000-0002-6671-9099
Notes
The apparent lack of appreciable isomerization in the Yoshi-
kai system36 may implicate alternative isomerization pathways
that are operative with different initiation reagents. For exam-
ple, activation of CoBr2 with the Grignard reagents tBuCH2MgX
or Me3SiCH2MgX may result in reduction to a Co(0) species as
the active catalyst. Such species may not be as active for olefin
isomerization as Co-Li, as illustrated by the observation of pri-
marily E-isomers in the Yoshikai system.36
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was primarily funded by the U.S. Department of Energy,
Office of Science, Office of Basic Energy Sciences, Chemical Sci-
ences, Geosciences, and Biosciences Division under Contract No.
DE-AC02-05CH11231. We acknowledge the NIH (Grant Nos.
SRR023679A, 1S10RR016634-01, S10OD024998) and NSF (Grant
No. CHE-0130862) for funding of the College of Chemistry NMR
facility (University of California, Berkeley). The QB3/Chemistry
Mass Spectrometry Facility (University of California, Berkeley) is
acknowledged for help and access to the LTQ-FT ESI-HRMS (SN
06053F) and AutoSpec EI-HRMS (SN P749, property
ID#20081000740) instruments. Dr. Hasan Celik is thanked for help
with high-field, variable temperature NMR spectroscopy experi-
ments. B.A.S. acknowledges the NSF-GRFP for a fellowship (DGE
1106400). Professor Robert G. Bergman, Dr. Ryan Witzke, Dr. Pat-
rick Smith, Dr. Gavin Kiel, Rex Handford, Harrison Bergman, Dr. Ad-
dison Desnoyer, Dr. D. Dawson Beattie, and T. Alex Wheeler are
thanked for providing useful discussions and insights. James Breen
is thanked for copious glassware repairs and fabrications.
CONCLUSIONS
Significantly, this mechanistic study has developed a highly
reduced, single-component cobalt catalyst for alkyne hy-
droarylations. Initiation of catalysis occurs via a three-step
pathway (i.e., transmetallation, β-H elimination, deprotona-
tion) to afford a dinitrogen Co(-I) complex, Co-Li. Evidence for
the catalytic mechanism, such as the moderate primary iso-
tope effect and the observed requirement that alkyne binds
prior to the C–H activation, implicates a CMD mecha-
nism.4,6,39,40,57,88,89 Modified Michaelis-Menten enzyme kinetic
analysis revealed a complex dependency of the substrates on
the observed reaction rate; while both substrates display sat-
uration-like kinetics, competitive substrate inhibition occurs at
non-equimolar concentrations of (N-aryl)aryl ethanimine and
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(20) Ebe, Y.; Nishimura, T. Iridium-Catalyzed Branch-Selective
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