Monovalent Nickel-Mediated Radical Formation: A Concerted Halogen-Atom Dissociation Pathway Determined by Electroanalytical Studies

Electroanalytical Studies

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Monovalent Nickel-Mediated Radical Formation: A Concerted

Halogen-Atom Dissociation Pathway Determined by

Qiao Lin, Yue Fu, Peng Liu,* and Tianning Diao*

Cite This: https://doi.org/10.1021/jacs.1c05255

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sı Supporting Information

ABSTRACT: The recent success of nickel catalysts in stereo-

convergent cross-coupling and cross-electrophile coupling reactions

partly stems from the ability of monovalent nickel species to activate

C(sp ) electrophiles and generate radical intermediates. This

electroanalytical study of the commonly applied (bpy)Ni catalyst

elucidates the mechanism of this critical step. Data rule out outer-

sphere electron transfer and two-electron oxidative addition

pathways. The linear free energy relationship between rates and

the bond-dissociation free energies, the electronic and steric eﬀects

of the nickel complexes and the electrophiles, and DFT calculations

support a variant of the halogen-atom abstraction pathway, the

inner-sphere electron transfer concerted with halogen-atom dis-

sociation. This mechanism accounts for the observed reactivity of

diﬀerent electrophiles in cross-coupling reactions and provides a mechanistic rationale for the chemoselectivity obtained in cross-

electrophile coupling over homocoupling.

INTRODUCTION

abstraction. Such studies, however, have not been carried out

with the most reactive catalytic systems, such as with

bipyridines (bpy), since the isolation of such active Ni(I)−

■

Nickel catalysts excel in conducting cross-coupling reactions of

C(sp ) electrophiles, owing to the slow β-H elimination of

−4

aryl complexes is challenged by their instability.

Ni−alkyl intermediates.

philes invokes alkyl radical formation arising from the

The activation of C(sp ) electro-

The dilemma between the desire to study catalytically active

species and their instability that hampers isolation has

historically been solved by electroanalytical methods, allowing

interaction of monovalent nickel species with C(sp ) electro-

−13

philes (Scheme 1A).

This fundamental step has two

for kinetic measurements of in situ generated transient

signiﬁcant consequences: (1) formation of the radical

intermediate erases the initial stereochemistry in the substrate

and thus creates opportunities for stereoconvergent coupling of

29−32

organometallic intermediates.

Recent cyclic voltammetry

(

CV) studies have shed light on the activation of benzyl

33,34

4,15

bromides by Co(I) complexes.

mediated radical formation from C(sp ) electrophiles, previous

electroanalytical studies have focused on macrocyclic

ﬁve-coordinated Ni(I) complexes, which are not directly

With respect to Ni(I)-

racemic alkyl halides,

and (2) in cross-electrophile

coupling reactions, C(sp ) and C(sp ) electrophiles are

separately activated by diﬀerent nickel species via diﬀerent

mechanisms, which accounts for the selectivity of cross-

electrophile coupling over homocoupling.

Stepwise and concerted pathways have been considered to

17−22

and

relevant to cross-coupling reactions. The latter example

demonstrates that diﬀerent ligands can alter the pathways.

Despite previous electrochemical studies of catalytic reac-

account for Ni(I)-mediated radical formation from C(sp )

36−39

tions

and the electronic structure of low-valent nickel

40,41

electrophiles: S 2 oxidative addition followed by radical

species,

the mechanism of (bpy)Ni(I)-mediated activation

ejection, electron transfer preceding homolytic cleavage of

of C(sp ) electrophiles has not been elucidated. The

17−22

the carbon−halogen bonds,

and halogen-atom abstraction

DFT calculations support the halogen-

atom abstraction mechanism in several nickel com-

0,23−25

(

Scheme 1B).

Received: May 22, 2021

0,23−25

plexes.

Experimental eﬀorts seeking to distinguish

among these pathways have focused on well-deﬁned (NHC)-

Ni(I) (NHC = N-heterocyclic carbene) and (xantphos)Ni(I)

complexes. Kinetic studies suggest that (xantphos)Ni(I)-

mediated radical formation proceeds through halogen-atom

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Scheme 1. Nickel(I)-Mediated Radical Formation as an

Intermediate Step in Cross-Coupling Reactions (A) and

Possible Pathways (B)

Figure 1. Variation of the peak current ratio (i /i ) in the CV of

pa pc

(

bpy)Ni(Mes)Br (1) in the presence and absence of 10 mM 1-

bromopropane with a scan rate of 5 mV/s (A) and at diﬀerent scan

rates (B). CVs were run with 1.0 mM 1 in a 600 mM solution of

mechanistic signiﬁcance of (bpy)Ni-mediated radical forma-

tion as an intermediate step in cross-coupling reactions, in

combination with the growing participation of nickel

Bu NBr in DMF at −60 °C, using a 0.071 cm glassy carbon working

electrode.

42−44

complexes in electrocatalysis,

prompted us to carry out

_t_h_e_w_o_r_k_i_n_g_e_l_e_c_t_r_o_d_e_,_C0 is the concentration of 1, R is the

a comprehensive CV study to uncover the mechanism of alkyl

halide activation by a (bpy)Ni(I) species (bpy = bipyridine).

Our data compare the reactivity of diﬀerent electrophiles and

account for the observed selectivity in catalytic cross-

electrophile coupling reactions.

ideal gas constant, T is the temperature, v is the scan rate, and

46,47

D_N_iis the diﬀusion coeﬃcient of 1 (eq 2).

The near 1:1

ratio of peak anodic current (i ) to cathodic current (i ),

together with the lack of a dependence of i /i on the scan

pa pc

rate [Figure S1 , Supporting Information (SI)], suggests that

the initial 1 can be recovered after the forward and reverse scan

cycles and that 2 is stable on the CV time scale.

RESULTS

■

Comparing the Activation Rates of Diﬀerent Electro-

philes. We conducted CV studies on (bpy)Ni(Mes)Br 1 as a

model complex (Figure 1). At −60 °C, the solution of 1

displays an electrochemically reversible CV wave (Figure 1A,

blue trace). We assign the cathodic peak to the one-electron

nFvD_N_i

i_p= 0.4463nFAC

(2)

In the presence of an electrophile, such as 1-bromopropane,

^t^h^e^C^V^b^e^c^o^m^e^s^q^u^a^sⁱ^r^e^v^e^r^sⁱ^b^l^e^wⁱ^t^h^a^d^e^c^r^e^a^s^e^d^r^a^tⁱ^o^o^fⁱpa^/ⁱpc

•

−

reduction of 1 to a ﬀ ord [(bpy)Ni(Mes)Br] (2 , eq 1 ). The

(

Figure 1A, red trace). We attribute this observation to an

electrochemical mechanism (EC): The reduction of 1 at the

cathode is followed by the oxidation of 2 with 1-bromopropane

that depletes 2 and thus decreases the anodic peak current (i_p_a)

(

eq 1). The ratio of i /i thus varies as a function of the scan

pa pc

rate (v), corresponding to the time allowed for 2 to react with

-bromopropane between the two peak current measurements

Figure 1B). Varying the scan rate enabled the measurements

(

of a series of i /i ratios, corresponding to diﬀerent degrees of

pa pc

current peaks are proportional to the concentration of the

species undergoing electron transfer and its diﬀusion

coeﬃcient according to the Randles−Sevcik equation, where

consumption of 2 by 1-bromopropane. Correlating i /i to

pa pc

the concentration of 2 allowed us to draw the time course for

the reaction of 2 with 1-bromopropane (Figure 2A). Fitting

the time course to a second-order kinetic model gave a rate

i is the peak current, n is the number of electrons for the Ni

−

−1 −1

redox couple, F is the Faraday constant, A is the surface area of

constant of 5.9 × 10

s .

Journal of the American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Figure 3. Cathodic sweeps of CVs of 1.0 mM (bpy)Ni(Mes)Br (1) in

a 100 mM solution of Bu NBF in DMF at 22 °C in the absence (blue

trace and inset) and presence of 100 equiv BnBr (red trace). Scan rate

500 mV/s.

chemically generated 2 by BnBr (k ). The signiﬁcantly higher

cathodic current peak (i ) relative to i indicates an

cat

electrocatalysis process (EC′), where Ni(I) 2 serves as a

30,46

catalyst that mediates the electroreduction of BnBr (eq 3).

Figure 2. Time course of electrochemically generated [(bpy)Ni-

•−

(

Mes)Br] (2) in the presence of diﬀerent electrophiles (A) and the

In this scenario, the current is created by the electrocatalytic

turnover of 2 occurring at the electrode. The increase of

electrophile concentration accelerates the turnover rate of

⧧

linear free-energy relationship between the activation energy (ΔG )

and the BDFE of carbon−halogen bonds (B). CVs were conducted

with 1.0 mM (bpy)Ni(Mes)Br (1) in a 600 mM solution of Bu NBr

nickel and, thus, a higher cathodic current (i ) (Figure S4,

cat

in DMF at −60 °C. Data were generated by varying the scan rates

SI). Increasing the BnBr loading to 100 equiv, however, was

from 5 to 1000 mV/s. The ﬁttings of the time courses were simulated

insuﬃcient to reach the KS zone, in the sense that no plateau

by COPASI.

was observed.

We adopted the “foot-of-the-wave” (FOW) analysis of the

We applied this technique to investigate the reaction rates of

with a range of electrophiles (Figure 2A). With 100 equiv of

background-corrected CV to determine the reaction rate of 2

51−53

with BnBr (k ) under EC′ conditions.

At the foot-of-

obs

PhBr, no conversion of 2 was observed over 70 s. Among

the-wave, i /i at a given potential (E) is described by a linear

cat pc

C(sp ) electrophiles, cyclohexyl chloride was inert, but modest

−1

function of {1 + exp[(F/RT)(E − E

)]} with the

/2(Ni /Ni )

reactivity was observed with 1-phenylethyl chloride. A variety

of alkyl bromides proceeded to react with 2 at diﬀerent rates.

Cyclohexyl iodide reacted substantially faster than cyclohexyl

slope dependent on the scan rate (ν) and k (eq 4). FOW

obs

analysis of the CV of 1 in the presence of 100 equiv BnBr

(

Figure 3, red trace) determined the pseudo-ﬁ rst-order rate

⧧

bromide. Plotting the ΔG of these reactions as a function of

−1

constant, k_o_b_s, to be 4.0 × 10

(Figure S5, SI),

the bond dissociation free energy (BDFE) of the carbon−

corresponding to a second-order rate constant k of 4.0 ×

halogen bonds gave a linear correlation with a slope of 0.24

−1 −1

0 M

(Scheme 2).

(

Figure 2B).

^R^T^kobs

Comparing the Rate of Bromide Dissociation to That

.24n

ⁱcat

Fν

of Electrophile Activation. Data collection at −60 °C was

complicated by temperature ﬂuctuations. We conducted

subsequent CV studies at 22 °C. A new anodic peak appeared

at a more positive potential, which is assigned to the oxidation

of (bpy)Ni(I)(Mes) (3), raised from the dissociation of

Å F

i_p

1 + expÅ (E − E )Ñ

1/2 Ñ

ÇÅ RT

ÖÑ

(4)

The drastically slower rate of bromide dissociation from 2

−

(k = 2.5 s ) relative to that of the consumption of 2 by BnBr

−1 −1

bromide from 2 (Figure 3, blue trace and the inset). By

varying the scan rate and measuring the corresponding shifts of

the cathodic peak on the potential scale, we determined the

ﬁrst-order rate constant of bromide dissociation from 2 to be

(k = 4.0 × 10 M s ) reveals that 2 is directly oxidized by

BnBr without forming 3 through bromide dissociation

(Scheme 2). To obtain further support of this assignment,

we determined the rate of 2-mediated BnBr oxidation in the

−

.5 s at 22 °C (cf. Figure S3, SI).

presence of Bu NBr (tetra-n-butylammonium bromide). If

In the presence of 100 equiv of BnBr at 22 °C, the CV of 1

bromide dissociation takes place prior to the reaction of 2 with

became irreversible (Figure 3, green trace). The lack of an

BnBr, we would observe inhibition by Bu NBr. The

anodic current peak (i ) reﬂects rapid oxidation of electro-

comparable rates of reaction in the absence (k ) and presence

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

dimethylphenyl ligand to mesityl led to a drastic rate decrease.

Scheme 2. Comparison of the Bromide Dissociation Rate

with Oxidation of 2 by BnBr

(

k ′) of Bu NBr substantiate the lack of bromide dissociation

under these conditions. This result is corroborated by the

beneﬁcial eﬀect of halide salt additives, such as NaI or MgI , in

cross-electrophile coupling reactions, suggesting that the

presence of coordinating anions may serve to stabilize

monovalent nickel intermediates.

Steric Eﬀect of Ni(I)−Ar. FOW analysis equipped us with

a convenient means to determine the electronic and steric

eﬀects of electrophiles and nickel species for the oxidation of

Ni(I) by a C(sp ) electrophile. Varying the aryl group on the

Ni center reveals that steric hindrance decreases the reaction

rate (Figure 4). In particular, the change of a 2,4-

Figure 5. (A) Hammett plot for electrocatalytic oxidation of benzyl

bromides catalyzed by 1. Reaction conditions: 1.0 mM (bpy)Ni-

(

[

Mes)Br (1) in a 100 mM solution of Bu NBF in DMF at 22 °C,

4 4

ArCH Br] = 100 mM. k = k of the electrocatalytic oxidation of

obs

benzyl bromides derived from FOW analysis. (B) Uniﬁed Hammett

model, split into charge (σ ) and radical (σ ) stabilization terms, for

−

•

electrocatalytic oxidation of benzyl bromides catalyzed by 1.

analysis seeking to unify the Hammett model. When

correlating the rate data with Jiang’s spin-delocalization

•

substituent constants σ , a parameter that describes the

58,59

stabilization eﬀect of a substituent to radicals,

we obtained

ﬁttings that underestimated the eﬀect of electron-withdrawing

substituents but overestimated that of electron-donating

groups (Figure S6 , SI). When utilizing both the charge factor

Figure 4. Steric eﬀect of nickel complexes on activation of benzyl

−

0.5

bromide: the slopes of FOW analysis plots against (scan rate) . The

slope of the linear ﬁts is proportional to k_o_b_s, according to eq 4.

Reaction conditions: 1.0 mM (bpy)Ni(Ar)Br in a 100 mM solution of

−

•

(σ ) and the radical factor (σ ) together to describe the

Bu NBF in DMF at 22 °C, BnBr = 100 mM.

electronic eﬀect, we obtained a good linear correlation (Figure

−

B). The positive coeﬃcient for σ reveals the buildup of

Electronic Eﬀect of the Electrophile. A Hammett study

of benzyl bromide derivatives with various para/meta-

substituents sheds light on the electronic eﬀect of the C(sp )

partial negative charges in the transition state. The radical

•

term, σ , with a larger coeﬃcient, reﬂects a more signiﬁcant

stabilization of spin density in the transition state. Such a two-

term linear free energy relationship is reminiscent of previous

studies on reactions forming nucleophilic radical intermediates,

electrophile. Both electron-rich and electron-deﬁcient sub-

stituents accelerated the reaction (Figure 5A). We obtained

excellent linear ﬁttings for electron-rich and electron-deﬁcient

substrates with negative and positive slopes, respectively, by

33,54

such as halogen-atom abstraction.

Electronic Eﬀect of Ni(I)−Ar. We explored the electronic

eﬀect of the nickel complexes on the activation rate of benzyl

bromide by varying the ligand and the para-substituents on the

aryl group in (bpy)Ni(Ar)(Br) (Figure 6). The electronic

eﬀect of the substituents on the molecule is represented by

−

correlating them with σ . A break in the Hammett relationship

may be assigned to a change in mechanism between

stabilization of a positive and negative charge in the transition

state or the formation of a radical intermediate at the benzylic

position, which can be stabilized by either mesomerically

their reduction potential E₁

. The rate (k) of each

/2(Ni /Ni )

54−56

donating or withdrawing groups.

reaction was determined by applying the FOW analysis as

outlined above. While the use of 4,4′-di-tert-butylbipyridine

resulted in a decrease of the reduction potential by 130 mV,

In order to delineate the electronic eﬀect of electrophiles on

oxidation of 2, we applied multiparameter linear regression

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the hyperﬁne splitting to the coupling of the radical to nitrogen

Article

and hydrogen atoms on bpy. The observation of a bpy-

centered radical suggests that 2 is best described as a Ni(II)

stabilized by a bpy radical anion. Moreover, EPR analysis of

•

−

[

(4,4′-di-tert-butylbipyridine)Ni(Mes)Br]

gave a similar

isotropic signal with a g value of 2.004 (Figure S8 , SI),

suggesting that the presence of electron-donating groups does

not detract the redox activity.

Computational Studies. We performed density functional

theory (DFT) calculations to explore the mechanism of

[

(bpy)Ni(Mes)Br]^•(2)-mediated activation of BnBr. Be-

−

cause the computational results may be aﬀected by the choice

of the DFT method and basis set, we assessed diﬀerent

methods using the explicitly correlated local coupled-cluster

method PNO-LCCSD(T)-F12 and the experimental activa-

tion free energies (Figure 5) as the reference. The details of the

benchmark studies are provided in the Supporting Information.

Several functionals, including BP86-D3, B3LYP-D3, and

M06L, provide reasonable agreement with the experimental

data. Although the use of BP86-D3 in single-point energy

calculations led to a systematic underestimation of the

activation free energy by several kilocalories/mole, the

correlation with the experimental barriers with diﬀerent

electrophiles is comparable to the results obtained using

B3LYP-D3. When comparing the relative activation energies of

^Fⁱ^g^u^r^e⁶^.^E^l^e^c^t^r^oⁿⁱ^c^e^ﬀ^e^c^t^o^f^Nⁱ^c^o^m^p^l^e^x^e^s^.^R^a^t^e^s⁽^kobs) are derived

from FOW analysis. E₁_/₂is the formal potential of the corresponding

Ni(II)−aryl/Ni(I)−aryl couple, reﬂecting their electronic properties.

Reaction conditions: 1.0 mM (bpy)Ni(Ar)Br 1 in a 100 mM solution

of Bu NBF in DMF at 22 °C, [BnBr] = 100 mM.

halogen-atom transfer and S 2 pathways with the PNO-

diﬀerent para-substituents on the aryl ligand varied the redox

potentials from −1.84 to −1.93 V. Despite the diﬀerent

reduction potentials, the reaction rates of these analogues to

BnBr remain similar.

LCCSD(T)-F12 energy values, BP86-D3 provided the best

agreement. Therefore, we chose the (U)BP86-D3/def2-

TZVPP, SMD(DMF)//(U)B3LYP-D3/6-31G(d)-SDD level

of theory in the computational study.

Electronic Structure of 2. The radical anion of (phen)-

Ni(Mes)(Br) has been determined by EPR spectroscopy,

featuring a redox-active phen ligand that stabilizes the Ni(II)

The ground state of 2 is computed to be a square planar

doublet with a ligand-centered radical, consistent with the EPR

data (Figure 7). A scan of the bromide dissociation reaction

center. We performed a similar EPR analysis to elucidate the

⧧

coordinate gave an activation energy (ΔE ) of 19.2 kcal/mol

electronic structure of 2. Reduction of 1 by 1 equiv of KC led

with respect to 2, although no transition state could be located.

The high barrier to bromide dissociation is consistent with the

experimentally observed slower rate of this process compared

to the reaction of 2 with BnBr (Scheme 2).

a color change from maroon to violet. EPR analysis of the

solution at room temperature gave an isotropic signal with a g

value of 2.0047 (Figure 7). Simulation of the spectrum assigns

The evaluation of diﬀerent pathways concludes with the

inner-sphere electron transfer (ISET) concerted with halogen-

35,62,63

atom dissociation (TS1) (Figure 8).

The early transition

state, TS1, features a long Ni−Br distance of 3.82 Å, in which₋

bpy remains redox-active. The NPA charge of −0.363 e

reﬂects that substantial electron density developed at the

benzylic carbon of BnBr. The C−Br−Ni bond angle in TS1 is

slightly bent (150.6°) due to the dispersion interaction

between the Bn group and the bpy ligand. The computed

⧧

activation free energy of ΔG

= 7.4 kcal/mol is slightly

DFT

lower than the experimental values determined in this study

= 11.2 kcal/mol) and a prior report. When the

B3LYP-D3 or M06L functional was used in the single-point

⧧

(

ΔG

exp

energy calculations in place of BP86-D3, a better agreement

⧧

with ΔG

can be obtained (see Table S8, SI).

exp

TS1 directly proceeds to form 1 and the benzyl radical upon

the dissociation of the bromide anion, as evident from intrinsic

reaction coordinate (IRC) calculations (Figure S40, SI).

Although the Ni−Br distance slightly decreases after

halogen-atom abstraction, a Ni−Br covalent bond is never

fully formed along the reaction coordinate. After the cleavage

−

of the Bn−Br bond, the Br spontaneously dissociates to form

Figure 7. X-band EPR spectrum of 2 in THF. Temperature = 295 K,

microwave frequency = 9.355 531 GHz, power = 0.6325 mW,

modulation frequency = 1 mT/100 kHz, modulation amplitude = 0.5

G. The simulated spectrum (red) uses the following parameters: g =

. The steric hindrance of the mesityl ligand, the high stability

of 1, and the weak interaction between Br and Ni (Figure

S41 , SI) prevented the formation of a ﬁve-coordinated

[(bpy)Ni(Mes)Br ] intermediate.

−

.0047, A_N_,_N_,_H_,_H_,_H= [11.666, 8.3360, 7.2980, 5.8227, 3.7990] MHz.

Journal of the American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Figure 9. Computed activation free energies with para-substituted

aryl nickelate complexes.

less hindered aryl ligands and with electron-deﬁcient benzyl

bromides. These trends are in qualitative agreement with the

experimental observations (Figures 4 and 5).

DISCUSSION

■

Concerted Halogen-Atom Dissociation Pathway.

Comparing the reactivity of various electrophiles reveals that

is inactive toward C(sp ) electrophiles (Figure 2A). This

Figure 8. Computed reaction proﬁles of the oxidation of 2 by benzyl

bromide.

observation is reminiscent of a previous mechanistic study,

where the activation of C(sp ) electrophiles is conducted by

The S 2 oxidative addition (TS2) is preceded by a geometry

Ni(I)−halides rather than Ni(I)−aryl species. Among alkyl

bromide electrophiles, the primary 1-bromopropane reacts

slower than tBuBr and benzyl bromides. This trend disagrees

with the oxidative addition mechanism, which would favor

primary alkyl bromides (Scheme 3). DFT calculations reveal

distortion of 2 to adopt a tetrahedral geometry in 2′, in which

the spin is predominantly located on nickel. This more

nucleophilic nickel center 2′, although it proceeds to a nearly

barrierless S 2 attack on BnBr, is less stable than 2 by 10.4

kcal/mol, resulting in an overall higher barrier relative to that

of halogen-atom abstraction. Finally, the activation free energy

of the outer-sphere concerted dissociative electron transfer

Scheme 3. Summary of Data that Supports the Concerted

Halogen-Atom Dissociation Mechanism

(

DET) mechanism was calculated using the modiﬁed Marcus

63,65,66

theory (i.e., the sticky model)

activation barrier (ΔG = 15.6 kcal/mol) than halogen-atom

abstraction.

and gave a higher

⧧

We then studied the electronic eﬀects of the nickelate

[

(bpy)Ni(aryl)Br]^•complex by varying the para-substituents

−

•−

on the aryl group. [(bpy)Ni(aryl)Br] complexes, bearing p-

methoxy, -methyl, and -cyano substituents, all show similar

activation energies toward BnBr (Figure 9). The similar

reactivities of these nickel complexes agree with the

experimental observations (Figure 6). We attribute this

negligible electronic eﬀect to the redox activity of bpy in

TS1. When BnBr approaches the square-planar nickel center

from the apical position, the unpaired electron is mainly

delocalized to the bpy ligand. This electronic structure dilutes

the electronic eﬀect of para-substituents of the aryl group on

the Ni center and, thus, results in insigniﬁcant changes of the

rate.

The steric eﬀects of the nickelate complexes bearing

diﬀerent aryl groups and the electronic eﬀects of the alkyl

halide electrophiles were also investigated computationally (cf.

Tables S9 and S10 , SI). The computed activation barriers are

sensitive to these eﬀectshalogen-atom transfer is faster with

that the S 2 pathway requires the distortion of square planar 2

to tetrahedral 2′, and this endergonic process is less favorable

than halogen-atom abstraction (Figure 8). The increase of the

steric hindrance on Ni(I) decreases the rate of electrophile

activation (Figure 4). This observation rules out the outer-

sphere electron transfer (OSET) mechanism, since OSET

would be insensitive to the steric eﬀect of the nickel center.

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

series of alkyl halides (Figure 10 ). The slope values are lower

Article

This assignment is consistent with DFT and Marcus theory

calculations.

Scheme 4. Preference of Ni(I) Species Reacting with C(sp )

and C(sp ) Electrophiles

Experimental and computational data are consistent with a

concerted halogen-atom dissociation pathway (Scheme 3,

orange pathway). The Hammett study of the electronic eﬀect

of benzyl bromides has shed light on the nature of the

transition state (Figure 5). Multiparameter linear regression

analysis suggests the formation of both radical and partial

negative charges at the benzylic carbon of the electrophile,

•

−

evident by the positive coeﬃcients of both σ and σ terms.

−

The polar term σ reﬂects the nucleophilic attack of the

electron-rich nickel(I) center to the σ* orbital of benzyl

bromide that creates a partial negative charge. The radical term

•

suggests homolytic C−Br bond cleavage that gives rise to

for the selectivity of cross-electrophile coupling over

homocoupling. This study provides further support to this

the radical character on the benzyl carbon. This description is

corroborated by the DFT calculations. In the halogen-atom

abstraction transition state, TS1, signiﬁcant negative charge

•

−

hypothesis. [(bpy)Ni(Mes)Br] (2) proved to mediate a

faster activation of C(sp ) relative to C(sp ) electrophiles. The

(

−0.363) on the benzylic carbon of BnBr reveals a strong

slower rate of [(bpy)Ni(Mes)Br]^•(2) with C(sp ) electro-

philes stems from the steric hindrance that prevents oxidative

addition through a three-centered transition state. The

coordination of the aryl group on nickel, as a strong σ-donor

ligand, gives a more electron-rich 2 relative to (bpy)NiBr,

−

electron-transfer character in the process, whereas the spin

density of 0.179 illustrates partial bond homolysis. After TS1,

the halide never transferred to the metal center but

spontaneously dissociated. Although having an analogous

transition state, this process diﬀers from a typical inner-sphere

halogen-atom abstraction, which involves halide transfer to the

which facilitates the activation of C(sp ) electrophiles to form

2,63

radicals. The reactivity of (bpy)Ni(I)Br is not discussed here,

and an investigation into the mechanism of (bpy)Ni(I)Br-

mediated electrophile activation is underway.

metal center.

Thus, this mechanism is best described as an

inner-sphere electron transfer (ISET) occurring concertedly

with the dissociation of the halogen atom.

The activation of C(sp ) electrophiles via halogen-atom

The kinetics of the reaction complies with that of halogen-

atom abstraction, since these transition states both engage

relatively strong interactions between nickel and the halogen

atom and involve carbon−halogen bond dissociation. A linear

abstraction dictates that the reactivity of electrophiles in

catalytic cross-coupling is dependent on the BDE of the

corresponding carbon−halogen and nickel−halogen bonds.

Traveling up the periodic table from iodides to ﬂuorides, the

BDEs of both carbon−halogen and nickel−halogen bonds

increase. The correlation of BDE

linear function with a slope ranging from 0.58 to 0.69 for a

⧧

free-energy relationship between the activation energy ΔG

and the BDFE of the carbon−halogen bond of the electrophile,

spanning chlorides, bromides, and iodides, demonstrates a

preference for substrates that contain weak carbon−halogen

bonds (Figure 2B). The slope of 0.24 in the linear ﬁtting is

within the range of slopes reported for halogen-atom

abstraction by silyl, germanyl, and stannyl radicals (0.13−

(C−X)

vs BDE

ﬁts a

(Ni−X)

8,69

.35).

The kinetics of halogen-atom abstraction promoted

by sodium metal was historically modeled by the crossing of

the Morse curves for the reactants and products to give a linear

⧧

correlation of the activation energy (ΔG ) to the bond

0−72

dissociation energy (ΔH) (eq 5).

The slope, ρ, depicts

the shapes of the pretransition and post-transition state

sections of the potential-energy curve. Saveant modiﬁed the

Marcus theory by replacing the inner-sphere reorganization

energy with the BDFE₍_C₋_X₎of the carbon−halogen bond to

describe concerted halogen-atom dissociation upon outer-

65,73

sphere electroreduction.

this model predicts a linear correlation between ΔG and

BDFE with a slope approximated to 0.25. Studies are

Through a range of electrophiles,

⧧

(

C−X)

underway to build a model for describing inner-sphere

halogen-atom abstraction/dissociation.

Figure 10. Correlation of BDE₍_N_i₋_X₎to BDE₍_C₋_X₎

⧧

ΔG = ρΔH

(5)

than 1, suggesting that the increase of BDE₍_N_i₋_X₎from iodides

to ﬂuorides is slower than the increase of BDE₍_C₋_X₎. As a result,

the driving force for Ni-mediated electrophile activation

decreases in the series from iodides to ﬂuorides, hence the

decrease of the rates.

Implications for Cross-Electrophile Coupling. Elucidat-

ing the mechanism of Ni(I)-mediated halogen-atom abstrac-

tion has several implications for nickel-catalyzed cross-

electrophile coupling reactions. In an earlier mechanistic

investigation, we discovered that C(sp ) and C(sp ) electro-

philes are sequentially activated through diﬀerent pathways to

generate Ni−aryl intermediates and alkyl radicals, respectively

Comparing alkyl halides as substrates in cross-coupling

reactions, alkyl iodides are activated fastest but are often

susceptible to homocoupling, owing to the direct reduction by

(

Scheme 4). The sequential reduction mechanism accounts

zinc or manganese (Scheme 5). The strong C−Cl bonds of

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

https://pubs.acs.org/doi/10.1021/jacs.1c05255.

Article

Scheme 5. Reactivity of C(sp ) Electrophiles

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

All experimental procedures, additional ﬁgures, details of

DFT calculations, CV measurements, and UV−vis and

NMR spectra (PDF )

AUTHOR INFORMATION

■

Corresponding Authors

Peng Liu − Department of Chemistry, University of Pittsburgh,

alkyl chlorides resist chlorine-atom abstraction by monovalent

Pittsburgh, Pennsylvania 15260, United States; orcid.org/

(

bpy)Ni species; their activation requires alternative ap-

0000-0002-8188-632X ; Email: pengliu@pitt.edu

proaches. Cross-coupling of alkyl chlorides has been achieved

Tianning Diao − Department of Chemistry, New York

University, New York, New York 10003, United States;

orcid.org/0000-0003-3916-8372; Email: diao@nyu.edu

by invoking halide exchange with bromides, applying more-

8,79

reducing Ni(0) species,

and promoting chlorine-atom

abstraction by silyl radicals. The bond strengths of alkyl

bromides result in a suitable rate of bromine-atom abstraction

by monovalent (bpy)Ni complexes that enables the radical to

enter the catalytic cycle. Therefore, alkyl bromides serve as the

most common electrophiles in these coupling reactions.

Among alkyl bromides, the rate diﬀerence between primary,

secondary, and tertiary substrates is rather small, whereas

benzylic bromides react signiﬁcantly faster.

Authors

Qiao Lin − Department of Chemistry, New York University,

New York, New York 10003, United States

Yue Fu − Department of Chemistry, University of Pittsburgh,

Pittsburgh, Pennsylvania 15260, United States

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c05255

The rate of halogen-atom abstraction is to some extent

insensitive to the electronic eﬀect of the aryl groups on nickel,

providing a basis for accommodating a broad scope of C(sp )

Notes

The authors declare no competing ﬁnancial interest.

electrophiles in coupling reactions. The electronic eﬀect of the

ligand appears to be insigniﬁcant on the activation of C(sp )

ACKNOWLEDGMENTS

■

(

electrophiles, as evident by the similar rates between bpy and

This work was supported by the National Institute of Health

,4′-tBu-bpy (Figure 6). The lack of an electronic eﬀect is

R01 GM-127778) and the National Science Foundation

CHE-1654122). T.D. thanks the Alfred P. Sloan Foundation

FG-2018-10354) and the Camille and Henry Dreyfus

Foundation (TC-19-019) for providing fellowships to partially

support this work. T.D. acknowledges NSF (1827902) for

funding to acquire the EPR spectrometer. P.L. thanks Pitt

CRC, XSEDE, and TACC Frontera for supercomputer

resources.

28,81

attributed to the redox activity of bpy and derivatives,

which dilutes the electronic eﬀect of spectator ligands on the

nickel center. The success of 4,4′-tBu-bpy in nickel-catalyzed

cross-coupling reactions may be attributed to its excellent

solubility in organic solvents or an improved reactivity of other

steps in the catalytic cycle.

SUMMARY

■

REFERENCES

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