Mechanism of Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes

Article abstract of DOI:10.1021/jacs.9b10026

Ni-catalyzed cross-electrophile coupling reactions have emerged as appealing methods to construct organic molecules without the use of stoichiometric organometallic reagents. The mechanisms are complex: plausible pathways, such as "radical chain" and "sequential reduction" mechanisms, are dependent on the sequence of the activation of electrophiles. A combination of kinetic, spectroscopic, and organometallic studies reveals that a Ni-catalyzed, reductive 1,2-dicarbofunctionalization of alkenes proceeds through a "sequential reduction" pathway. The reduction of Ni by Zn is the turnover-limiting step, consistent with Ni(II) intermediates as the catalyst resting-state. Zn is only sufficient to reduce (phen)Ni(II) to a Ni(I) species. As a result, commonly proposed Ni(0) intermediates are absent under these conditions. (Phen)Ni(I)-Br selectively activates aryl bromides via two-electron oxidation addition, whereas alkyl bromides are activated by (phen)Ni(I)-Ar through single-electron activation to afford radicals. These findings could provide insight into achieving selectivity between different electrophiles.

Full text of DOI:10.1021/jacs.9b10026

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Article
Mechanism of Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes
Qiao Lin, and Tianning Diao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10026 • Publication Date (Web): 07 Oct 2019
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Mechanism of Ni-Catalyzed Reductive 1,2-
Dicarbofunctionalization of Alkenes
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Qiao Lin and Tianning Diao*
Department of Chemistry, New York University, 100 Washington Square East
New York, NY 10003
E-Mail: diao@nyu.edu
ABSTRACT
Ni-catalyzed cross-electrophile coupling reactions have emerged as appealing methods to
construct organic molecules without the use of stoichiometric organometallic reagents. The
mechanisms are complex: plausible pathways, such as “radical chain” and “sequential reduction”
mechanisms, are dependent on the sequence of the activation of electrophiles. A combination of
kinetic, spectroscopic, and organometallic studies reveals that a Ni-catalyzed, reductive 1,2-
dicarbofunctionalization of alkenes proceeds through a “sequential reduction” pathway. The
reduction of Ni by Zn is the turnover-limiting step, consistent with Ni(II) intermediates present
as the catalyst resting-state. Zn is only sufficient to reduce (phen)Ni(II) to Ni(I) species. As a
result, commonly proposed Ni(0) intermediates are absent under these conditions. (Phen)Ni(I)–
Br selectively activates aryl bromides via two-electron oxidation addition, whereas alkyl
bromides are activated by (phen)Ni(I)–Ar through single-electron activation to afford radicals.
Answers to mechanistic questions in Ni-catalyzed cross-coupling reactions could provide insight
into achieving selectivity between different electrophiles.
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INTRODUCTION
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Nickel-catalyzed cross-coupling reactions have advanced to powerful methods for
constructing organic molecules.1 Cross-electrophile coupling reactions, under reductive
conditions, can bypass the need for pre-generated, air-sensitive organometallic reagents, and thus
improve the reaction scope and functional group compatibility.2 Understanding the mechanisms
of Ni-catalyzed cross-coupling reactions could inform the design of catalysts and the control of
selectivity, but it presents a challenge due to the diversity of possible pathways and the
complexity of electronic structures of Ni intermediates in different oxidation states.3 Since the
seminal study of Ni(PPh3)4 by Kochi,4 contemporary work has focused on modern systems with
bidentate and tridentate ligands.5,6 The mechanisms appear to be system-dependent. While
(NHC)Ni catalysts lead to two-electron redox processes mediated by Ni(0)/Ni(II) intermediates,5
catalysts with chelating ligands often involve radical pathways going through
Ni(0)/Ni(I)/Ni(II)/Ni(III) intermediates.5
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Previous efforts to characterize the mechanisms of Ni-catalyzed cross-electrophile coupling
reactions leave several key questions unanswered. Evidence for distinguishing “Radical Chain”
from “Sequential Reduction” pathways remains ambiguous (Scheme 1).5l These two pathways
differ by the sequence of activations of Csp2 and Csp3 electrophiles, which are critical to
achieving chemoselectivity in cross-electrophile coupling reactions.2 Moreover, despite recent,
rigorous efforts in characterizing paramagnetic Ni reaction intermediates,7 the identity of the
catalyst resting-state in a catalytic reaction with N-ligands has been rarely characterized.5h,n
Finally, previous studies have identified the reduction of the Ni catalyst as the turnover-limiting
step, 5l,8 but ambiguity remains in the structural characterization of the resulting Ni species.
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Reductive alkene carbofunctionalization with electrophiles has found widespread utility.9 We
recently developed a Ni-catalyzed, reductive, two-component 1,2-dicarbofunctionalization of
alkenes (Scheme 1).10 ,11 This reaction exhibits a broad scope and is compatible with a large
variety of functional groups, allowing access to important pyrrolidine and piperidine derivatives.
The combination of NiBr2•DME with 1,10-phenanthroline (phen) in DMA (N,N-
dimethylacetamide) as the solvent, and Zn as the reductant, represents common conditions for
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reductive cross-coupling reactions.8, “Radical Chain”5m,n and “Sequential Reduction”
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pathways are both plausible (Scheme 1), based on recent mechanistic studies. “Radical Chain”
mechanisms (cycles A and B) feature the activation of alkyl halides by (phen)Ni(I)Br to form a
radical (step i), which then combines with the reduced Ni species. In cycle A, radicals combine
with Ni(0) (step iii) followed by oxidative addition to PhBr (step iv); in cycle B, oxidative
addition of PhBr takes place (step vi) prior to radical combination with Ni(II) (step vii). The
alternative “Sequential Reduction” mechanism, cycle C, reverses the sequence of electrophile
activation in the “Radical Chain” mechanism. Oxidative addition of Ni(0) to PhBr affords
Ni(II)(Ph)(Br) (step vi), followed by the reduction of Ni(II) to form Ni(I)–Ph (step viii).
Activation of the alkyl bromide by Ni(I)–Ph generates a radical (step ix), which combines with
Ni(II) to form a Ni(III) intermediate (step x).14
Scheme 1. Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes and Possible
Mechanisms
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Ph
N
N
(12 mol%)
N
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N
Et
O
Br
NiBr2∙DME (10 mol%)
modulator of the cholesterol
biosythetic pathway
O
+ R– X
Z
Z
Zn (2 equiv)
DMA, 50 ºC
R
()
Z = CR2, NTs or O
N
N
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- broad scope (40 examples)
- good functional group compatibility
- high yields
X = Br, I, OMs
R = alkyl, aryl, and
heteroaryl
N
N
somatostatin SST1 receptor antagonist
- mild conditions
“Sequential Reduction”
“Radical Chain”
Br
(vii)
N
N
1/2 ZnBr2
NiI
Ph
(B)
1/2 Zn
(ix)
(viii)
N
N
Br
NiIII
PhBr
Ph
(iv)
N
N
Br
NiII
Ph
N
N
Br
Ph
(v)
NiII
N
N
NiI
Ph
(iii)
(C)
(vi)
PhBr
Ni0
(x)
N
(A)
NiI
N
Br
N
N
(i)
N
N
Br
(xii)
NiIII
(ii)
Br
Ph
1/2 ZnBr2
1/2 Zn
(xi)
N
N
Br
Br
N
NiII
NiI Br
ZnBr2
N
Ph
Zn
Herein, we report a mechanistic study on the reductive 1,2-dicarbofunctionalization reaction.
Kinetic studies, in combination with the characterization of reaction intermediates, differentiate
the “Radical Chain” pathways from the “Sequential Reduction” mechanism. In addition, results
answer several critical questions, including the identity of the turnover-limiting step and the
catalyst resting-state, the nature of the interaction between Ni and Zn, and the sequence of
activation of different electrophiles. Data highlight the importance of the catalyst reduction step,
and elucidate mechanistic attributes behind the selectivity achieved in cross-electrophile
coupling reactions.
RESULTS AND DISCUSSION
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Substrate Probes. Substrate probes were subjected to the standard reaction conditions,
NiBr2•DME in combination with 1,10-phenanthroline and Zn in DMA (N,N-dimethylacetamide)
at 50 ºC, in order to shed light on the presence of radical intermediates. The coupling of 1 with
PhBr afforded dimer 4 in 8% yield under standard conditions (Scheme 2A).10 Replacing 1,10-
phenanthroline with the bulkier neocuproine increased the yield of 4 to 30%. Both cis- and trans-
5 proceeded to give the same mixture of cis- and trans-6 in a ratio of 1:1.6 (Scheme 2B). Radical
clock substrates 7 and 9 underwent cyclopropyl ring-opening upon cross-coupling, to afford
products 8 and 10, respectively (Scheme 2C).
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Scheme 2. Substrate Probes for Determining Radical Intermediates
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These data provide evidence for the formation of radicals upon activation of alkyl bromides.
Product 4, resulting from the dimerization of 1, is a common indication of radical
intermediates.15 Although the C–C bond formed in 4 could have also arisen from reductive
elimination from a dialkyl Ni species, the increased yield of 4 with bulkier neocuproine suggests
that the formation of 4 does not involve metal and competes with the Ni-mediated pathway to
generate 2. The convergence of the stereocenter for cis and trans-5 upon cyclization is consistent
with formation of a radical intermediate to erase the substrate stereo-information. The poor
diastereoselectivity reflects a small energy difference in the chair and boat conformations in the
transition states of cyclization,16 and is consistent with the stereo-outcome of previous radical
cyclizations initiated by tin hydride.17 The ring-opening of the cyclopropyl groups of 7 and 9
implies that radical intermediates are formed at the C1 position of 7 and the C5 position of 9.
Kinetic Studies. We carried out kinetic studies for the coupling of 11 with PhBr to form 12
as the model reaction, to solve the orders of each reactant (eq 1). Reactions were monitored by
analyzing aliquots of the reaction mixture with GC. The decays of 11, starting at two different
concentrations, were compared in order to establish the catalyst’s robustness using reaction
progress kinetic analysis (RPKA) (Figure 1).18 The time courses of two experiments, starting
from different substrate concentrations, fully overlay, when the time was adjusted as the two
reactions proceed under identical substrate concentrations onward from the point of intersection
of the arrows. This result indicates that neither catalyst decomposition nor product inhibition
took place over extended turnovers.
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(1)
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Figure 1. “Same-excess” experiment for alkene 1,2-dicarbofunctionalization shown in eq 1 with
[excess] = [PhBr]0 – [11]0 = 0.05 M. Reaction conditions: [NiBr2•DME] = 5 mM, [1,10-
phenanthroline] = 6 mM, Zn = 0.1 mmol, solvent = DMA, agitation rate = 850 rpm; (a) [11]0 =
0.1 M; [PhBr]0 = 0.15 M; (b) [11]0 = 0.05 M; [PhBr]0 = 0.1 M.
The time-courses for the reaction shown in eq 1 reveal that the decay of 11 and formation of
12 both fit into a linear function (Figure 2A). The formation of the side-product, biphenyl,
appears to be dependent on [PhBr]. “Different excess” experiments reveal that the formations of
12 overlay when starting at different [11] and [PhBr] at agitation rates of 900 rpm and 1200 rpm,
suggesting a zero-order dependence on [11] and [PhBr] (Figures 2B and 2C). A series of
experiments with different [Ni] were performed, in order to evaluate the order of [Ni]. Plotting
the data according to variable time normalization analysis reveals that the power law order in [Ni]
is 1 (Figure 2D).19 Attempts to fit the data with other possible orders of [Ni] resulted in poor
overlay of the time-courses (Figure S6). The “different excess” experiments allow us to estimate
the kobs to be 8.6*10-4 s-1 and 12*10-4 s-1, at 900 rpm and 1200 rpm, respectively.
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(B)
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(C)
(D)
Figure 2. (A) Time-courses of the alkene 1,2-dicarbofunctionalization reaction shown in eq 1.
Reaction conditions: [11]0 = 0.05 M, [PhBr]0 = 0.1 M, [NiBr2•DME] = 5 mM, [phen] = 6 mM,
Zn = 0.1 mmol, solvent = DMA, agitation rate = 850 rpm. (B) “Different excess” experiments
for determining the substrate orders at an agitation rate of 900 rpm. (C) “Different excess”
experiments for determining the substrate orders at an agitation rate of 1200 rpm. (D)
Determining [Ni] order based on the variable time normalization analysis, [(phen)NiBr2•DME] =
2.5, 4, 5, 7.5 mM.
The presence of heterogeneous Zn prompted us to assess mass-transfer limitations.20
Reactions were mixed in a shaker with orbital agitation. The reaction rate increases with
increasing agitation speed (Figure 3A), but this rate acceleration plateaus when agitation rates
exceeds 1200 rpm. At a fixed agitation rate of a 900-rpm, the reaction rate increases as Zn
loading increases (Figure 3B). The use of larger Zn dust reduces the rate compared to fine Zn
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powder. Tetrabutylammonium iodide (TBAI) is a known additive to facilitate heterogeneous
reduction.21 Addition of 10% TBAI indeed accelerated the reaction (Table S2).
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(B)
Figure 3. Formation of 12 over time under identical conditions shown in Figure 2A, except with
different mixing speeds (A) and Zn loading (B).
The lack of kinetic dependence on substrates, first-order dependence on [Ni], in combination
with the observed rate dependence on the mixing speed and Zn loading, reveals that the
reduction of Ni by Zn is the turnover-limiting step. The reduction is expected to occur in two
steps: mass-transfer when Ni is adsorbed to the surface of Zn, followed by electron-transfer from
Zn to Ni.22 The reduction is dependent on several factors, including convective transfer rate, the
electron transfer rate, and the available surface area. Increasing the mixing speed up to 1200 rpm
leads to an increase in rate due to enhanced convective mass transfer. At agitation speeds greater
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than 1200 rpm, the effect of enhanced mass transfer is saturated, and results in no further
acceleration. In this scenario, the limiting factor becomes electron transfer on the Zn surface. The
rate is proportional to the density of available surface area. Higher Zn loading increases the
overall surface area, and thus the reaction rate.
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Collectively, the rate law for the 1,2-dicarbofunctionalization of alkenes is expressed in eq 2.
The zero-order dependence on organic substrates reveals that neither olefin nor PhBr participates
in the turnover-limiting step. The combination of the first-order dependence on [Ni] and the rate
enhancement by increasing mixing speed and Zn loading suggests that the reduction of Ni by Zn
is the rate-determining step. The power-law order of Zn is dependent on the distribution of Zn
powder in solution.
rate = kobs[olefin]0[PhBr]0[Ni][Zn]x (2)
Spectroscopic Characterization of the Catalyst Resting State. We then probed the identity
of the catalyst resting state through EPR, 1H NMR, and UV-Visible spectroscopy. An aliquot of
the catalytic reaction mixture of eq 1 was withdrawn, after reacting for 30 min, immediately
frozen, and analyzed by EPR spectroscopy at 10 K, only to show the absence of an EPR signal.
Performing the reaction shown in eq 3 under standard conditions in DMA-d9 allowed us to take a
snapshot of the catalyst resting-state using 1H NMR spectroscopy. After 15 min, the reaction was
1
cooled to room temperature, filtered to remove Zn, and recorded by H NMR spectroscopy
(Figure S17). Two Ni species are present, a paramagnetic species featuring broad resonances at
25.5 and 18.0 ppm and a diamagnetic species showing a group of downfield aromatic peaks
(Figure 4C). Independently prepared (phen)NiBr2 exhibits a group of paramagnetic peaks around
25.5 and 18.0 ppm, consistent with the paramagnetic resonances observed in the reaction mixture
(Figure 4A).23 Independently prepared (phen)Ni(o-Tol)(Br), by mixing Ni(cod)2 with phen and
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o-Tol-Br,24 exhibits a set of diamagnetic peaks between 9.5 and 7.0 ppm, in agreement with the
diamagnetic species observed in the reaction mixture (Figure 4B). The ratio of [(phen)NiBr2] to
[(phen)Ni(o-Tol)(Br)] is estimated to be 0.7:1. When (phen)Ni(o-Tol)(Br) was used as the pre-
catalyst in place of NiBr2•DME, the catalyst transforms to a similar mixture of (phen)NiBr2 and
(phen)Ni(o-Tol)(Br) at 25% conversion (Figure S17-2). Performing the same NMR experiments
for the reaction shown in eq 1 resulted in identical paramagnetic resonances, but the intensity of
the diamagnetic species was attenuated (Figures S18-S19). We attribute it to the instability of
(phen)Ni(Ph)(Br), which also underwent rapid decomposition during independent synthesis.
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(3)
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Figure 4. (A) H NMR spectra of (phen)NiBr2 14; (B) (phen)Ni(o-Tol)Br 15; (C) Paramagnetic
and diamagnetic regions of the reaction mixture shown in eq 3 under standard conditions.
Solvent = DMA-d9, * = uncoordinated 1,10-phenanthroline.
The UV-Visible spectrum of the reaction mixture from eq 1 exhibits two absorptions at 421
and 456 nm, matching with the absorption spectrum of (phen)Ni(Ph)(Br) 16 (Figure 5). The
reduction of (phen)NiBr2 by Zn gives a purple solution, displaying a strong, distinct absorption at
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565 nm. Addition of PhBr to this purple mixture resulted in a red solution with absorptions at
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421 and 456 nm, consistent with the spectrum of (phen)Ni(Ph)(Br) 16, as well.
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Figure 5. UV-Visible spectra of (phen)NiBr2 (A), (phen)NiBr2 reduced by Zn (B), (phen)NiBr2
reduced by Zn followed by addition of PhBr (C), (phen)Ni(Ph)(Br) 16 (D), and reaction mixture
from eq 1 after 30 min (E).
1
The H NMR data of the reaction mixture and the comparison with independently prepared
complexes led us to assign the catalyst resting-state as a mixture of (phen)NiBr2 and
(phen)Ni(Ar)Br in a ratio of 0.7:1. This assignment is consistent with the lack of an EPR signal
for this species and the reduction of Ni by Zn as the turnover-limiting step, as determined by
kinetics. The UV-Visible spectrum of the reaction mixture agrees with that of (phen)Ni(Ph)Br 16,
since (phen)NiBr2 does not display any strong absorption in the measured region. The “addition
mixture” (Figure 5C), prepared by reduction of (phen)NiBr2 by Zn followed by addition of PhBr,
resembles the reaction mixture in their UV-Visible spectra, suggesting that the catalyst resting-
state could result from such a sequence of reactions.
Reduction of Ni by Zn, Characterized by Spectroscopy and Cyclic Voltammetry. Since
the reduction of Ni by Zn is identified to be the turnover-limiting step, our subsequent study
seeks to closely characterize the Ni product from reduction, although previous investigations
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assign Ni(0) as the resulting species.5l,8 Synthesis of model complex (phen*)NiBr2 17 (phen* =
2,9-di-sec-butyl-phenanthroline) allows us to isolate the reduction product, in which the Ni
center is protected with the bulky phen* ligand. Treating 17 with excess Zn at room temperature
generates a dark blue complex 18 in qualitative yield (eq 4). Single crystal X-ray diffraction
established the structure of 18 to be (phen*)Ni(I)Br (Figure 6A). The spin-density plot obtained
from DFT calculations using the ORCA package revealed that the unpaired electron is located
primarily on Ni (Figure 6B).25 This result is corroborated with the EPR spectrum of 18, which
exhibits an axial signal (Figure 6C). No hyperfine splitting was resolved, probably due to small
coupling constants.
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(4)
(A)
(B)
0.045
0.947
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Figure 6. (A) X-ray crystal structure of Ni(phen*)Br 18 at 50% probability thermal ellipsoids.
Hydrogen atoms are omitted for clarity. Selected bond lengths (Å): Ni(1)–Br(1)= 2.2879(8),
Ni(1)-N(1) = 1.969(4), Ni(1)–N(2) = 1.968(4). (B) Spin-density plot based on DFT calculations.
(C) X-Band EPR Spectrum of complex 18. Temperature = 10 K, solvent = Toluene. Microwave
frequency = 9.380 GHz, power = 0.02 mW, modulation amplitude = 1 mT/100 kHz, g = [2.4777
2.1203 2.0872].
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Stirring the pale green (phen)NiBr2 with excess Zn in DMA resulted in a dark purple solution
19, which displays a series of paramagnetic 1H NMR resonances (Figure S61) and an axial EPR
signal (Figure 7). The integration of this EPR signal, against an external standard, accounts for
10% of the starting Ni species. This purple species, however, is prone to decomposition, and
prevented further characterization.
Figure 7. X-Band EPR Spectrum of complex 19. Temperature = 10 K, solvent = DMA.
Microwave frequency = 9.380 GHz, power = 2.0 mW, modulation amplitude = 1 mT/100 kHz, g
= [2.247 1.993 1.986].
We then investigated the reduction potentials of relevant Ni species (Table 1). Data shown in
Table 1 suggests that Zn can transform Ni(II) complexes 14, 16, and 17 to Ni(I) species, but the
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reduction potential of -1.37 (V vs. SHE) for (phen*)Ni(I)Br 18 implies that Zn provides
insufficient reducing power for producing (phen)Ni(0) species via outer-sphere electron transfer.
Table 1. Reduction Potentials of Ni Complexes and Comparison with Zn
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Complexes
Ep/2(NiII/NiI) Ep/2((NiI/Ni0)
(V vs. SHE) (V vs. SHE)
(phen)NiBr2 14
(phen)Ni(o-Tol)Br 15
(phen*)NiBr2 17
-0.86a
-1.12a
-0.69b
-1.37b
-1.26a
(phen*)NiBr 18
ZnBr2 Ep/2(ZnII/Zn)
a In DMA at 25 °C, internal reference = Fc+/Fc, electrolyte = Bu4NBr. b In THF.
The quantitative conversion of 17 to (phen*)Ni(I)Br 18, upon Zn reduction, is corroborated
with the lower reduction potential of 18, relative to Zn, indicating that Zn is insufficient to
reduce 17 to a (phen*)Ni(0) state. Although phen* lacks catalytic reactivity, owing to its steric
hindrance, its structural and electronic synergy to phen allows us to assign the structure of 19 by
1
comparing their CV and EPR data with those of 18. The paramagnetic H NMR spectrum of 19
(Figure S61) is inconsistent with formation of d10 Ni(0) species. Comparing the CV of 14 with
17 reveals similar reduction potentials, which suggests that the reduction of (phen)NiBr2 14
likely gives a Ni(I) species. The EPR spectra of 19 and 18 contain analogous features, which led
us to assign the reduction intermediate 19 to (phen)Ni(I)Br. The EPR signal of this Ni-centered
radical, however, only accounts for 10% of the Ni species. The loss of the EPR signal could be
attributed to the fast decomposition of the Ni(I) species or the dimerization of 19, as observed by
Hazari and coworkers (eq 5).7b Previous studies assign the reduced Ni species to Ni(0) in the
presence of MgI2.5l Further investigations into the salt effect on the redox potentials and their
catalytic implications are essential and underway.
(5)
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Stoichiometric Experiments to Probe Electrophile Activation. A solution of (phen)NiBr
19, upon in-situ generated by reacting (phen)NiBr2 14 with Zn, was divided in two portions. In
the presence of 2 equiv Zn, the solutions of 19 were separately treated with 1 equiv PhBr and 11.
Monitoring both reactions by GC revealed that PhBr was consumed at a rate of 1.2 mM/min to
form biphenyl, whereas the activation of 11 took place at a rate of 0.42 mM/min to afford dimer
20 (Figure 8). This kinetic comparison suggests that 19 reacts with PhBr faster than 11.
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Figure 8. Kinetic comparison of PhBr with 11 in reacting with reduced Ni species 19.
The purple solution of 19, generated from the reduction of (phen)NiBr2 by Zn, was filtered to
remove excess Zn (eq 6). Addition of 2 equiv o-TolBr to this solution 19 immediately forms
1
(phen)NiBr2 14 and (phen)Ni(o-Tol)(Br) 15 in a ratio of 5:3, based on H NMR analyses
(Figures S20-S22).
(6)
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The activation of PhBr by (phen)Ni(I)–Br 19 is faster than alkyl bromide 11, evident from
the comparison experiment shown in Figure 8. Results of eq 6 reveal that the activation of PhBr
by (phen)Ni(I)–Br proceeds via a bimolecular oxidative addition to give 14 and 15. Although the
precise mechanism is unknown, this step may proceed via oxidative addition of o-TolBr to 19
followed by comproportionation of Ni(III) with another molecule of 19. The observed ratio of 14
to 15 is greater than 1 (eq 6), and could be attributed to partial decomposition of 19 in the
absence of Zn after filtration.
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The formation of 15 from the reaction of 19 with o-TolBr prompted us to probe how possible
intermediates, (phen)Ni(II)(o-Tol)(Br) 15 and (phen)Ni(Mes)(Br) 21 (Mes = 2,4,6-mesityl),
interact with substrate 11. Treating 15 with 1 equiv of 11 at 50 ºC forms 12 in 21% yield and
dimer 20 in 4% yield (entry 1, Table 2). Reducing 15 by Zn, followed by removal of Zn via
filtration, generates a purple solution which reacted with 11 to afford 12 in 37% yield and 20 in
12% yield (entry 2). Full conversion of 11 to 12 and 20 was achieved when Zn was retained in
the reaction (entry 3). Complex 21 was inert towards 11 in the absence of Zn (entry 4). The
reduction of complex 21 by Zn, followed by treating it with 11, led to 30% conversion of 11 to
form 20 overnight (entry 5).
Table 2. Stoichiometric Reaction of 15 and 21 with 11.a
Entry
Ar
Zn
Reaction 11
12
20
(equiv) Time (h) (%) (%) (%)
1
2
o-Tol
o-Tol
0
2b
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2
70
50
21
37
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o-Tol
Mes
Mes
2
0
2
12
12
0
100
69
50
0
0
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0
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2b
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a Yields were determined by 1H NMR spectroscopy with 1,3,5-trimethoxylbenzene as the internal
standard.
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b Zn was removed by filtration before addition of 11.
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Stoichiometric experiments between 15 and 11 suggest that 15 is capable of activating 11,
but the rate of this background reaction is exceeded by treating 11 with the reduced Ni species.
The formation of dimer 20 implies a radical intermediate that undergoes cyclization and
dimerization. The cross-coupling product 12 arises from the capture of the radical by Ni
followed by reductive elimination. We attribute the incomplete conversion of 11 in entry 2 to the
instability of the reduced Ni intermediate that underwent unproductive disproportionation in the
absence of Zn after filtration. The more sterically hindered 21 suppressed the background
activation of 11. The radical intermediate, formed from activation of 11 by the reduced 21, is
restricted to bind to the Ni center due to the steric hindrance. Therefore, 20 is formed exclusively.
Characterization of the Reduction of (phen)Ni(Ar)(Br) by Zn. EPR analysis has shed
light on the reduction of (phen)Ni(Mes)(Br) 21 by Zn. The dark red solution of
(Phen)Ni(Mes)(Br) 21 was allowed to stir with Zn to afford a purple solution. The EPR spectrum
of a frozen sample was recorded to give an isotropic signal with the g value of 2.009 (Figure 9).
Treating (phen)Ni(I)–Br 19 with MesMgBr also afforded a purple solution with an analogous
isotropic EPR spectrum (Figure S63). In contrast, transmetalation of MesMgBr to (phen*)Ni(I)–
Br 18 gave a rhombic EPR signal with g values of 2.530, 2.141, and 2.058 (Figure S64).
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Figure 9. X-Band EPR Spectrum of reduction reaction mixture of 21 with Zn.
Temperature = 10 K, solvent = DMA. The spectrum is simulated with Easyspin.
Spectroscopic parameters: g = 2.009. Microwave frequency = 9.380 GHz, power = 0.63
mW, modulation amplitude = 1 mT/100 kHz.
Yakhvarov and coworkers have electrochemically generated (phen)Ni(Mes) 25, which shows
an organic centered radical in the EPR spectrum.26 This electronic structure has been attributed
to the spin-tautomer 25’, in which the redox-active phen delocalizes the electron to its * orbital
to give a Ni(II) center and an organic radical (Scheme 3). Similar redox activity has been
observed and characterized in (bpy)Ni(Mes)27 and (terpy)Ni(Mes) complexes.28 The EPR
spectrum of the reduction mixture of 21 by Zn displays an isotropic signal with a g value of
2.009, close to the free-electron value of 2.0023 (Figure 9). This observation indicates the ligand
character of the SOMO, consistent with the previous characterization of (phen)Ni(Mes) 25. The
assignment of 25 has found support in the analogous EPR spectrum obtained from
transmetalation of MesMgBr to 19 (Figure S63). In contrast, transmetalation of MesMgBr to 18
generates a Ni-centered radical. We assign this species to (phen*)Ni(Mes), based on the report
by Hazari.7b The different electronic structures between (phen)Ni(Mes) 25 and (phen*)Ni(Mes)
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could be attributed to the electron-donating effect of the sec-butyl substituents, and further
research is underway to verify this hypothesis.
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Scheme 3. Proposed Ni(I) Species Upon Reduction of 21 by Zn
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Radical Clock Cyclization as a Function of [Ni]. In the original method development, we
reported that substrates undergoing slower radical cyclization give direct coupling product
without cyclization.10 We evaluated the product distribution as a function of [Ni]. Substrate 22
couples with PhBr to afford a mixture of 23, derived from the direct coupling of alkyl bromide to
PhBr, and the six-membered ring product 24 (Figure 10). Varying [Ni] resulted in a linear
increase in the ratio of 23/24 with a slope of 0.22. The linear dependence of the ratio of 23/24 on
[Ni] resembles the observations by Hu5d and Weix,5e in reactions going through free radical
intermediates, but contrasts with the direct transmetalation mechanism, reported by Shenvi, when
the group transfer occurs in the solvent cage.5k
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Figure 10. The ratio of uncyclized/cyclized products (23/24) as a function of [Ni] in the coupling
of 22 with PhBr. Reaction conditions: [22]0 = 0.05 M, [PhBr]0 = 0.1 - 0.2 M, Zn = 0.1 mmol,
solvent = DMA, agitation rate = 900 rpm, [(phen)NiBr2•DME] = 1, 2.5, 5, 7.5,10 mM.
Data reflect the average of three independent trials.
Control Experiments. Zn is known to activate alkyl halides, iodides in particular, to form
organozinc species.29 We performed control experiments to verify whether bromo-alkene
substrates could be activated with Zn in the absence of Ni. In the absence of Ni catalysts, heating
Zn with 1 or 11 both led to decomposition of a small portion of the substrates, without formation
of any reducing products or carbocycles (eqs 7-8). These control experiments and the absence of
carbocyle products reveal that alkyl bromide substrates must be activated by the Ni catalysts.
(7)
(8)
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Evaluation of Mechanisms (A) and (B). Collectively, kinetic data reveal that the rate of
reductive 1,2-dicarbofunctionalization is independent of substrate concentration, and the
turnover-limiting step is the reduction of Ni by Zn. Spectroscopic characterization identifies a
mixture of (phen)NiBr2 and (phen)Ni(Ar)(Br) as the catalyst resting-state. Stoichiometric studies
suggest that the reduction of Ni(II) complexes by Zn generates (phen)Ni(I)Br. (phen)Ni(I)Br
activates PhBr more rapidly than alkyl bromides via a bimolecular oxidative addition. EPR
spectroscopy characterizes the reduction of (phen)Ni(Ar)(Br) by Zn to form (phen)Ni(I)(Ar). The
reaction of (phen)Ni(I)(Ar) with alkyl bromides generates radicals that can combine with Ni to
form cross-coupling products.
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“Radical Chain” mechanisms (A) and (B) have been invoked in Ni-catalyzed cross-coupling
and cross-electrophile coupling reactions (Scheme 1).5 These pathways feature the activation of
the alkyl bromide by (phen)Ni(I)–Br to form a radical (step i, Scheme 1), which combines with
Ni(0) (step iii) or Ni(II) (step vii) species proceeding to further C–C bond formation. The kinetic
comparison experiment shows that (phen)Ni(I)–Br activates PhBr more rapidly than alkyl
bromides (Figure 8). This result contradicts with the activation of alkyl bromide by (phen)Ni(I)–
Br in the “Radical Chain” mechanism (step i). In addition, kinetic and spectroscopic data suggest
that the reduction of (phen)Ni(II) by Zn is the turnover-limiting step (Figures 2-5), with a rate
constant of 8.6*10-4 s-1 at a 900-rpm agitation rate. Free alkyl radicals dimerize with a
bimolecular rate constant on the scale of 109 M-1s-1.30 The drastically faster radical dimerization
than Ni reduction by Zn suggests that the radical intermediate would not live long enough to be
captured by (phen)Ni(0), if it is not the catalyst resting-state (Pathway A, Scheme 1). In
summary, the “Radical Chain” pathway is inconsistent with the kinetic data in this system.
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Evaluation of Mechanism (C) and the Revised Mechanism. Our data support part of the
“Sequential Reduction” mechanism shown in Scheme 1C, in which PhBr is activated prior to
alkyl bromide. However, NMR, EPR, and CV characterizations of the reduction of (phen)NiBr2
by Zn, and the comparison with model complex (phen*)NiBr 18 establishes that Zn is only
sufficient to reduce (phen)Ni(II)Br2 14 to (phen)Ni(I)Br 19.31 (Phen)Ni(0) is never formed under
these conditions. Accordingly, we revised the “Sequential Reduction” mechanism to exclude
Ni(0) intermediates (Scheme 4).
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Stoichiometric experiments reveal that the activation of PhBr by (phen)Ni(I)Br 19 proceeds
via bimolecular oxidative addition to generate (phen)NiBr2 14 and (phen)Ni(Ph)(Br) 16. This
step is reminiscent of previous reports on dinuclear Ni-mediated oxidative addition5d,32 and
reductive elimination.33 (Phen)NiBr2 14 and (phen)Ni(Ph)(Br) 16 both exist as the catalyst
resting-state. They are separately reduced by Zn, to form 19 and 25, respectively, both as the
turnover-limiting steps. The structures of 19 and 25 are assigned by comparing their EPR spectra
with those of known analogous complexes. The reduction as the turnover-limiting step accounts
for the lack of kinetic dependence on substrates and the observed kinetic dependence on the
mixing speed and Zn loading (Figures 2-3), as well as the spectroscopic characterization of the
catalyst resting state (Figures 4-5).
Scheme 4. Revised Mechanism for Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of
Alkenes
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Br
4
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N
N
NiI Ph
ZnBr2
Zn
25
t.l.s.
8
N
N
Br
NiII
Ph
9
Br
Br
16
N
N
N
Br
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NiII
NiII
26
N
Ph
14
16
resting state
Zn
ZnBr2
t.l.s.
PhBr
N
N
Br
NiIII
N
N
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Ph
NiI
NiI
Br
Br
27
19
19
Ph
(Phen)Ni(I)–Ph 25 can activate alkyl bromides to form radical intermediates. The presence of
a radical intermediate is verified by stereochemical probes and radical clock substrates (Scheme
2). The reaction of 22 affords a mixture of the direct coupling product 23 and the cyclized
product 24; the ratio of 23/24, proportional to the rate of step ii over the rate of step iv (Scheme
5), exhibits a linear correlation with [Ni] (Figure 10). Since radical cyclization is mono-
molecular (step iv), the linear correlation of 23/24 with [Ni] reflects a bimolecular process for
radical coordination to Ni (step ii). Based on radical cyclization rates, we are able to estimate the
range of radical capture rate by Ni(II) (k4) to be higher than 107 Ms-1 and lower than 6 * 109 Ms-1
at 50 ºC (see SI for the calculation),34 which is close to the calculated barrier of 4 kcal/mol.5g
Increasing the steric bulk of the ligand promotes the formation of dimer 4, which can be
attributed to a decreased radical trapping rate (Scheme 2A). Accordingly, substrates that would
form seven-membered rings (kcyclization = 103 s-1) underwent direct coupling with PhBr without
cyclization.10
Scheme 5. Proposed Mechanism for Forming 23 and 24 via a Radical Intermediate
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Selectivity for Activation of Electrophiles. Our data shed light on the selectivity of cross-
electrophile coupling reactions, which is a result of the different steric and electronic properties
of Ni(I)-Br and Ni(I)-Ar intermediates. Csp2 and Csp3 electrophiles are independently activated
by Ni(I)-Br and Ni(I)-Ar species, respectively, via distinct mechanisms (Scheme 6). Since
oxidative addition of Csp2–Br is most likely going through a two-electron, concerted pathway,
the activation of Csp2–Br is dominated by steric effects. (phen)Ni(I)Br is sterically more
accessible than (phen)Ni(I)Ar, thus it preferentially reacts with Csp2–Br over Csp3–Br. The
activation of Csp3–Br generates radicals via halogen-atom abstraction or single-electron transfer,
and is most influenced by electronic effects. The more electron-rich, yet sterically hindered,
(phen)Ni(I)Ar therefore reacts with Csp3–Br faster than Csp2–Br.
Scheme 6. Illustration of Selectivity for Cross-Electrophile Coupling
SUMMARY
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The Ni-catalyzed two-component reductive dicarbofuntionalization of alkenes proceeds via a
“Sequential Reduction” pathway. Kinetic data rules out the “Radical Chain” mechanism. Ni(I)–
Br first activates ArBr to form Ni(II)(Br)(Ar), followed by subsequent reduction to a Ni(I)–Ar
species. Ni(I)–Ar reacts with the alkyl bromide to form a radical that rapidly cyclizes and
coordinates to Ni to afford a Ni(III) intermediate prior to reductive elimination. The key findings
are: (1) The turnover-limiting step is the reduction of Ni(II) by Zn, with Ni(II) species as the
catalyst resting-state. This result highlights the importance of catalyst reduction. (2) Zn is only
sufficient to reduce (phen)Ni(II) to (phen)Ni(I), and (phen)Ni(0) is absent from the reaction. (3)
In the “Sequential Reduction” pathway, two-electron, bimolecular oxidation addition of PhBr by
(phen)Ni(I)–Br precedes the activation of alkyl bromides by (phen)Ni(I)–Ph via single-electron
activation to give radicals. This sequence accounts for selectivity observed in cross-electrophile
coupling reactions.
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ASSOCIATED CONTENT
Supporting Information
All experimental procedures, additional figures, details of DFT calculations, NMR spectra, and
crystallographic data (PDF, CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
diao@nyu.edu
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank Professor Donna Blackmond for helpful discussions and suggestions and Chunhua
(Tony) Hu for solving the X-ray crystal structure of complex 18. Lin thanks Margalit Feuer for
help with UV-Vis measurements and Colin Anson (UW-Madison) for assistance with the EPR
measurements. This work was supported by National Institute of Health (NIH) under Award
Number 1R01GM127778. T.D. is a recipient of the Alfred P. Sloan Research Fellowship (FG-
2018-10354) and the Camille-Dreyfus Teacher-Scholar Award (TC-19-019). T.D. acknowledges
NSF (1827902) for funding to acquire an EPR spectrometer.
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