mechanism of ni-catalyzed reductive 1,2

doi.org/10.26434/chemrxiv.9161855.v1

Mechanism of Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization ofAlkenesQiao Lin, Tianning Diao

Submitted date: 29/07/2019 • Posted date: 30/07/2019Licence: CC BY-NC-ND 4.0Citation information: Lin, Qiao; Diao, Tianning (2019): Mechanism of Ni-Catalyzed Reductive1,2-Dicarbofunctionalization of Alkenes. ChemRxiv. Preprint.

A mechanistic study on Ni-catalyzed reductive 1,2-dicarbofunctionalization of alkenes distinguishes the"radical chain" mechanism from the "sequential reduction" mechanism.

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S1

Mechanism of Ni-Catalyzed Reductive

1,2-Dicarbofunctionalization of Alkenes

Qiao Lin and Tianning Diao*

Department of Chemistry, New York University, 100 Washington Square East

New York, NY 10003

E-Mail: [email protected]

mailto:[email protected]

S2

Table of Contents

1. General Considerations S2

2. General Kinetics Experimental Procedure S3

3. Kinetics Modeling and Data S3

4. NMR Spectroscopy Characterization of Catalyst Resting State S14

5. Stoichiometric Studies of Substrate Activation S20

6. Ni Loading Control Experiments of Radical Capture and Cyclization Rate S28

7. Calculation of Radical Capture and Cyclization Rate S29

8. Synthesis and Characterization of Radical Clock Substrates and Ni Complexes S30

9. Crystallographic data for Ni(phen*)Br 18 S37

10. Electrochemical Analysis S38

11. NMR Spectra S41

12. UV/Vis Spectra S55

13. EPR Experiments S57

14. DFT Calculations S59

15. References S60

1. General Considerations

1.1 Materials: Metals, ligands, solvents, and most substrates were obtained from

commercial sources. All air- and moisture-sensitive manipulations were carried out in a

glove box. THF was dried and deoxygenated by passing through alumina in a solvent

purification system. N,N-dimethylacetamide (DMA) was dried over CaH2, distilled, and

degassed before use. Dimethylsulfoxide-d6, acetone-d6, dimethylacetamide-d9 were

purchased from Cambridge Isotope Laboratories, Inc. and stored with molecular sieve over

3 days before use. 1H and 13C NMR spectra were recorded on Bruker 400, 500, or 600

Avance spectrometers (400 MHz, 500 MHz, or 600 MHz). Chemical shifts are reported in

ppm relative to tetramethylsilane, with the residual solvent resonance (CDCl3, δ = 7.26;

S3

DMA-d9, δ = 1.83, 2.66, 2.84) as the internal reference. Spectra are reported as follows:

chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet), coupling constant (Hz), and integration. 13C NMR spectra were recorded on

Bruker 400 and 600 Avance spectrometers (101 or 151 MHz). Chemical shifts were

reported in ppm relative to tetramethylsilane with the solvent resonance used as the internal

reference (CDCl3, δ = 77.16). High resolution mass spectra (HRMS) were recorded on an

Agilent 6224 TOF LC/MS (APCI source). GC-MS data were obtained using a Shimadzu

GCMS-TQ8040 with a Shimadzu SH-Rxi-5Sil MS column (L 30 m, ID 0.25, DF 0.25).

Reactions were monitored by thin-layer chromatography (TLC) on Merck TLC silica gel

60 F254 plates and compounds were visualized by UV light (254 nm) or staining with

KMnO4. Aryl bromides were purchased from commercial sources, with liquids dried over

CaH2, degassed, and distilled, and solids were dried overnight under reduced pressure (~20

mtorr) before being brought into a nitrogen-filled glove box and stored at –35°C. Zinc was

washed with acid and grinded into powder.

2. General Kinetics Experimental Procedure

In a nitrogen-filled glove box, NiBr2•DME, phenanthroline and naphthalene were

separately dissolved in DMA to form stock solutions in concentration of 6.25 mM, 60 mM,

and 0.2 M, respectively. To a 2 mL crimp-top vial was added 11 (15.9 mg, 0.05 mmol),

PhBr (15.7mg, 0.1 mmol), and zinc powder (2.0 equiv.). After addition of stock solutions

of NiBr2•DME (0.8 mL), phenanthroline (0.1 mL) and naphthalene (internal standard,

0.1mL), the vial was sealed and removed from the glove box. The reaction was placed in a

shaker and heated to 50 °C. The agitation speed was set to 850 rpm. The reaction progress

was monitored by removing aliquots (~15 µL) from the reaction mixture via syringe. Each

aliquot was quenched by saturated ammonium chloride (0.5 mL) in a 2 mL GC vial. The

mixture was extracted by diethyl ether and the resulting organic layer was collected,

washed with water twice, dried over Na2SO4, and analyzed by gas chromatography.

3. Kinetics Modeling and Data

Parameters were simulated in CoPaSi software. First, kinetic models are built based on the

S4

following reactions. After input of the experimental time-course data, rate constants and

initial concentrations of components were varied until the calculated values agreed with

the experimental data. The stimulated time courses were evaluated by weighted error and

root mean square, and the best model was chosen. The final output was attached as an excel

spreadsheet.

Overall reactions:

3.1. Kinetic plots for same excess experiment

Same excess studies were completed using general kinetics experimental procedure with

an excess of 0.05 M.

(eq S1)

S5

Figure S1. Time-course for the reaction shown in eq S1. Reaction conditions:

[NiBr2•DME] = 5 mM, [phenanthroline] = 6 mM, Zn = 0.1 mmol, solvent = DMA; [11]0

= 0.1 M; [PhBr]0 = 0.15 M.

3.2. Kinetic plots with different Ni loading

The study of kinetic orders in the catalyst was completed following the general procedure

described above.

(eq S2)

Figure S2. Time-course for the reaction shown in eq S2 with 5% Ni loading. Reaction

conditions: [NiBr2•DME] = 2.5 mM, [phenanthroline] = 3 mM, Zn = 0.1 mmol, solvent =

DMA; [11]0 = 0.05 M; [PhBr]0 = 0.1 M.

S6


conditions: [NiBr2•DME] = 4 mM, [phenanthroline] = 4.8 mM, Zn = 0.1 mmol, solvent =

DMA; [11]0 = 0.05 M; [PhBr]0 = 0.1 M.


conditions: [NiBr2•DME] = 5 mM, [phenanthroline] = 6 mM, Zn = 0.1 mmol, solvent =

DMA; [11]0 = 0.05 M; [PhBr]0 = 0.1 M.

S7


conditions: [NiBr2•DME] = 7.5 mM, [phenanthroline] = 9 mM, Zn = 0.1 mmol, solvent =

DMA; [11]0 = 0.05 M; [PhBr]0 = 0.1 M.

Figure S6-1. Various normalization analysis of product vs. [catalyst]0.5·(time). The lack of

overlay fitting suggests that the catalyst order is not 0.5.

S8

Figure S6-2. Various normalization analysis of product vs. [catalyst]2·(time). The lack of

overlay fitting suggests that the catalyst order is not 2.

3.3. Kinetic Plots for Study of Agitation Speed

(eq S3)

Reaction order in catalyst studies were elucidated by following general kinetics

experimental procedures with the exception of agitation rate. The first 2 hrs of the reaction

progress was monitored.

S9

Figure S7. Kinetic profile of the reaction shown in eq S3 with an agitation speed of 500

rpm. Reaction conditions: [NiBr2•DME] = 5 mM, [phenanthroline] = 6 mM, Zn = 0.1

mmol, solvent = DMA; [11]0 = 0.05 M; [PhBr]0 = 0.1 M.




S10







S11




Figure S12. The dependence of the initial rate on the agitation speed for the reaction in eq

S3.

3.4. Kinetic plots for Zn loading experiments.

S12

(eq S4)

The study to elucidate the effect on Zn loading on rates was completed following the

general procedure. The first 2 hrs of the reaction progress was monitored.

Figure S13. Kinetic profile for the reaction shown in eq S4 with 1 equiv. Zn loading.

Reaction conditions: [NiBr2•DME] = 5 mM, [phenanthroline] = 6 mM, Zn = 0.05 mmol,

solvent = DMA; [11]0 = 0.05 M; [PhBr]0 = 0.1 M. Mixing Speed at 900 rpm.

S13







S14

Figure S16. The reaction rate vs. Zn loading for the reaction shown in eq S4.

3.5. Comparison of Activation Rates for Different Electrophiles

To a 2 mL crimp-top vial was added (Phen)NiBr2 14 (19.9 mg, 0.05 mmol), zinc (2.0

equiv.) and DMA 2 mL. The reaction was placed in a shaker, heated to 50 °C, and agitated

at a speed of 850 rpm. After reacting for 30mins, the resulting purple solution was cooled

and filtered to remove Zn. This solution was divided into two 2 mL crimp-top vials,

containing 11 (7.9 mg, 0.025 mmol) and PhBr (3.9 mg, 0.025 mmol), respectively. After

charging with zinc (2.0 equiv.), both vials were placed in a shaker and allowed to react at

50 °C. The reaction progress was monitored in the same way as described in the general

procedure.

4. NMR Spectroscopy Characterization of Catalyst Resting State

4.1. NMR study of the reaction mixture with (o-Tol)Br as the electrophile.

In a nitrogen-filled glove box, NiBr2•DME, phenanthroline and 1,3,5-trimethoxybenzene

were separately dissolved in DMA-d9 to form stock solutions in concentration of 6.25 mM,

60 mM, and 0.2 M, respectively. To a 2 mL crimp-top vial was added 11 (15.9 mg, 0.05

mmol), PhBr (15.7mg, 0.1 mmol), and zinc powder (2.0 equiv.). After addition of stock

solutions of NiBr2•DME (0.8 mL), phenanthroline (0.1mL) and 1,3,5-trimethoxybenzene

S15

(internal standard, 0.06 mL), the vial was sealed and removed from the glove box. The

reaction was placed in a shaker and heated to 50 °C. The agitation speed was set to 850

rpm. After reacting for 15 min, the mixture was cooled, followed by filtration with glass

wool into a J-Young tube and analyzed by 1H NMR spectroscopy.

(eq S5-1)

Figure S17. The diamagnetic region of the reaction shown in eq S5-1 at 21% conversion.


solvent = DMA-d9; [11]0 = 0.05 M; [o-TolBr]0 = 0.1 M. Agitation rate = 850 rpm. Probe

temperature = 25 oC. 11( ). 13 ( ), (Phen)Ni(o-Tol)Br ( ).

4.2. NMR study of the reaction mixture with PhBr as the electrophile.

(eq S5-2)

S16

Figure S18. 1H NMR spectrum of the reaction shown in eq S5-2 at 17% conversion.


solvent = DMA-d9; [11]0 = 0.05 M; [PhBr]0 = 0.1 M. Mixing Speed at 850 rpm. Probe

temperature = 50 oC. 11( ), 12 ( ) (Phen)Ni(Ph)Br 16 residue is shown as ( ).

S17

Figure S19. Comparison of (a) (Phen)NiBr2 14 in DMA-d9 and (b)the paramagnetic region

of the reaction mixture shown in eq S5-2. Probe temperature = 50 oC.

No significant (Phen)NiPh(Br) 16 peaks were observed in diamagnetic region due to the

low stability of 16 in DMA. The decomposition of 16 was also observed when dissolving

the independently prepared 16 into DMA.

4.3. Stoichiometric Experiments to probe the activation of electrophiles

1,3,5-trimethoxybenzene as the internal standard was added to a 2 mL crimp-top vial and

dissolved in DMA-d9 to prepare stock solutions (0.22 M).

To a 2 mL crimp-top vial was added (Phen)NiBr2 14 (4.7 mg, 0.01 mmol), 1,3,5-

trimethoxybenzene solution (30 μL) and DMA-d9 0.6 mL. This green solution was filtered

through glass wool into a J-Young tube and analyzed by 1H NMR spectroscopy (Figure

S6a). The solution was then transferred to a 2 mL crimp-top vial, recharged with activated

zinc (2.0 equiv.), sealed, and placed in a shaker at 50°C for 30 min to give a purple mixture.

The dark purple mixture 19 was cooled, followed by filtration with glass wool into a J-

a)

b)

S18

Young tube. To the J-Young tube was then added (o-Tol)Br (1.7 mg, 0.01 mmol) to afford

a orange solution. The orange mixture was then cooled to room temperature and analyzed

by 1H NMR spectroscopy. (Figure S6b).

(eq S6)

Figure S20. Comparison of (a) (Phen)NiBr2 14 in DMA-d9 with (b) the paramagnetic

region of the reaction mixture shown in eq S6. Reaction conditions: [14] = 0.015 M; [o-

TolBr] = 0.015 M; Zn = 0.02 mmol, solvent = DMA-d9. Probe temperature = 50 ºC.

a)

b)

S19

Figure S21. Comparison of (a) (Phen)Ni(o-Tol)Br 15 in DMA-d9 with (b) the diamagnetic


TolBr] = 0.015 M; Zn = 0.02 mmol, solvent = DMA-d9.

4.4. Bimolecular Oxidative Addition in DMSO-d6

(eq S7)

Due to the low solubility of (Phen)NiBr2 in DMA, we repeated the quantitive experiment

in DMSO-d6 using the same procedure.

a)

b)

S20

Figure S22. Comparison of (a) (Phen)NiBr2 14 in DMSO-d6 with (b) the paramagnetic


TolBr] = 0.015 M; Zn = 0.02 mmol, solvent = DMSO-d6. Probe temperature = 25 oC.

5. Stoichiometric Studies of Substrate Activation

5.1. Reaction of (Phen)Ni(Ar)Br with 11

5.1.1. Activation of 11 by (Phen)Ni (o-Tol)Br 15

(eq S8)

To a 2 mL crimp-top vial was added (Phen)Ni (o-Tol)Br 15 (8.2 mg, 0.02 mmol), 11 (6.4

mg, 0.02 mmol) and DMA (0.4 mL). The vial was sealed, removed from the glove box,

and placed in a shaker at 50 °C with a mixing speed of 850 rpm. After reacting overnight,

the mixture was quenched with saturated ammonium chloride, and extracted with diethyl

ether. The organic phase was washed with water twice, dried over Na2SO4, filtered,

concentrated under N2 and analyzed by 1H NMR spectroscopy.

a)

b)

S21

Figure S23. Crude 1H NMR spectrum for the reaction shown in eq S8. Reaction

conditions: [15] = 0.05 M; [11] = 0.05 M; solvent = DMA; 11 ( ) , 12 ( ) and 20 ( )

were observed.

5.1.2. 11 activation with reduced product (Phen)Ni (o-Tol) 15-a

(eq S9)

To a 2 mL crimp-top vial was added (Phen)Ni(o-Tol)Br 15 (8.2 mg, 0.02 mmol), ground,

activated zinc (2.0 equiv.) and DMA (0.4 mL), which was then placed in a shaker, heated

to 50 °C with mixing speed at 850 rpm for 30 min. The resulting purple-red solution was

filtered with glass wool into a new 2 mL crimp-top vial, followed by adding 11 (6.4 mg,

0.02 mmol) and placed back to the shaker. After 2 hrs, the mixture was quenched with

saturated ammonium chloride. The mixture was extracted by diethyl ether and the resulting

organic layer was collected, washed with water twice, dried over Na2SO4, filtered,


S22

Figure S24. Crude 1H NMR spectrum for the reaction shown in eq S9. Reaction conditions:

[15] = 0.05 M; [11] = 0.05 M; Zn = 0.04 mmol, solvent = DMA; 11 ( ) , 12 ( ) and 20

( ) were observed.

5.1.3. 11 activation with (Phen)Ni (o-Tol)Br 15 and Zn

(eq S10)

To a 2 mL crimp-top vial was added (Phen)Ni(o-Tol)Br 15 (8.2 mg, 0.02 mmol), ground,

activated zinc (2.0 equiv.) and DMA (0.4 mL), which was then placed in a shaker heated

to 50 °C, with mixing speed at 850 rpm for 2 hrs. The mixture was quenched with saturated

ammonium chloride. The mixture was extracted by diethyl ether and the resulting organic

layer was collected, washed with water twice, dried over Na2SO4, filtered, concentrated

under N2 and analyzed by 1H NMR spectroscopy.

S23


conditions: [15] = 0.05 M; [11] = 0.05 M; Zn = 0.04 mmol, solvent = DMA; All 11 was

consumed, 12 ( ) and 20 ( ) were observed.

5.1.4. 11 activation with reduced product (Phen)Ni (Mes) 21-a

(eq S11)

To a 2 mL crimp-top vial was added (Phen)Ni (Mes)Br 21 (8.6 mg, 0.02 mmol), ground,

activated zinc (2.0 equiv.) and DMA (0.4 mL), which was then placed in a shaker heated

to 50 °C, with mixing speed at 850 rpm overnight. The resulting purple-red solution was

filtered with glass wool into a new 2 mL crimp-top vial, followed by adding 11 (6.4 mg,

0.02 mmol) and placed back to the shaker. After reacting overnight, the mixture was

quenched with saturated ammonium chloride. The mixture was extracted by diethyl ether

and the resulting organic layer was collected, washed with water twice, dried over Na2SO4,

filtered, concentrated under N2 and analyzed by 1H NMR spectroscopy.

S24


conditions: [21] = 0.05 M; [11] = 0.05 M; Zn = 0.04 mmol (Filtered off before adding 11),

solvent = DMA; 11 ( ) and 20 ( ) were observed.

5.1.5. 11 activation with (Phen)Ni(Mes)Br 15 and Zn

(eq S12)

To a 2 mL crimp-top vial was added (Phen)Ni(Mes)Br (8.6 mg, 0.02 mmol), 11 (6.4 mg,

0.02 mmol), ground, activated zinc (2.0 equiv.) and DMA (0.4 mL), which was then placed

in a shaker heated to 50 °C, with mixing speed at 850 rpm. After reacting overnight, the

mixture was quenched with saturated ammonium chloride. The mixture was extracted by

diethyl ether and the resulting organic layer was collected, washed with water twice, dried

over Na2SO4, filtered, concentrated under N2 and analyzed by 1H NMR spectroscopy.

S25


conditions: [21] = 0.05 M; [11] = 0.05 M; Zn = 0.04 mmol, solvent = DMA; All 11 was

consumed and corresponding 20 ( ) was observed.

5.1.6. 11 activation with (Phen)Ni (Mes)Br 21

(eq S13)

To a 2 mL crimp-top vial was added (Phen)Ni(Mes)Br (8.6 mg, 0.02 mmol), 11 (6.4 mg,

0.02 mmol) and DMA (0.4 mL), which was then placed in a shaker heated to 50 °C, with

mixing speed at 850 rpm. After reacting overnight, the mixture was quenched with

saturated ammonium chloride. The mixture was extracted by diethyl ether and the resulting

organic layer was collected, washed with water twice, dried over Na2SO4, filtered,


S26


conditions: [21] = 0.05 M; [11] = 0.05 M; solvent = DMA; 11 ( ) was remained.

5.2. Zn Activation Pathway

5.2.1. 1 activation with Zn.

(eq S14)

To a 2 mL crimp-top vial was added 1 (7.0 mg, 0.025 mmol), ground, activated zinc (2.0

equiv.) and DMA 0.5mL, which was then placed in a shaker heated to 50°C, with mixing

speed at 850 rpm. After reacting overnight, the mixture was quenched with saturated

ammonium chloride. The mixture was extracted by diethyl ether and the resulting organic

layer was collected, washed with water twice, dried over Na2SO4, filtered, concentrated

under N2 and analyzed by 1H NMR spectroscopy.

S27


conditions: [1] = 0.05 M; Zn = 0.05 mmol; solvent = DMA; 1 ( ) and 1-a ( ) were

observed.

5.2.2. The activation of 11 with Zn.

(eq S15)

To a 2 mL crimp-top vial was added 11 (6.4 mg, 0.02 mmol), ground, activated zinc (2.0

equiv.) and DMA (0.4 mL), which was then placed in a shaker heated to 50 °C, with

mixing speed at 850 rpm. After reacting overnight, the mixture was quenched with

saturated ammonium chloride. The mixture was extracted by diethyl ether and the

resulting organic layer was collected, washed with water twice, dried over Na2SO4,

filtered, concentrated under N2 and analyzed by 1H NMR spectroscopy.

S28


conditions: [11] = 0.05 M; Zn = 0.04 mmol; solvent = DMA; 11 ( ) and 11-a ( ) were

observed.

6. Ni Loading Control Experiments of Radical Capture and Cyclization Rate

(eq S16)

Trial 1

Ni loading(mM) 23/24 Ratio Yield of 23 (%) Yield of 24 (%)

1.0 0.33 8.4 25

2.5 0.62 13 21

5.0 1.28 8.1 6.3

7.5 1.43 5.9 4.1

10 2.37 10 4.0

Trial 2

1.0 0.23 5.6 25

2.5 0.49 13 27

5.0 1.04 13 12

S29

7.5 0.80 4.9 6.2

Trial 3a

1.0 0.36 10 28

2.5 0.68 18 26

5.0 0.90 12 13

7.5 1.57 14 8.6

10 2.46 20 8.1

Table S1. Ratio of 23/24 and yields of 23 and 24 from three independent trials. Reaction

conditions: [23] = 0.05 M, [PhBr] = 0.1 M, Zn = 0.1 mmol, solvent = DMA, agitation rate

= 900 rpm. The yield and ratio are determined by GC analysis with 1,3,5-

trimethoxybenzene as internal standard.

a:[PhBr] = 0.2 M.

7. Calculation of Radical Capture and Cyclization Rate

The rate for cyclization of hept-6-enyl is estimated from previous experiments in radical

initiation and capture by Bu3SnH.1 The Thorpe-Ingold effect of tosylamine in substrate 22

is not accounted for due to the lack of available data. At steady state, [16] is estimated to

be 0.0025 M with 0.005 M catalyst loading, given the distribution of 16 and 14 based on

NMR measurements. Eq S17 reveals that the lower limit for k2 is 107 Ms-1.

𝟐𝟒

𝟐𝟑=

𝑘4

𝑘2[𝑁𝑖]=

𝑘4

𝑘2∗0.0025𝑀= 1.1 (eq S17).

𝑘2 =𝑘4

0.0025𝑀∗ 1.1

𝑘4 > 2.7 ∗ 104 𝑠−1

𝑘2 > 1.2 * 107 𝑀𝑠−1

The upper limit of k2 is estimated based on lack of direct coupling product with substrate

11. The radical cyclization rate of gem-dimethyl hexa-5-enyl is estimated to be 1.6 x 107s-

1. According to eq S19, the upper limit of k2 is 6.4 x 109 Ms-1

𝑘2[𝑁𝑖] < 𝑘5−𝑒𝑥𝑜 (eq S18).

𝑘5−𝑒𝑥𝑜 = 1.6 ∗ 107 𝑠−1

S30

𝑘2 < 6.4 ∗ 109 𝑀𝑠−1 (eq S19).

8. Synthesis and Characterization of Radical Clock Substrates and Ni Complexes

Compound 1 and 11 were synthesized following the literature report2.

Radical Clock Synthesis

Aldehyde S1:

A solution of 11 in DCM (954 mg, 3 mmol, 0.2 M) was cooled to -78 °C. Ozone was

allowed to bubble through the solution for 10 min until the solution became blue. After

addition of excess Me2S, the reaction was warmed to rt and stirred overnight. The resulting

mixture was washed with water. The combined organic layers were dried over MgSO4,

filtered, and concentrated by rotary evaporation to afford 1.15 g (99% yield) light yellow

oil, which was used without further purification.

1H NMR (400 MHz, Chloroform-d) δ 9.64 (t, J = 1.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H),

7.34 (d, J = 8.0 Hz, 2H), 4.02 (d, J = 1.1 Hz, 2H), 3.60 – 3.47 (m, 4H), 2.45 (s, 3H).

13C NMR (101 MHz, Chloroform-d) δ 197.5, 144.5, 135.5, 130.2, 127.5, 58.8, 51.7, 30.0,

21.7.

HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H15NO3SBr 319.9951, found 319.9948.

S31

Radical Clock 9:

A solution of (cyclopropylmethyl)triphenylphosphonium bromide in THF (1.02 mL, 1.6

M in Hexane, 1.05 eq, synthesized based on the literature procedure3) was cooled to -78 °C,

followed by dropwise addition of nBuLi. The mixture was stirred for 1 h, followed by

dropwise addition of the aldehyde (1.56 mmol, 500 mg, in 3 mL THF). The resulting

mixture was warmed to rt and stirred overnight. The reaction was washed with sat. NH4Cl

and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4,

filtered, concentrated by rotary evaporation and purified by column chromatography

(hexane: ethyl acetate = 20 ~ 8:1) to give 70.6 mg (13% yield) of a mixture of the E/Z

isomers in a ratio of 1:1.6 of light as a yellow oil.

1H NMR (400 MHz, Chloroform-d) δ 7.71 (dd, J = 10.4, 8.3 Hz, 2H), 7.39 – 7.26 (m, 2H),

5.38 – 5.25 (dt, J = 10.5 Hz, 6.8Hz, 0.27H, E isomer), 5.25 – 5.02 (m, 1H), 4.93 (t, J = 10.5

Hz, 0.67H, Z isomer), 3.98 (dd, J = 7.3, 1.3 Hz, 1.4H, Z isomer), 3.74 (dd, J = 6.9, 1.2 Hz,

0.6H, E isomer), 3.57 – 3.30 (m, 4H), 2.43 (s, 3H), 1.52 – 1.42 (m, 0.75H, Z isomer), 1.39

– 1.27 (m, 0.25H, E isomer), 0.86 – 0.64 (m, 2H), 0.35 (ddt, J = 17.5, 6.5, 4.5 Hz, 2H).

13C NMR (101 MHz, Chloroform-d) δ 143.7, 140.5, 140.1, 136.6, 130.0, 129.9, 127.4,

127.4, 121.5, 121.3, 51.3, 49.0, 48.7, 46.1, 29.7, 29.6, 21.7, 13.5, 9.7, 7.4, 7.0.

HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H21NO2SBr 358.0471, found 358.0454.

Radical Clock Experiment:

The reaction was set up in accordance with the standard procedure3.

The mixture was quenched with sat. NH4Cl, and extracted by diethyl ether twice and the

resulting organic layer was collected, washed with brine, dried over Na2SO4, filtered and

concentrated by rotary evaporation and purified by column chromatography (hexane: ethyl

acetate = 20 ~ 10:1). Colorless oil was collected. 84% yield (NMR) and E/Z isomer ratio

S32

is 2:1 (GC)

E isomer:

1H NMR (400 MHz, Chloroform-d): δ 7.78 – 7.67 (m, 2H), 7.39 – 7.25 (m, 4H), 7.25 –

7.15 (m, 1H), 7.21 – 7.10 (m, 2H), 5.46 (dtd, J = 15.4, 6.7, 1.0 Hz, 1H), 5.29 – 5.04 (m,

1H), 3.55 – 3.10 (m, 3H), 2.88 (dd, J = 9.9, 8.2f Hz, 1H), 2.87 – 2.55 (m, 3H), 2.45 (s, 3H),

2.37 – 2.20 (m, 2H), 1.92 (dtd, J = 13.5, 6.8, 3.8 Hz, 1H), 1.57 – 1.32 (m, 1H).

13C NMR (101 MHz, Chloroform-d, 25 °C): δ 143.45, 141.76, 134.15, 131.14, 130.08,

129.76, 128.57, 128.41, 127.68, 125.99, 53.10, 47.61, 41.73, 35.80, 34.32, 32.13, 21.67.

Z isomer:

1H NMR (400 MHz, Chloroform-d): δ 7.69 (d, J = 8.3 Hz, 2H), 7.36 – 7.27 (m, 4H), 7.22

– 7.16 (m, 1H), 7.15 – 7.10 (m, 2H), 5.41 (dtd, J = 10.7, 7.5, 1.0 Hz, 1H), 5.08 (dd, J =

10.7, 9.0 Hz, 1H), 3.36 – 3.24 (m, 2H), 3.17 (ddd, J = 9.9, 9.0, 7.1 Hz, 1H), 2.81 – 2.73 (m,

1H), 2.70 (dd, J = 9.4, 8.5 Hz, 1H), 2.61 (q, J = 7.3 Hz, 2H), 2.43 (s, 3H), 2.29 (qd, J =

7.4, 1.5 Hz, 1H), 1.73 (dtd, J = 13.0, 6.8, 3.4 Hz, 1H), 1.38 (dt, J = 12.4, 8.8 Hz, 1H).

13C NMR (101 MHz, Chloroform-d): δ 143.47, 141.60, 134.09, 130.96, 129.91, 128.63,

128.44, 127.21, 126.14, 116.97, 66.00, 53.18, 47.71, 36.88, 35.89, 32.38, 29.66.

HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24NO2S 356.1684 and 357.1718, found

356.1685 and 357.1711.

Alcohol S2:

To a solution of amine (185.4 g, 1.5 mmol, 1 equiv.) and toluenesulfonyl chloride (314.6

g, 1.1 equiv.) in DCM (3 mL, 0.45 M) at 0°C was added triethylamine (1.04 mL, 7.5 mmol,

5 equiv.). The reaction mixture was warmed to ambient temperature and stirred for 24

hours. The reaction was quenched with NaHCO3 solution and washed with H2O. The

aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were washed

with brine, dried over MgSO4, filtered, and concentrated. The crude product, sulfonamide

(306.8 mg, 85% yield), was used in the next step without further purification.

S33

1H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H),

5.20 (bs, 1H), 3.43 (d, J = 6.0 Hz, 2H), 2.44 (s, 3H), 0.84 – 0.74 (m, 2H), 0.64 (t, J = 3.6

Hz, 2H).

Allylamine S3:

To a solution of sulfonamide (96.2 mg, 0.32 mmol) in MeCN (0.5 M) was added allyl

bromide (5 equiv.), K2CO3 (5 equiv.). The reaction mixture was heated to reflux and

stirred for 16 hours. The reaction was quenched with the NH4Cl solution and the aqueous

layer was extracted with DCM (3x). The combined organic layers were washed with

brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by

flash chromatography (Hexane: ethyl acetate 1:1). S3 was obtained as a colorless oil

(78.6 mg, 85%)

1H NMR (400 MHz, Chloroform-d) δ 7.76 – 7.67 (m, 2H), 7.33 – 7.24 (m, 2H), 5.89

(ddtd, J = 16.7, 10.1, 6.3, 1.5 Hz, 1H), 5.25 – 5.10 (m, 2H), 3.98 (dq, J = 6.4, 1.5 Hz, 2H),

3.59 (d, J = 5.8 Hz, 2H), 2.76 (td, J = 5.9, 1.8 Hz, 1H), 2.43(s, 3H), 0.95 – 0.76 (m, 4H).

HRMS (ESI-TOF) m/z: [M+H-H2O]+ calcd for C14H18NO2S 264.1053, found 264.1056.

Radical Clock 7:

To a solution of triphenylphosphine (3 equiv.) in THF (0.25 M) at 0°C was added CBr4

(3 equiv.). This solution was stirred at 0 °C for 5 minutes until the solution transforms

into a bright yellow color. The solution of the alcohol (298.1mg, 1.1mmol) in THF (5

mL) was then added dropwise. The reaction mixture was warmed to ambient temperature

and was stirred for 16 hours. After quenching with H2O, the aqueous layer was extracted

with ethyl acetate (3x). The combined organic layers were washed with brine, dried over

MgSO4, filtered, and concentrated. The crude product was purified by flash

chromatography (hexane: ethyl acetate = 20 ~ 10:1) to afford 7 as a white solid (308.6

mg, 84%)

S34

1H NMR (400 MHz, Chloroform-d) δ 7.77 – 7.67 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.86

– 5.73 (m, 1H), 5.18 – 5.03 (m, 2H), 4.11 (dt, J = 6.0, 1.6 Hz, 2H), 3.62 (bs, 1H), 2.43 (s,

3H), 1.29 (bs, 2H), 0.96 (bs, 2H).


42.3, 41.6, 32.7, 21.7.

HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H19NO2SBr 344.0320 and 346.0299, found

344.0318 and 346.0293.

The reaction was set up based on the standard procedure2. The product 8 was purified by

column chromatography (hexane: ethyl acetate = 20 ~ 10:1). Colorless oil was collected.

48% yield (NMR).

1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.61 (m, 2H), 7.34 – 7.13 (m, 5H), 7.13 –

7.04 (m, 2H), 5.03 (d, J = 1.5 Hz, 1H), 4.81 (d, J = 1.8 Hz, 1H), 4.05 (ddd, J = 13.2, 4.0,

2.1 Hz, 1H), 2.84 (dd, J = 13.1, 10.6 Hz, 1H), 2.52 (dd, J = 13.6, 6.8 Hz, 1H), 2.43 (s,

3H), 2.40 (dd, J = 13.6, 6.8 Hz, 1H), 2.16 (dt, J = 13.8, 4.0 Hz, 1H), 1.86 (dddd, J = 13.8,

12.1, 4.7, 1.7 Hz, 1H), 1.68 (dddq, J = 18.3, 11.0, 7.5, 3.9 Hz, 2H), 1.32 – 1.12 (m, 1H).


126.5, 108.6, 52.6, 39.9, 36.6, 31.1, 29.9, 21.7.

HRMS (ESI-TOF) m/z: [M+H]+ calcd for C20H24NO2S 342.1521, found 342.1524.

Complex (Phen)NiBr2 14 was synthesized by literature report.4

1H NMR (500 MHz, DMSO-d6) δ 48.83 (bs, 2H), 45.77(bs, 2H), 25.28 (bs, 2H), 23.52 (bs,

2H), 19.86 – 16.77 (m, 4H).

UV-Vis (DMA, 23 °C): 635 nm (3.3 M-1cm-1)

Complex (Phen)Ni (Mes)Br 21 was synthesized followed by modified literature report.5

S35

To a 20 mL scintillation vial was added phenanthroline (36 mg, 0.2 mmol), Ni(cod)2 (55

mg, 0.2 mmol) and THF (8 mL). MesBr (47.8 mg, 1.2 equiv.) was added the next day after

stirring the reaction mixture at room temperature overnight. After stirring at room

temperature overnight an additional day, the solution changed from dark purple to red and

was then concentrated under reduced pressure. The solid was washed several times with

dry n-pentane and then dried under vacuum for 2 hrs to give complex 21 (60 mg, 69%

yield) as a red solid. 1H NMR matched the literature report6.

Complex (Phen)Ni (o-Tol)Br 15

Following the same procedure reported for (Phen)Ni(Mes)Br, using (o-Tol)Br in place of

MesBr, complex 15 was afforded (64.1 mg, 78%) as a red solid.

1H NMR (500 MHz, Acetone-d6) δ 9.61 (dd, J = 5.1, 1.5 Hz, 1H), 8.93 – 8.63 (m, 2H),

8.27 – 8.11 (m, 2H), 8.06 (dd, J = 8.2, 5.0 Hz, 1H), 7.80 – 7.64 (m, 1H), 7.60 (dd, J = 7.3,

1.4 Hz, 1H), 7.43 (dd, J = 5.4, 1.4 Hz, 1H), 6.95 – 6.61 (m, 4H), 3.06 (s, 3H).

1H NMR (500 MHz, DMA-d9) δ 9.5 (d, J = 4.7 Hz, 1H), 8.8 (dd, J = 19.5, 8.0 Hz, 2H), 8.2

(q, J = 8.8 Hz, 2H), 8.1 (dd, J = 8.1, 4.8 Hz, 1H), 7.8 – 7.7 (m, 1H), 7.5 (d, J = 7.2 Hz, 1H),

7.3 (d, J = 4.9 Hz, 1H), 6.7 – 6.6 (m, 3H), 3.0 (s, 3H).

UV-Vis (THF, 23 °C): 532 nm (shoulder, 2164.5 M-1cm-1); 487 nm (3304.1 M-1cm-1); 451

nm (shoulder, 2835.6 M-1cm-1).

Complex (Phen)Ni(Ph)Br 16

Following the same procedure reported for (Phen)Ni(Mes)Br, except for a shortened

stirring time (5 min) following the addition of PhBr, complex 16 was afforded (54.1mg,

68%) as a red solid.

NMR shows PhBr residue due to low stability of 16 in solution.

1H NMR (500 MHz, Acetone-d6) δ 9.61 (s, 1H), 8.78 (m, 2H), 8.19 (d, J = 7.6 Hz, 2H),

8.05 (s, 1H), 7.74 (s, 1H), 7.58 (d, J = 7.2 Hz, 3H), 6.92 (t, J = 7.3 Hz, 2H), 6.78 (t, J = 7.3

Hz, 1H).

UV-Vis (DMA, 23 °C): 510 nm (shoulder); 466 nm (shoulder); 401 nm.

S36

*phen was synthesized following the literature report7.

Complex Ni(phen*)Br2 17 was synthesized following a modified literature procedure8.

To a stirred solution of (s-Bu)2Phen (160 mg, 0.60 mmol) in EtOH (5 mL)

was added NiBr2(DME) (572 mg, 1.8 mmol) at room temperature. After stirring for

overnight at room temperature, the purple solid was collected after filtration and washed

with Et2O. The solid was dissolved in CH3CN and heated to reflux. After cooling to room

temperature, crystallization in the fridge overnight gave grape-purple crystals.

The crystals were filtered and washed with Et2O and dried under reduced pressure for

overnight to afford 17 (167 mg, 54%) as a purple crystal.

1H NMR (500 MHz, Acetone-d6) δ 80.93 (s, 2H), 50.06 – 40.10 (bs, 1H), 27.00 (s, 2H),

25.73 (s, 2H), 14.11 (s, 1H), 13.92 (s, 1H), 12.59 (s, 1H), 12.43 (s, 1H), 11.01 (s, 3H),

10.80 (s, 3H), 2.85 (s, 3H), 2.57 (s, 3H).

UV-Vis (Acetone, 23 °C): 520 nm (237.4 M-1 cm-1)

HRMS (ESI-TOF) m/z: [M-Br]+ calcd for C20H24N2NiBr 429.0476 and 431.0456, found

429.0492 and 431.0499.

Elemental Analysis: C : 47.23 % H : 4.55 % N : 5.48 %

Complex Ni(phen*)Br 18:

To a 20 mL vial was added Ni(phen*)Br2 (10.4 mg, 0.02 mmol), zinc (50.0 equiv.) and

THF (2 mL). The reaction was allowed to stir for 2 hrs at r.t. The resulting dark blue

solution was filtered with glass wool, concentrated, extracted with Et2O, washed with

pentane and dried under vacuum, to yield 18 ((8.5 mg, 98%) as a black solid.

The X-ray quality crystals were obtained by cooling the acetone solution at -35oC for 3

days.

1H NMR (500 MHz, Acetone-d6) δ 37.64 – 33.94 (m, 2H), 26.43 – 23.01 (m, 3H), 11.64

S37

(s, 3H), 3.87 – 3.07 (m, 3H), 2.01 – 1.59 (m, 8H), 0.57 – -0.57 (m, 12H), -17.46 – -24.55

(m, 2H).

UV-Vis (THF, 23 °C): 663 nm; 603 nm(shoulder); 474 nm(shoulder); 434 nm;

Compound 23:

To a solution of sulfonamide (689.3 mg, 3.11 mmol) in MeCN (0.5 M) was added 1-

Bromo-3-phenylpropane (1 equiv.), K2CO3 (3 equiv.). The reaction mixture was heated

to reflux and stirred for 16 hours. The reaction mixture was filtered and concentrated. The

crude product was purified by flash chromatography (Hexane: ethyl acetate 20-5:1). 23

was obtained as a colorless oil (607.2 mg, 59%)

1H NMR (400 MHz, Chloroform-d) δ 7.69 – 7.64 (m, 2H), 7.32 – 7.24 (m, 4H), 7.23 –

7.09 (m, 3H), 5.63 (ddt, J = 16.7, 9.9, 6.4 Hz, 1H), 5.18 – 5.02 (m, 2H), 3.78 (dt, J = 6.6,

1.4 Hz, 2H), 3.24 – 3.03 (m, 2H), 2.59 (t, J = 7.8 Hz, 2H), 2.42 (s, 3H), 1.84 (tt, J = 9.0,

6.7 Hz, 1H).


127.3, 126.1, 118.9, 50.9, 47.1, 33.0, 29.9, 21.7.

9. Crystallographic data for Ni(phen*)Br 18

Formula: C20H24BrN2Ni, Mr = 431.02, black needle, 0.030mm x 0.070mm x 0.360 mm,

S38

space group P 1 21/n 1, a = 7.7077(11) Å, b = 19.398(3) Å, c = 12.6503(19) Å, α = 90°, β

= 106.8787(18)°, γ = 90°, V = 1809.9(5) Å3, Z = 4, ρcalcd = 1.582 g/cm3, μ = 3.283 mm–1 ,

F(000) = 884, T = 100(2) K, R1 = 0.0465, wR2 = 0.0969, 3201 independent reflections.

10. Electrochemical Analysis

(Phen)NiBr2 14:

Figure S31. Cyclic voltammetry (CV) of (Phen)NiBr2 14. Solvent = DMA, temperature =

25 °C, concentration = 1 – 2 mM. Fc was added as the internal standard. Electrolyte =

NBu4Br (0.4 M), scan rate = 650 mV/s. NiII/NiI Ep/2 = –0.86 V vs. SHE

(Phen)Ni (o-Tol)Br 15:

S39

Figure S32. Cyclic voltammetry (CV) of (Phen)Ni (o-Tol)Br 15. Solvent = DMA,

temperature = 25 °C, concentration = 1 – 2 mM. Fc was added as the internal standard.

Electrolyte = NBu4Br (0.4 M), scan rate = 650 mV/s. NiII/NiI EP/2 = –1.12 V vs. SHE

Ni(phen*)Br2 17 :

Figure S33. Cyclic voltammetry (CV) of Ni(phen*)Br2 17. Solvent = THF, temperature

= 25 °C, concentration = 1 mM. Fc was added as the internal standard. Electrolyte =

NBu4PF6 (0.4 M), scan rate = 50 mV/s. NiII/NiI EP/2 = –0.69 V vs. SHE

S40

Ni(phen*)Br 18:

Figure S34. Cyclic voltammetry (CV) of Ni(phen*)Br 18. Solvent = THF, temperature =

25 °C, concentration = 1 mM. Fc was added as the internal standard. Electrolyte =

NBu4PF6 (0.4 M), scan rate = 50 mV/s. NiI/Ni0 EP/2 = –1.37 V vs. SHE

ZnBr2:

Figure S35. Cyclic voltammetry (CV) of ZnBr2. Solvent = THF, temperature = 25 °C,

concentration = 1 mM. Fc was added as the internal standard. Electrolyte = NBu4PF6 (0.4

M), scan rate = 50 mV/s ZnII/Zn0 EP/2 = –0.79 V vs. SHE

S41

Figure S36. Cyclic voltammetry (CV) of ZnBr2. Solvent = DMA, temperature = 25 °C,

concentration = 1 – 2 mM. Fc was added as the internal standard. Electrolyte = NBu4BF4

(0.4 M), scan rate = 120 mV/s. ZnII/Zn0 EP/2 = –1.26 V vs. SHE

11. NMR Spectra

Figure S37. (Phen*)NiBr2 17 in Acetone-d6. Probe temperature = 25 oC.

(Phen*)NiBr2 17

S42

Figure S38. (Phen)Ni (o-Tol)Br 15 in DMA-d9. Probe temperature = 25 oC.

Figure S39. Ni(phen*)Br 18 in Acetone-d6. Probe temperature = 25 oC.

(Phen)Ni (o-Tol)Br 15

(Phen*) NiBr 18

S43

Figure S40. (Phen)Ni(Ph)Br 16 in Acetone-d6. Probe temperature = 25 oC.

Figure S41. 1H NMR of S1 in CDCl3. Probe temperature = 25 oC.

(Phen)Ni(Ph)Br 16

S44

Figure S42. 13C NMR of S1 in CDCl3. Probe temperature = 25 oC.

Figure S43. 1H NMR of 9 in CDCl3. Probe temperature = 25 oC.

S45

Figure S44. 13C NMR of 9 in CDCl3. Probe temperature = 25 oC.

Figure S45. HSQC of 9 in CDCl3. Probe temperature = 25 oC.

S46



+

+

S47


Figure S49. 1H NMR of 10-cis in CDCl3. Probe temperature = 25 oC.

S48

Figure S50. 1H NMR of 10-trans in CDCl3. Probe temperature = 25 oC.


S49



S50



S51



S52


Figure S59-1. 1H NMR of 23 in CDCl3. Probe temperature = 25 oC.

S53

Figure S59-2. 13C NMR of 23 in CDCl3. Probe temperature = 25 oC.

Figure S60. 1H NMR of 14 in DMSO-d6. Probe temperature = 25 oC.

(Phen)NiBr2 14

S54

Figure S61. 1H NMR of 19 in DMSO-d6. Probe temperature = 25 oC.


S55

12. UV/Vis Spectra

(Phen)NiBr2 14 (DMA, 23 oC )

(Phen)Ni(Ph)Br 16 (DMA, 23 oC )

S56

(Phen)Ni(o-Tol)Br 15 (THF, 23 oC)

(Phen*)NiBr2 17 (Acetone, 23 oC )

S57

13. EPR Experiments

Figure S63. X-Band EPR Spectrum of complex 18. Temperature = 10 K, solvent =

Toluene. Microwave frequency = 9.380 GHz, power = 0.63 mW, modulation amplitude =

1 mT/100 kHz.

(Phen*)NiBr 18 (THF, 23 oC)

S58

Figure S64. X-Band EPR Spectrum of complex 19. Temperature = 10 K, solvent = DMA.

Spectroscopic parameters: Microwave frequency = 9.380 GHz, power = 0.63 mW,

modulation amplitude = 1 mT/100 kHz.

Figure S65. 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 = 2.003, A = 22.5 MHz. Microwave frequency = 9.380 GHz,

power = 0.63 mW, modulation amplitude = 1 mT/100 kHz.

S59

14. DFT Calculations

Input File for Energy and MullikenSpin Density Calculation of Ni(phen*)Br 18

! UKS B3LYP RIJCOSX SlowConv TightSCF def2-SV(P) def2-SVP/J Normalprint UCO

OPT

%basis NewGTO 28 "def2-TZVP(-f)" end

NewGTO 7 "def2-TZVP(-f)" end



NewAuxGTO 28 "def2-TZVP/J" end




end

%scf

MaxIter 1500

TolE 1E-7

TolErr 1E-6

end

* xyz 0 2

Ni 0.00000 0.00000 0.00000

Br 0.00000 -0.00000 2.28773

N -1.05759 0.82425 -1.44167

N 1.13883 -0.61617 -1.48181

C -2.20549 1.50709 -1.37578

C -2.82435 2.00313 -2.54333

H -3.66243 2.44531 -2.48147

C -2.22754 1.85205 -3.75834

H -2.64652 2.19638 -4.53769

C -0.99194 1.18727 -3.85949

C -0.46228 0.67014 -2.65555

C 2.24621 -1.38288 -1.45950

C 2.99748 -1.57942 -2.62719

H 3.78079 -2.11586 -2.58874

C 2.63000 -1.01923 -3.81804

H 3.15854 -1.14804 -4.59731

C 1.45764 -0.24996 -3.86953

C 0.74996 -0.08111 -2.67419

C -0.24609 1.01155 -5.06143

H -0.58728 1.36249 -5.87646

C 0.92555 0.36114 -5.06608

H 1.41923 0.29960 -5.87603

C -2.80532 1.68298 -0.01524

S60

H -2.04255 1.68016 0.63089

C -3.52537 3.02309 0.17133

H -3.86751 3.08502 1.08659

H -4.27044 3.08437 -0.46218

H -2.89607 3.75686 0.00678

C -3.65342 0.47729 0.32146

H -4.44619 0.46469 -0.27176

H -3.13065 -0.34465 0.14463

C -4.11401 0.46662 1.75667

H -4.59154 -0.36891 1.94023

H -4.71323 1.22654 1.91256

H -3.33696 0.53649 2.34932

C 2.55416 -2.04041 -0.13644

H 2.42492 -1.34636 0.57187

C 3.98748 -2.53252 -0.02149

H 4.17630 -2.77126 0.90981

H 4.59976 -1.82308 -0.30782

H 4.10878 -3.31947 -0.59215

C 1.51903 -3.15053 0.12489

H 0.61056 -2.77621 -0.00148

H 1.64405 -3.86847 -0.54409

C 1.60882 -3.75653 1.52041

H 2.58652 -4.16485 1.66971

H 0.87912 -4.53278 1.61980

H 1.42387 -2.99742 2.25147

*

%plots format cube

dim1 100 dim2 100 dim3 100

SpinDens("Ni(disBuphen)Br.cube");

end

15. References

1. (a) Beckwith, A. L. J.; Moad, G., Intramolecular addition in hex-5-enyl, hept-6-

enyl, and oct-7-enyl radicals. J. Chem. Soc. Chem. Commun. 1974, 12, 472-473 ; (b)

Chatgilialoglu, C.; Newcomb, M., Hydrogen Donor Abilities of the Group 14 Hydrides. In

Advances in Organometallic Chemistry Volume 44, 1999; pp 67-112.

2. Kuang, Y.; Wang, X.; Anthony, D.; Diao, T., Ni-catalyzed two-component

reductive dicarbofunctionalization of alkenes via radical cyclization. Chem. Comm. 2018,

54, 2558-2561.

3. Lee, R. J.; Lindley, M. R.; Pritchard, G. J.; Kimber, M. C., A biosynthetically

inspired route to substituted furans using the Appel reaction: total synthesis of the furan

fatty acid F5. Chem. Comm. 2017, 53, 6327-6330.

S61

4. Khake, S. M.; Jain, S.; Patel, U. N.; Gonnade, R. G.; Vanka, K.; Punji, B.,

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

Bromide. Organometallics 2018, 37, 2037-2045.

5. Jia, X.-G.; Guo, P.; Duan, J.; Shu, X.-Z., Dual nickel and Lewis acid catalysis for

cross-electrophile coupling: the allylation of aryl halides with allylic alcohols. Chem. Sci.

2018, 9 (3), 640-645.

6. Yakhvarov, D. G.; Petr, A.; Kataev, V.; Büchner, B.; Gómez-Ruiz, S.; Hey-

Hawkins, E.; Kvashennikova, S. V.; Ganushevich, Y. S.; Morozov, V. I.; Sinyashin, O. G.,

Synthesis, structure and electrochemical properties of the organonickel complex

[NiBr(Mes)(phen)] (Mes = 2,4,6-trimethylphenyl, phen = 1,10-phenanthroline). J.

Organomet. Chem. 2014, 750, 59-64.

7. Wang, T.; Chen, F.; Qin, J.; He, Y.-M.; Fan, Q.-H., Asymmetric Ruthenium-

Catalyzed Hydrogenation of 2- and 2,9-Substituted 1,10-Phenanthrolines. Angew. Chem.

Int. Ed. 2013, 52, 7172-7176.

8. Venning, A. R. O.; Kwiatkowski, M. R.; Roque Peña, J. E.; Lainhart, B. C.;

Guruparan, A. A.; Alexanian, E. J., Palladium-Catalyzed Carbocyclizations of Unactivated

Alkyl Bromides with Alkenes Involving Auto-tandem Catalysis. J. Am. Chem. Soc. 2017,

139, 11595-11600.

download fileview on ChemRxivSupporting information.pdf (5.33 MiB)



Mechanism of Ni-Catalyzed Reductive 1,2-

Dicarbofunctionalization of Alkenes



New York, NY 10003


ABSTRACT

Ni-catalyzed cross-electrophile coupling reactions have emerged as an appealing method to

construct organic molecules without the use of stoichiometric organometallic reagents. The

mechanisms are complex: plausible pathways, dubbed “radical chain” and “sequential reduction”,

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 via a “sequential reduction” pathway. The

reduction of Ni by Zn is the turnover-limiting step, consistent with two Ni(II) species present as

the catalyst resting-state. Zinc is only sufficient to reduce (phen)Ni(II) to a Ni(I) species. As a

result, commonly proposed Ni(0) intermediates do not form under these conditions. (Phen)Ni(I)–

Br selectively activates aryl bromides via bimolecular oxidation addition, whereas alkyl

bromides are activated by (phen)Ni(I)–Ar through halogen-atom abstraction to afford radicals.

These results answer some long-standing questions in Ni-catalyzed cross-coupling reactions, and

could provide insight into achieving selectivity between different electrophiles in future reaction

design.

INTRODUCTION

Nickel-catalyzed cross-coupling reactions have advanced to become powerful methods for

constructing organic molecules. 1 In particular, 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.1f,i,2 Understanding the

mechanisms of Ni-catalyzed cross-coupling reactions could inform the design of catalysts and

the control of selectivity, but it remains 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 The mechanisms appear to be system-dependent. While

(NHC)Ni catalysts lead to two-electron redox processes mediated by Ni(0)/Ni(II)

intermediates,5c,5l,6 catalysts with chelating ligands often involve radical pathways going through

Ni(0)/Ni(I)/Ni(II)/Ni(III) intermediates.5

Previous efforts to characterize the mechanisms of Ni-catalyzed cross-electrophile coupling

reactions leave many key questions unanswered. Evidence for distinguishing “radical chain”

from “sequential reduction” pathways remains ambiguous (see elaborations below, Scheme 1).5l

This remains an important distinction as the mechanism and sequence of activations of different

electrophiles, which differ between the pathways, are critical to achieving chemoselectivity in

cross-electrophile coupling reactions.1g,i Previous experiments have also not identified the

turnover-limiting step and the catalyst resting state, which are critical bottlenecks of catalytic

reactions. Finally, previous studies have focused on substrate activation and C–C bond forming

steps,5e but the reduction of the Ni catalysts by reductants has not been characterized.

Reductive alkene carbofunctionalization with electrophiles has found widespread utility.7 We

recently developed a Ni-catalyzed, reductive, two-component 1,2-dicarbofunctionalization of

alkenes (Scheme 1).8 ,9 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

reductive cross-coupling reactions.10 “Radical Chain” 5e and “Sequential Reduction” 11 pathways

are both plausible (Scheme 1), based on recent mechanistic studies.5l “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).5g The

alternative “Sequential Reduction” mechanism, cycle C, reverses the sequence of electrophile

activation in the “Radical Chain” mechanism. Ni(0) oxidatively adds to PhBr to give

Ni(II)(Ph)(Br) (step vi), followed by a second reduction to form Ni(I)–Ph (step xi). Activation of

the alkyl bromide by Ni(I)–Ph generates a radical (step viii), which combines with Ni(II) to form

a Ni(III) intermediate (step ix).12

Scheme 1. Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes and Possible

Mechanisms

Herein, we report a mechanistic study on the reductive 1,2-dicarbofunctionalization reaction.

Our data differentiates 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

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, to shed light on the presence of radical intermediates. The coupling of 1 with PhBr

afforded dimeric 4 in 8% yield under standard conditions (Scheme 2A).8 Replacing 1,10-

Br

1/2 Zn

PhBr

NiIIIN

N

Ph

Br

Br

Ph

Ph

NiIIN

N

Ph

Br

Ni0N

N

NiIN

NPh

NiIIIN

N

Ph

Br

NiIIN

N

Ph

Br

NiIN

NBrNiII

N

N

Br

Br

NiIN

NBr

1/2 ZnBr2

1/2 Zn

1/2 ZnBr2

ZnZnBr2

“Radical Chain” “Sequential Reduction”

NiIN

N

(A)

(B)

(C)

Z = CR2, NTs or O

Z

Br

ZR

NiBr2∙DME (10 mol%)

Zn (2 equiv)DMA, 50 ºC

+ R–X

(±)N

O

N

N

N

somatostatin SST1 receptor antagonist

modulator of the cholesterol biosythetic pathway

NN

Ph

OEt

X = Br, I, OMsR = alkyl, aryl, and heteroaryl

- broad scope (40 examples)

- good functional group compatibility

- high yields

- mild conditions

N N (12 mol%)

PhBr

(i)

(ii)

(iii)

(iv)

(v)

(vii)

(viii)

(ix)

(x)

(vi)

(xi)

(xi)

phenanthroline with the bulkier neocuproine increases 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).

Scheme 2. Substrate Probes for Determining Radical Intermediates

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.13 Although the C–C bond formed in 4 could have also arisen from reductive

elimination from a dialkyl Ni intermediate, the increased yield of 4 with bulkier neocuproine

suggests that the formation of 4 is metal-free 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 as well. The poor diastereoselectivity reflects a small

energy difference in the chair and boat conformations in the transition states of cyclization,14 and

is consistent with the stereochemistry of previous radical cyclizations initiated by tin hydride.15

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. Kinetic studies were carried out for the coupling of 11 with PhBr to form 12

as the model reaction (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). 16 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.

(1)

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] =

0.1 M; [PhBr] = 0.15 M; (b) [11] = 0.05 M; [PhBr] = 0.1 M.

The time-courses for the reaction shown in eq 1 were fitted into kinetic models using

COPASI, to give the kobs for 12 formation as 7*10-4 s-1 and the kobs for biphenyl byproduct as

1*10-3 M-1s-1 (Figure 2A).17 The formation of 12 exhibits dependence on neither [11] nor [PhBr],

whereas the formation of biphenyl is second-order with respect to [PhBr]. 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 1.18 Attempts to fit the data with other possible orders of [Ni] resulted in no overlay of the

time-courses (Figure S6).

(A)

(B)

Figure 2. (A) Time-courses of the alkene 1,2-dicarbofunctionalization reaction shown in eq 1;

(B) Determining [Ni] order based on the variable time normalization analysis. Reaction

conditions: [11]0 = 0.05 M, [PhBr] = 0.1 M, Zn = 0.1 mmol, solvent = DMA, agitation rate = 850

rpm, (A) [NiBr2•DME] = 5 mM, [phenanthroline] = 6 mM; (B) [(phen)NiBr2•DME] = 2.5, 4, 5,

7.5 mM.

The presence of heterogeneous Zn prompted us to assess mass-transfer limitations. 19

Reactions were mixed in a shaker with orbital agitation. The reaction rate increases with

increasing agitation speed (Figure 3A), but this rate acceleration plateaus with agitation rates

above 1200 rpm. When the agitation rate is fixed to 900 rpm, the reaction rate increases as Zn

loading increases (Figure 3B).

(A)

(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 observed rate dependence on the mixing speed and Zn loading reveal that the reduction

of Ni by Zn is the turnover-limiting step. The reduction occurs in two steps: mass-transfer takes

place when Ni is adsorbed to the surface of Zn, then electron-transfer from Zn to Ni follows. The

rate of reduction is affected by the mass transfer rate (kc), the electron transfer rate (kr), and the

available surface area (S) (eq 2).20 Increasing the mixing speed up to 1200 rpm leads to an

increase in rate due to enhanced convective mass transfer (kc). At agitation speeds greater 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 (kr). The rate is

proportional to the density of available surface area (S/V), where S represents the overall surface

area of Zn and V is the volume of the reaction (eq 2). Increased Zn loading increases the overall

surface area (S), and thus the reaction rate. However, S does not increase proportionally with

increasing Zn loading, because S also depends on the distribution of the heterogeneous particles

in solution. This distribution, in turn, varies based on mixing rate, vessel shape, mixing mode,

and the particle size of Zn.

v = –𝑘c∙𝑘r∙𝑆∙(𝐶l−𝐶s)

(𝑘c+𝑘r)𝑉 (2)

kc: mass-transfer rate

kr: electron transfer rate

S: area of available surface

Cl: the concentration of Ni in solution

Cs: the concentration of Ni on zinc surface

V: volume of the reaction

Collectively, the rate law for the 1,2-dicarbofunctionalization of alkenes is expressed in eq 3.

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 = 7*10-4 s-1[olefin]0[PhBr]0[Ni][Zn]x (3)

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 from eq 1, after 30 min, was withdrawn, 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 4 under standard conditions in DMA-d9 allowed us to take a snapshot of

the catalyst resting state using 1H NMR spectroscopy. After 15 min, we cooled the reaction to

room temperature, filtered to remove Zn and quickly recorded its 1H NMR spectrum (Figure

S17). The reaction solution displays two Ni species, 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).21 Independently prepared (phen)Ni(o-Tol)(Br), by

mixing Ni(cod)2 with phen and o-TolBr,22 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. 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.

(4)

Figure 4. (A) 1H 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 4 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 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 565 nm.

Addition of PhBr to this purple mixture resulted in a red solution with absorptions at 421 and

456 nm, consistent with the spectrum of (phen)Ni(Ph)(Br) 16, as well.

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).

The above 1H NMR data of the reaction mixture and its comparison with independently

prepared complexes support the assignment of 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 that

was 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.

Isolation of Ni Species. The identity of the turnover-limiting step, the reduction of Ni by Zn,

prompted us to closely investigate this fundamental step. The reduction of (phen)NiBr2 14 by Zn

results in a purple mixture, which displays a series of paramagnetic 1H NMR resonances (Figure

S61) and a rhombic EPR signal (Figure S64).23 This observation is inconsistent with d10 Ni(0)

species, as previously proposed in the literature. This purple species, however, is prone to

decomposition, and prevented further characterization.

In order to generate a more stable reduction intermediate, we prepared (phen*)NiBr2 17

(phen* = 2,9-di-sec-butyl-phenanthroline), 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.

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).24 The EPR spectrum of 18 shows a Ni-

centered radical (Figure S63).

(5)

(A)

(B)

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.

Cyclic Voltammetry. The reduction of Ni(II) to Ni(I) by Zn led us to investigate the

reduction potentials of 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,25 but the 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

Complexes Ep/2(NiII/NiI)

(V vs. SHE)

Ep/2((NiI/Ni0)

(V vs. SHE)

(phen)NiBr2 14 -0.86a

(phen)Ni(o-Tol)Br 15 -1.12a

(phen*)NiBr2 17 -0.69b

(phen*)NiBr 18 -1.37b

ZnBr2 Ep/2(ZnII/Zn) -1.26a a In DMA at 25 °C, internal reference = Fc+/Fc, electrolyte = Bu4NBr. b In THF.

Stoichiometric Experiments to Probe Electrophile Activation. Stirring the pale green

(phen)NiBr2 with excess Zn in DMA resulted in a dark purple solution 19. This solution was

0.9470.045

0.045

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 7). This kinetic comparison

experiment suggests that the reduced Ni species 19 reacts with PhBr faster than 11.

Figure 7. 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 for 30 min,

was filtered to remove excess Zn (eq 6). Addition of 2 equiv o-TolBr to this solution 19 led to

formation of (phen)NiBr2 14 and (phen)Ni(o-Tol)(Br) 15 in a ratio of 5:3, evident from the 1H

NMR spectra (Figures S20-S22).

(6)

The paramagnetic 1H NMR spectrum of 19 (Figure S61), EPR signal of a Ni-centered radical

(Figure S64), isolation of (phen*)Ni(I)–Br 18, and cyclic voltammetry studies suggest that 19 is

a Ni(I) species, (phen)Ni(I)–Br. The activation of PhBr by (phen)Ni(I)–Br 19 is faster than alkyl

bromide 11, evident from the competition experiment (Figure 7). 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 (eq 7). 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 decomposition

of 19 in the absence of Zn after filtration.

(7)

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 led to formation of 12 in 21%

yield and dimer 20 in 4% yield (entry 1, Table 2). Reduction of 15 by Zn, followed by removal

of Zn via filtration, led to a purple solution which reacted with 11 to afford 12 and 20 in a higher

conversion relative to that without Zn reduction (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). EPR analysis of the frozen mixture of 21

with Zn reveals an organic centered radical (Figure S65).

Table 2. Stoichiometric Reaction of 15 and 21 with 11.a

Entry Ar Zn

(equiv)

Reaction

Time (h)

11 (%)

12 (%)

20

(%)

1 o-Tol 0 2 70 21 4

2 o-Tol 2b 2 50 37 12

3 o-Tol 2 2 0 50 50

4 Mes 0 12 100 0 0

5 Mes 2b 12 69 0 30

a Yields were determined by 1H NMR spectroscopy with 1,3,5-trimethoxylbenzene as the internal

standard.

b Zn was removed by filtration before addition of 11.

Stoichiometric experiments between 15 and 11 suggest that 15 is capable of activating 11,

but the rate of this background reaction is exceeded by the rate of reduced Ni species reacting

with 11. EPR analysis of the reduction mixture of 21 by Zn supports formation of a Ni(I)–Ar

species upon reduction, where phen is redox-active.25 The formation of dimer 20 implies a

radical intermediate that underwent cyclization and dimerization. The cross-coupling product 12

arises from 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 kept distant from the Ni center by the steric

hindrance. Therefore, 20 is formed exclusively.

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.8 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 8). 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 transmetalation mechanism, reported by Shenvi, where free

radical is absent.5k

Figure 8. The ratio of uncyclizaed/cyclized products (23/24) as a function of [Ni] in the coupling

of 22 with PhBr. Reaction conditions: [22]0 = 0.05 M, [PhBr] = 0.1 - 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. 26 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 8-9). These control experiments and the absence of

carbocyle products reveal that alkyl bromide substrates must be activated by the Ni catalysts.

(8)

(9)

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 Ni(I) intermediates. (phen)Ni(I)–

Br activates PhBr more rapidly than alkyl bromides via a bimolecular oxidative addition.

Reduction of (phen)Ni(Ar)(Br) by Zn followed by addition of alkyl bromides generates radicals

that can combine with Ni to form cross-coupling products.

“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) after the reduction of Ni and activation of PhBr. In the system

under investigation, the kinetic comparison experiment shows that (phen)Ni(I)–Br activates PhBr

more rapidly than alkyl bromides (Figure 7). 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 Ni(II) by Zn is the turnover-limiting step

(Figures 2-5). The reduction rate constant is estimated to be 1 s-1 at a 900-rpm agitation rate. Free

alkyl radicals dimerize with a bimolecular rate constant on the scale of 109 M-1 s-1.27 The

drastically faster radical dimerization than Ni reduction by Zn suggests that the radical

intermediate would not live long enough to be captured by Ni after its reduction. As a result, the

“Radical Chain” pathways are not kinetically plausible in this system.

Evaluation of Mechanism (C) and Revised Mechanism. Our data support part of the

“Sequential Reduction” mechanism shown in Scheme 1C, where PhBr is activated prior to alkyl

bromide. However, the electrochemical potentials of Ni species, the observation of paramagnetic

species upon reduction of Ni(II) by Zn, in combination with the stoichiometric study of the

reduction of (phen*)NiBr2 17 by Zn, establishes that Zn is only sufficient to reduce

(phen)Ni(II)Br2 14 to (phen)Ni(I)Br 19.28 (Phen)Ni(0) is never formed under these conditions.

Accordingly, we revised the “Sequential Reduction” mechanism to exclude Ni(0) intermediates,

and the mechanism shown in Scheme 3 is most consistent with our data. Stoichiometric

experiments reveal that the activation of PhBr by (phen)Ni(I)Br proceeds via bimolecular

oxidative addition to generate (phen)NiBr2 14 and (phen)Ni(Ph)(Br) 16. This step is reminiscent

of previous reports of dinuclear Ni-mediated oxidative addition5d,29 and reductive elimination.30

(Phen)NiBr2 14 and (phen)Ni(Ph)(Br) 16 both exist as the catalyst resting state. They are

separately reduced by Zn, both as the turnover-limiting steps. This proposal accounts for the lack

of kinetic dependence on substrates and the 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 3. Revised Mechanism for Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of

Alkenes

The reduction of 16 by Zn affords (phen)Ni(I)–Ph 25, which activates alkyl bromides to form

radical intermediates, likely via a concerted halogen-atom abstraction mechanism.12b The

presence of a radical intermediate is verified by stereochemical probes and radical clock

substrates (Scheme 2). The reaction of 22 gave 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 4), exhibits a linear correlation with [Ni] (Figure 8). 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 rate range of radical capture 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),31 close to the calculated barrier of 4 kcal/mol.5g

Increasing steric bulk of the ligand increases 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.8

Scheme 4. Proposed Mechanism for Forming 23 and 24 via a Radical Intermediate

Selectivity for Activation of Electrophiles. Our data shed light on the selectivity of cross-

electrophile coupling reactions, which is a result of the steric and electronic properties of Ni

intermediates. Csp2 and Csp3 electrophiles are independently activated by different Ni(I) species

via distinct mechanisms (Scheme 5). (phen)Ni(I)–Br selectively activates Csp2–Br via oxidative

addition, facilitated by the sterically assessible Ni(I)–Br center. In contrast, the increased steric

bulk of (phen)Ni(I)–Ph hinders oxidative addition, but its electron-rich property promotes

halogen-atom abstraction of Csp3–Br to give radicals.12b

Scheme 5. Illustration of Selectivity for Cross-Electrophile Coupling

SUMMARY

The Ni-catalyzed two-component reductive dicarbofuntionalization of alkenes proceeds via a

“Sequential Reduction” pathway. Evidence unambiguously rules out the “Radical Chain”

mechanism. Ni(I)–Br first activates ArBr to form a 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.

The result highlights the importance of catalyst reduction, which has not been recognized in

previous studies. (2) Zn is insufficient to reduce Ni(II) to Ni(I), and Ni(0) is absent. (3)

Bimolecular oxidation addition of PhBr by (phen)Ni(I)–Br precedes activation of alkyl bromides

by (phen)Ni(I)–Ph via concerted halogen-atom abstraction. This sequence accounts for

selectivity observed in cross-electrophile coupling reactions.

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

[email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

We thank Chunhua (Tony) Hu for solving the X-ray crystal structure of complex 18. Lin thanks

Margalit Feuer for editing the manuscript and help with UV-Vis measurements, and Paul

Peterson and John Eng (Princeton University) for assistance with the EPR spectroscopy. This

work was supported by National Institute of Health (NIH) under Award Number

1R01GM127778. Qiao Lin is supported by the MacCracken Fellowship. 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.

REFERENCES

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Alkyl Halides and Pseudohalides with Organometallic Compounds. Adv. Synth. Catal. 2004, 346,

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Haloboranes with Unactivated Olefins. J. Am. Chem. Soc. 2018, 140, 12765-12769. (j) Zhao, X.; Tu,

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nickel-catalyzed reductive radical relay. Nat. Commun. 2018, 9, 3488. (k) Anthony, D.; Lin, Q.;

Baudet, J.; Diao, T., Nickel-Catalyzed Asymmetric Reductive Diarylation of Vinylarenes. Angew.

Chem. Int. Ed. 2019, 58, 3198-3202. (l) Jin, Y.; Wang, C., Ni-catalyzed reductive arylalkylation of

unactivated alkenes. Chem. Sci. 2019, 10, 1780-1785. (m) Tian, Z. X.; Qiao, J. B.; Xu, G. L.; Pang,

X.; Qi, L.; Ma, W. Y.; Zhao, Z. Z.; Duan, J.; Du, Y. F.; Su, P.; Liu, X. Y.; Shu, X. Z., Highly

Enantioselective Cross-Electrophile Aryl-Alkenylation of Unactivated Alkenes. J. Am. Chem. Soc.

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8 Kuang, Y.; Wang, X.; Anthony, D.; Diao, T., Ni-catalyzed two-component reductive

dicarbofunctionalization of alkenes via radical cyclization. Chem. Commun. 2018, 54, 2558-2561.

9 Peng, Y.; Xu, X. B.; Xiao, J.; Wang, Y. W., Nickel-mediated stereocontrolled synthesis of

spiroketals via tandem cyclization-coupling of beta-bromo ketals and aryl iodides. Chem. Commun.

2014, 50, 472-474. 10 (a) Everson, D. A.; Jones, B. A.; Weix, D. J., Replacing Conventional Carbon Nucleophiles with

Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134, 6146-6159. (b) Wang, X.; Liu, Y.; Martin, R., Ni-Catalyzed Divergent Cyclization/Carboxylation of Unactivated Primary and Secondary Alkyl Halides with CO2. J. Am. Chem. Soc. 2015, 137, 6476-6479. (c) Zhang, Y.; Xu, X.; Zhu, S., Nickel-catalysed selective migratory hydrothiolation of alkenes and alkynes with thiols. Nat Commun 2019, 10, 1752-1761.

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Metal Shape on the Determination of Kinetic Parameters. Water Environ. Res 2010, 82, 648-656.

21 The relatively sharp resonances in (phen)NiBr2 are not present in the reaction mixture, which we

attribute to isomers formed from solvent coordination. The peaks converge in DMSO-d6 (Figure

S22).

22 Jia, X.-G.; Guo, P.; Duan, J.; Shu, X.-Z., Dual nickel and Lewis acid catalysis for cross-electrophile

coupling: the allylation of aryl halides with allylic alcohols. Chem. Sci. 2018, 9, 640-645.

23 The low intensity of the EPR signal may result from dimerization of Ni(I)–Br complexes: Mohadjer

Beromi, M.; Brudvig, G. W.; Hazari, N.; Lant, H. M. C.; Mercado, B. Q., Synthesis and Reactivity

of Paramagnetic Nickel Polypyridyl Complexes Relevant to C(sp2)–C(sp3)Coupling Reactions.

Angew. Chem. Int. Ed. 2019, 58, 6094-6098.

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download fileview on ChemRxivLin-2019-July 15.pdf (1.31 MiB)



Mechanism of Ni-Catalyzed Reductive 1,2-

Dicarbofunctionalization of Alkenes



New York, NY 10003


ABSTRACT

Ni-catalyzed cross-electrophile coupling reactions have emerged as an appealing method to

construct organic molecules without the use of stoichiometric organometallic reagents. The

mechanisms are complex: plausible pathways, dubbed “radical chain” and “sequential

reduction”, 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 via a “sequential reduction” pathway. The reduction

of Ni by Zn is the turnover-limiting step, consistent with two Ni(II) species present as the

catalyst resting-state. Zinc is only sufficient to reduce (phen)Ni(II) to a Ni(I) species. As a result,

commonly proposed Ni(0) intermediates do not form under these conditions. (Phen)Ni(I)–Br

selectively activates aryl bromides via bimolecular oxidation addition, whereas alkyl bromides

are activated by (phen)Ni(I)–Ar through halogen-atom abstraction to afford radicals. These

results answer some long-standing questions in Ni-catalyzed cross-coupling reactions, and could

provide insight into achieving selectivity between different electrophiles in future reaction

design.

INTRODUCTION

Nickel-catalyzed cross-coupling reactions have advanced to become powerful methods for

constructing organic molecules.1 In particular, 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.1f,i,2

Understanding the mechanisms of Ni-catalyzed cross-coupling reactions could inform the design

of catalysts and the control of selectivity, but it remains 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 The mechanisms appear to be

system-dependent. While (NHC)Ni catalysts lead to two-electron redox processes mediated by

Ni(0)/Ni(II) intermediates,5c,5l,6 catalysts with chelating ligands often involve radical pathways

going through Ni(0)/Ni(I)/Ni(II)/Ni(III) intermediates.5

Previous efforts to characterize the mechanisms of Ni-catalyzed cross-electrophile coupling

reactions leave many key questions unanswered. Evidence for distinguishing “radical chain”

from “sequential reduction” pathways remains ambiguous (see elaborations below, Scheme 1).5l

This remains an important distinction as the mechanism and sequence of activations of different

electrophiles, which differ between the pathways, are critical to achieving chemoselectivity in

cross-electrophile coupling reactions.1g,i Previous experiments have also not identified the

turnover-limiting step and the catalyst resting state, which are critical bottlenecks of catalytic

reactions. Finally, previous studies have focused on substrate activation and C–C bond forming

steps,5e but the reduction of the Ni catalysts by reductants has not been characterized.

Reductive alkene carbofunctionalization with electrophiles has found widespread utility.7 We

recently developed a Ni-catalyzed, reductive, two-component 1,2-dicarbofunctionalization of

alkenes (Scheme 1).8 ,9 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 reductive cross-

coupling reactions.10 “Radical Chain” 5e and “Sequential Reduction” 11 pathways are both

plausible (Scheme 1), based on recent mechanistic studies.5l “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).5g The alternative

“Sequential Reduction” mechanism, cycle C, reverses the sequence of electrophile activation in

the “Radical Chain” mechanism. Ni(0) oxidatively adds to PhBr to give Ni(II)(Ph)(Br) (step vi),

followed by a second reduction to form Ni(I)–Ph (step xi). Activation of the alkyl bromide by

Ni(I)–Ph generates a radical (step viii), which combines with Ni(II) to form a Ni(III)

intermediate (step ix).12

Scheme 1. Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes and Possible

Mechanisms

Br

1/2 Zn

PhBr

NiIIIN

N

Ph

Br

Br

Ph

Ph

NiIIN

N

Ph

Br

Ni0N

N

NiIN

NPh

NiIIIN

N

Ph

Br

NiIIN

N

Ph

Br

NiIN

NBrNiII

N

N

Br

Br

NiIN

NBr

1/2 ZnBr2

1/2 Zn

1/2 ZnBr2

Zn ZnBr2

“Radical Chain” “Sequential Reduction”

NiIN

N

(A)

(B)

(C)

Z = CR2, NTs or O

ZBr

ZR

NiBr2∙DME (10 mol%)

Zn (2 equiv)DMA, 50 ºC

+ R–X

()N

O

NN

N

somatostatin SST1 receptor antagonist

modulator of the cholesterol biosythetic pathway

NN

Ph

OEt

X = Br, I, OMsR = alkyl, aryl, and heteroaryl

- broad scope (40 examples)- good functional group compatibility- high yields- mild conditions

N N (12 mol%)

PhBr

(i)

(ii)

(iii)

(iv)(v)

(vii)

(viii)

(ix)

(x)

(vi)

(xi)

(xi)

Herein, we report a mechanistic study on the reductive 1,2-dicarbofunctionalization reaction.

Our data differentiates 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

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, to shed light on the presence of radical intermediates. The coupling of 1 with PhBr

afforded dimeric 4 in 8% yield under standard conditions (Scheme 2A).8 Replacing 1,10-

phenanthroline with the bulkier neocuproine increases 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).

Scheme 2. Substrate Probes for Determining Radical Intermediates

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.13 Although the C–C bond formed in 4 could have also arisen from reductive

elimination from a dialkyl Ni intermediate, the increased yield of 4 with bulkier neocuproine

suggests that the formation of 4 is metal-free 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 as well. The poor diastereoselectivity reflects a small

energy difference in the chair and boat conformations in the transition states of cyclization,14 and

is consistent with the stereochemistry of previous radical cyclizations initiated by tin hydride.15

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. Kinetic studies were carried out for the coupling of 11 with PhBr to form 12

as the model reaction (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).16 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.

(1)

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] = 0.1 M; [PhBr] = 0.15 M; (b) [11]

= 0.05 M; [PhBr] = 0.1 M.

The time-courses for the reaction shown in eq 1 were fitted into kinetic models using

COPASI, to give the kobs for 12 formation as 7*10-4 s-1 and the kobs for biphenyl byproduct as 1*10-

3 M-1s-1 (Figure 2A).17 The formation of 12 exhibits dependence on neither [11] nor [PhBr],

whereas the formation of biphenyl is second-order with respect to [PhBr]. 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 1.18 Attempts to fit the data with other possible orders of [Ni] resulted in no overlay of the

time-courses (Figure S6).

(A)

(B)

Figure 2. (A) Time-courses of the alkene 1,2-dicarbofunctionalization reaction

shown in eq 1; (B) Determining [Ni] order based on the variable time

normalization analysis. Reaction conditions: [11]0 = 0.05 M, [PhBr] = 0.1 M, Zn =

0.1 mmol, solvent = DMA, agitation rate = 850 rpm, (A) [NiBr2•DME] = 5

mM, [phenanthroline] = 6 mM; (B) [(phen)NiBr2•DME] = 2.5, 4, 5, 7.5 mM.

The presence of heterogeneous Zn prompted us to assess mass-transfer limitations.19

Reactions were mixed in a shaker with orbital agitation. The reaction rate increases with

increasing agitation speed (Figure 3A), but this rate acceleration plateaus with agitation rates

above 1200 rpm. When the agitation rate is fixed to 900 rpm, the reaction rate increases as Zn

loading increases (Figure 3B).

(A)

(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 observed rate dependence on the mixing speed and Zn loading reveal that the reduction

of Ni by Zn is the turnover-limiting step. The reduction occurs in two steps: mass-transfer takes

place when Ni is adsorbed to the surface of Zn, then electron-transfer from Zn to Ni follows. The

rate of reduction is affected by the mass transfer rate (kc), the electron transfer rate (kr), and the

available surface area (S) (eq 2).20 Increasing the mixing speed up to 1200 rpm leads to an

increase in rate due to enhanced convective mass transfer (kc). At agitation speeds greater 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 (kr). The rate is

proportional to the density of available surface area (S/V), where S represents the overall surface

area of Zn and V is the volume of the reaction (eq 2). Increased Zn loading increases the overall

surface area (S), and thus the reaction rate. However, S does not increase proportionally with

increasing Zn loading, because S also depends on the distribution of the heterogeneous particles

in solution. This distribution, in turn, varies based on mixing rate, vessel shape, mixing mode,

and the particle size of Zn.

v = – k c ∙ k r ∙ S ∙(C l−C s)

(k c+k r)V (2)

kc: mass-transfer rate

kr: electron transfer rate

S: area of available surface

Cl: the concentration of Ni in solution

Cs: the concentration of Ni on zinc surface

V: volume of the reaction

Collectively, the rate law for the 1,2-dicarbofunctionalization of alkenes is expressed in eq 3.

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 = 7*10-4 s-1[olefin]0[PhBr]0[Ni][Zn]x (3)

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 from eq 1, after 30 min, was withdrawn, 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 4 under standard conditions in DMA-d9 allowed us to take a snapshot of

the catalyst resting state using 1H NMR spectroscopy. After 15 min, we cooled the reaction to

room temperature, filtered to remove Zn and quickly recorded its 1H NMR spectrum (Figure

S17). The reaction solution displays two Ni species, 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).21 Independently prepared (phen)Ni(o-Tol)(Br), by

mixing Ni(cod)2 with phen and o-TolBr,22 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. 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.

(4)

Figure 4. (A) 1H 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 4 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 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 565 nm.

Addition of PhBr to this purple mixture resulted in a red solution with absorptions at 421 and

456 nm, consistent with the spectrum of (phen)Ni(Ph)(Br) 16, as well.

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).

The above 1H NMR data of the reaction mixture and its comparison with independently

prepared complexes support the assignment of 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 that

was 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.

Isolation of Ni Species. The identity of the turnover-limiting step, the reduction of Ni by Zn,

prompted us to closely investigate this fundamental step. The reduction of (phen)NiBr2 14 by Zn

results in a purple mixture, which displays a series of paramagnetic 1H NMR resonances (Figure

S61) and a rhombic EPR signal (Figure S64).23 This observation is inconsistent with d10 Ni(0)

species, as previously proposed in the literature. This purple species, however, is prone to

decomposition, and prevented further characterization.

In order to generate a more stable reduction intermediate, we prepared (phen*)NiBr2 17

(phen* = 2,9-di-sec-butyl-phenanthroline), 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.

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).24 The EPR spectrum of 18 shows a Ni-

centered radical (Figure S63).

(5)

(A) (B)

0.9470.045

0.045

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.

Cyclic Voltammetry. The reduction of Ni(II) to Ni(I) by Zn led us to investigate the

reduction potentials of 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,25 but the 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

Complexes Ep/2(NiII/NiI)(V vs. SHE)

Ep/2((NiI/Ni0)(V vs. SHE)

(phen)NiBr2 14 -0.86a

(phen)Ni(o-Tol)Br 15 -1.12a

(phen*)NiBr2 17 -0.69b

(phen*)NiBr 18 -1.37b

ZnBr2 Ep/2(ZnII/Zn) -1.26a

a In DMA at 25 °C, internal reference = Fc+/Fc, electrolyte = Bu4NBr. b In THF.

Stoichiometric Experiments to Probe Electrophile Activation. Stirring the pale green

(phen)NiBr2 with excess Zn in DMA resulted in a dark purple solution 19. This solution was

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 7). This kinetic comparison experiment

suggests that the reduced Ni species 19 reacts with PhBr faster than 11.

Figure 7. 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 for 30 min,

was filtered to remove excess Zn (eq 6). Addition of 2 equiv o-TolBr to this solution 19 led to

formation of (phen)NiBr2 14 and (phen)Ni(o-Tol)(Br) 15 in a ratio of 5:3, evident from the 1H

NMR spectra (Figures S20-S22).

(6)

The paramagnetic 1H NMR spectrum of 19 (Figure S61), EPR signal of a Ni-centered radical

(Figure S64), isolation of (phen*)Ni(I)–Br 18, and cyclic voltammetry studies suggest that 19 is

a Ni(I) species, (phen)Ni(I)–Br. The activation of PhBr by (phen)Ni(I)–Br 19 is faster than alkyl

bromide 11, evident from the competition experiment (Figure 7). 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 (eq 7). 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

decomposition of 19 in the absence of Zn after filtration.

(7)

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 led to formation of 12 in 21%

yield and dimer 20 in 4% yield (entry 1, Table 2). Reduction of 15 by Zn, followed by removal

of Zn via filtration, led to a purple solution which reacted with 11 to afford 12 and 20 in a higher

conversion relative to that without Zn reduction (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). EPR analysis of the frozen mixture of 21

with Zn reveals an organic centered radical (Figure S65).

Table 2. Stoichiometric Reaction of 15 and 21 with 11.a

Entry

Ar Zn(equiv)

ReactionTime (h)

11(%)

12(%)

20(%)

1 o-Tol 0 2 70 21 42 o-Tol 2b 2 50 37 123 o-Tol 2 2 0 50 504 Mes 0 12 100 0 05 Mes 2b 12 69 0 30

a Yields were determined by 1H NMR spectroscopy with 1,3,5-trimethoxylbenzene as the internal

standard.

b Zn was removed by filtration before addition of 11.

Stoichiometric experiments between 15 and 11 suggest that 15 is capable of activating 11, but

the rate of this background reaction is exceeded by the rate of reduced Ni species reacting with

11. EPR analysis of the reduction mixture of 21 by Zn supports formation of a Ni(I)–Ar species

upon reduction, where phen is redox-active.25 The formation of dimer 20 implies a radical

intermediate that underwent cyclization and dimerization. The cross-coupling product 12 arises

from 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 kept distant from the Ni center by the steric hindrance.

Therefore, 20 is formed exclusively.

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.8 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 8). 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 transmetalation mechanism, reported by Shenvi, where free

radical is absent.5k

Figure 8. The ratio of uncyclizaed/cyclized products (23/24) as a function of [Ni] in the coupling

of 22 with PhBr. Reaction conditions: [22]0 = 0.05 M, [PhBr] = 0.1 - 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.26 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 8-9). These control experiments and the absence of

carbocyle products reveal that alkyl bromide substrates must be activated by the Ni catalysts.

(8)

(9)

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 Ni(I) intermediates. (phen)Ni(I)–

Br activates PhBr more rapidly than alkyl bromides via a bimolecular oxidative addition.

Reduction of (phen)Ni(Ar)(Br) by Zn followed by addition of alkyl bromides generates radicals

that can combine with Ni to form cross-coupling products.

“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) after the reduction of Ni and activation of PhBr. In the system

under investigation, the kinetic comparison experiment shows that (phen)Ni(I)–Br activates PhBr

more rapidly than alkyl bromides (Figure 7). 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 Ni(II) by Zn is the turnover-limiting step

(Figures 2-5). The reduction rate constant is estimated to be 1 s -1 at a 900-rpm agitation rate. Free

alkyl radicals dimerize with a bimolecular rate constant on the scale of 109 M-1 s-1.27 The

drastically faster radical dimerization than Ni reduction by Zn suggests that the radical

intermediate would not live long enough to be captured by Ni after its reduction. As a result, the

“Radical Chain” pathways are not kinetically plausible in this system.

Evaluation of Mechanism (C) and Revised Mechanism. Our data support part of the

“Sequential Reduction” mechanism shown in Scheme 1C, where PhBr is activated prior to alkyl

bromide. However, the electrochemical potentials of Ni species, the observation of paramagnetic

species upon reduction of Ni(II) by Zn, in combination with the stoichiometric study of the

reduction of (phen*)NiBr2 17 by Zn, establishes that Zn is only sufficient to reduce

(phen)Ni(II)Br2 14 to (phen)Ni(I)Br 19.28 (Phen)Ni(0) is never formed under these conditions.

Accordingly, we revised the “Sequential Reduction” mechanism to exclude Ni(0) intermediates,

and the mechanism shown in Scheme 3 is most consistent with our data. Stoichiometric

experiments reveal that the activation of PhBr by (phen)Ni(I)Br proceeds via bimolecular

oxidative addition to generate (phen)NiBr2 14 and (phen)Ni(Ph)(Br) 16. This step is reminiscent

of previous reports of dinuclear Ni-mediated oxidative addition5d,29 and reductive elimination.30

(Phen)NiBr2 14 and (phen)Ni(Ph)(Br) 16 both exist as the catalyst resting state. They are

separately reduced by Zn, both as the turnover-limiting steps. This proposal accounts for the lack

of kinetic dependence on substrates and the 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 3. Revised Mechanism for Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of

Alkenes

The reduction of 16 by Zn affords (phen)Ni(I)–Ph 25, which activates alkyl bromides to form

radical intermediates, likely via a concerted halogen-atom abstraction mechanism.11b The

presence of a radical intermediate is verified by stereochemical probes and radical clock

substrates (Scheme 2). The reaction of 22 gave 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 4), exhibits a linear correlation with [Ni] (Figure 8). 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 rate range of radical capture 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),31 close to the calculated barrier of 4 kcal/mol.5g

Increasing steric bulk of the ligand increases 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.8

Scheme 4. Proposed Mechanism for Forming 23 and 24 via a Radical Intermediate

Selectivity for Activation of Electrophiles. Our data shed light on the selectivity of cross-

electrophile coupling reactions, which is a result of the steric and electronic properties of Ni

intermediates. Csp2 and Csp3 electrophiles are independently activated by different Ni(I) species

via distinct mechanisms (Scheme 5). (phen)Ni(I)–Br selectively activates Csp2–Br via oxidative

addition, facilitated by the sterically assessible Ni(I)–Br center. In contrast, the increased steric

bulk of (phen)Ni(I)–Ph hinders oxidative addition, but its electron-rich property promotes

halogen-atom abstraction of Csp3–Br to give radicals.11b

Scheme 5. Illustration of Selectivity for Cross-Electrophile Coupling

SUMMARY

The Ni-catalyzed two-component reductive dicarbofuntionalization of alkenes proceeds via a

“Sequential Reduction” pathway. Evidence unambiguously rules out the “Radical Chain”

mechanism. Ni(I)–Br first activates ArBr to form a 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.

The result highlights the importance of catalyst reduction, which has not been recognized in

previous studies. (2) Zn is insufficient to reduce Ni(II) to Ni(I), and Ni(0) is absent. (3)

Bimolecular oxidation addition of PhBr by (phen)Ni(I)–Br precedes activation of alkyl bromides

by (phen)Ni(I)–Ph via concerted halogen-atom abstraction. This sequence accounts for

selectivity observed in cross-electrophile coupling reactions.

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

[email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

We thank Chunhua (Tony) Hu for solving the X-ray crystal structure of complex 18. Lin thanks

Margalit Feuer for editing the manuscript and help with UV-Vis measurements, and Paul

Peterson and John Eng (Princeton University) for assistance with the EPR spectroscopy. This

work was supported by National Institute of Health (NIH) under Award Number

1R01GM127778. Qiao Lin is supported by the MacCracken Fellowship. 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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3 For a recent review, see: Hu, X., Nickel-catalyzed cross coupling of non-activated alkyl halides: amechanistic perspective. Chem. Sci. 2011, 2, 1867.

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Radical Intermediates in Nickel-Catalyzed Alkyl–Alkyl Kumada Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004-12012. (e) Biswas, S.; Weix, D. J., Mechanism and Selectivity in Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2013, 135, 16192-16197. (f) Schley, N. D.; Fu, G. C., Nickel-Catalyzed Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc. 2014, 136, 16588-16593. (g) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C., Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings. J. Am. Chem. Soc. 2015, 137, 4896-4899. (h) Mohadjer Beromi, M.; Nova, A.; Balcells, D.; Brasacchio, A. M.; Brudvig, G. W.; Guard, L. M.; Hazari, N.; Vinyard, D. J., Mechanistic Study of an Improved Ni Precatalyst for Suzuki–Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species. J. Am. Chem. Soc. 2017, 139, 922-936. (i) Manzoor, A.; Wienefeld, P.; Baird, M. C.; Budzelaar, P. H. M., Catalysis of Cross-Coupling and Homocoupling Reactions of Aryl Halides Utilizing Ni(0), Ni(I), and Ni(II) Precursors; Ni(0) Compounds as the Probable Catalytic Species but Ni(I) Compounds as Intermediates and Products. Organometallics 2017, 36, 3508-3519. (j) Kc, S.; Dhungana, R. K.; Shrestha, B.; Thapa, S.; Khanal, N.; Basnet, P.; Lebrun, R. W.; Giri, R., Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)–C(sp3)/C(sp3)–C(sp2) Bond Formation and Mechanistic Studies. J. Am. Chem. Soc. 2018, 140, 9801-9805. (k) Shevick, S. L.; Obradors, C.; Shenvi, R. A., Mechanistic Interrogation of Co/Ni-Dual Catalyzed Hydroarylation. J. Am. Chem. Soc. 2018, 140, 12056-12068. (l) Wang, X.; Ma, G.; Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T. D.; Wang, X.; Gong, H., Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl Iodides with Tertiary Alkyl Halides. J. Am. Chem. Soc. 2018, 140, 14490-14497. (m) Chen, P. P.; Lucas,E. L.; Greene, M. A.; Zhang, S. Q.; Tollefson, E. J.; Erickson, L. W.; Taylor, B. L. H.; Jarvo, E. R.; Hong, X., A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study. J. Am. Chem. Soc. 2019, 141, 5835-5855.

6 (a) Wang, S. C.; Troast, D. M.; Conda-Sheridan, M.; Zuo, G.; LaGarde, D.; Louie, J.; Tantillo, D. J., Mechanism of the Ni(0)-Catalyzed Vinylcyclopropane−Cyclopentene Rearrangement. J. Org. Chem. 2009, 74, 7822-7833. (b) Ritleng, V.; Henrion, M.; Chetcuti, M. J., Nickel N-Heterocyclic Carbene-Catalyzed C–Heteroatom Bond Formation, Reduction, and Oxidation: Reactions and Mechanistic Aspects. ACS Catalysis 2016, 6, 890-906. (c) Diccianni, J. B.; Heitmann, T.; Diao, T., Nickel-CatalyzedReductive Cycloisomerization of Enynes with CO2. J. Org. Chem. 2017, 82, 6895-6903.

7 (a) Kuang, Y.; Anthony, D.; Katigbak, J.; Marrucci, F.; Humagain, S.; Diao, T., Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-Controlled trans Selectivity. Chem 3, 268-280. (b) Qin, X.; Lee, M. W. Y.; Zhou, J. S., Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl Halides to Afford Indolines. Angew. Chem. Int. Ed. 2017, 56, 12723-12726. (c) He, Y.; Cai, Y.; Zhu, S., Mild and Regioselective Benzylic C–H Functionalization: Ni-Catalyzed Reductive Arylation of Remoteand Proximal Olefins. J. Am. Chem. Soc. 2017, 139, 1061-1064. (d) García-Domínguez, A.; Li, Z.; Nevado, C., Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2017, 139, 6835-6838. (e) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.-M.; Zhu, S., Remote Migratory Cross-Electrophile Coupling and Olefin Hydroarylation Reactions Enabled by in Situ Generation of NiH. J. Am. Chem. Soc. 2017, 139, 13929-13935. (f) Thapa, S.; Basnet, P.; Giri, R., Copper-Catalyzed Dicarbofunctionalization of Unactivated Olefins by Tandem Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2017, 139, 5700-5703. (g) Qin, X.; Lee, M. W. Y.; Zhou, J. S., Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl Halides to Afford Indolines. Angew. Chem. Int. Ed. 2017, 56, 12723-12726. (h) Wang, K.; Ding, Z.; Zhou, Z.; Kong, W., Ni-Catalyzed Enantioselective Reductive Diarylation of Activated Alkenes by Domino Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2018, 140,12364-12368. (i) Sun, S.-Z.; Börjesson, M.; Martin-Montero, R.; Martin, R., Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes with Unactivated Olefins. J. Am. Chem. Soc. 2018, 140, 12765-12769. (j) Zhao, X.; Tu, H. Y.; Guo, L.; Zhu, S.; Qing, F. L.; Chu, L., Intermolecular selective carboacylation of alkenes via nickel-catalyzed reductive radical relay. Nat. Commun. 2018, 9, 3488. (k) Anthony, D.; Lin, Q.; Baudet, J.; Diao, T., Nickel-Catalyzed Asymmetric Reductive Diarylation of Vinylarenes. Angew. Chem. Int. Ed. 2019, 58, 3198-3202. (l) Jin, Y.; Wang, C., Ni-catalyzed reductive arylalkylation of unactivated alkenes. Chem. Sci. 2019, 10, 1780-1785. (m) Tian, Z. X.; Qiao, J. B.; Xu, G. L.; Pang, X.; Qi, L.; Ma, W. Y.; Zhao, Z. Z.; Duan, J.; Du, Y. F.; Su, P.; Liu, X. Y.; Shu, X. Z., Highly Enantioselective Cross-Electrophile Aryl-Alkenylation of Unactivated Alkenes. J. Am. Chem. Soc. 2019, 141, 7637-7643.

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21 The relatively sharp resonances in (phen)NiBr2 are not present in the reaction mixture, which we attribute to isomers formed from solvent coordination. The peaks converge in DMSO-d6 (Figure S22).

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23 The low intensity of the EPR signal may result from dimerization of Ni(I)–Br complexes: Mohadjer Beromi, M.; Brudvig, G. W.; Hazari, N.; Lant, H. M. C.; Mercado, B. Q., Synthesis and Reactivity of Paramagnetic Nickel Polypyridyl Complexes Relevant to C(sp2)–C(sp3)Coupling Reactions. Angew. Chem. Int. Ed. 2019, 58, 6094-6098.

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