S
1
Mechanistic Investigation of Ni
-
Catalyzed Reductive Cross
-
Coupling of Alkenyl and Benzyl Electrophiles
Raymond F. Turro, Julie L.H. Wahlman, Z. Jaron Tong, Xiahe
Chen, Miao
Yang, Emily P. Chen,
Xin Hong,
4
Ryan G. Hadt,
2
K. N. Houk,
5
Yun
-
Fan
Yang,
3
*
Sarah E. Reisman
1
*
1
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125, United States
2
Arthu
r Amos Noyes Laboratory of Chemical Physics, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California, 91125, United States
3
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zheji
ang
310014, China
4
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
5
Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095, United States
*reisman@caltech.edu
Supporting Information
Table of Contents
1.
Experimental Details ............................................................................
........
..............
S
3
2.
Synthetic Procedures
.....
............................................................................
........
......... S4
3.
Kinetics and Time Course Experiments
............................................
...
.............
.......
... S5
3.1.
Heterogenous Reaction Kinetics
..........................................................
..........
S5
3.2.
Homogeneous Reaction Kinetics
.........................................................
........
S13
4.
Mechanism of Substrate Activation
..................................................................
........
S2
3
S
2
4.1.
Additive Effects on NHP Ester Reduction Rate
.................................
.........
. S2
3
4.2.
Comparison of
1a
and
2a
Activation Rates by
L1
·
NiCl
2
....................
........
.
S3
5
4.3.
Catalyst
-
Mediated
1a
Activation
Control
Experiments
......................
.........
S3
7
4.4.
Preliminary Kinetic Simulations of Rate
-
Controlling Activation of NHP esters
...................................................................................................................... S
38
5.
Cyclic Voltammetry Experiments
.......................................................................
.....
. S
40
5.1.
CV’s of
L1
·
NiX
2
,
2b
,
and TDAE
..........................................................
.....
. S
40
5.2.
Substrate Titration and Catalytic Current Comparison
..........................
.....
. S
44
6.
NMR Reaction Monitoring
..............................................................
.....................
..
. S
45
6.1.
19
FNMR Reaction Monitoring
...................................................
..............
... S
45
6.2.
Room Temperature
1
H and
19
F NMR
.....................................................
....
. S
50
6.3.
Attempts to assign
7b
with
1
H NMR ..........................................................
.
S
51
7.
Electron Paramagnetic Spectroscopy (EPR)
....................................................
......... S
61
7.1.
Generation of Ni(I)
from
Chemical Reduct
ion of
L1
·
NiX
2
........................ S
61
7.2.
Reaction of
L1
·Ni(COD) with
1a
................................................................ S
64
7.3.
Reduction of
L1
·
NiCl
2
with Zn
0
Time Course
............................................ S
66
7.4.
Reaction Monitoring with EPR
................................................
................
.... S
69
8.
Catalyst Loading Experiments (Figure
5d
)
............................................................... S
70
9.
Computational
Data
............................................................................
.....................
. S
71
9.1.
DFT
-
Computed Gibbs Free Energy Barriers for Radical Addition and
Reductive Elimination ..................................................................
............... S
75
9.2.
Table of Energies ......................................................................................... S
76
9.3.
Cartesian Coordinates for Calculated Species ............................................. S
77
10.
References
..................
.................................................................................
.....
...... S
109
S
3
1.
Experimental Details
Materials and Methods
Unless otherwise stated, reactions were performed under a N
2
atmosphere using freshly dried
solvents. All reagents were purchased from commercial suppliers (Sigma Aldrich, Combi
-
Blocks, TCI, Enamine, Strem) and used without further purification unless mentioned
otherwise. Tetrahydrofuran (THF)
, acetonitrile (MeCN),
and methylene chloride (CH
2
Cl
2
)
were dried by passing through activated alumina columns. Anhydrous dimethylacetamide
(DMA) was purchased from Aldrich and stored in a N
2
-
filled glovebox
. NiCl
2
·dme was
purchased from Strem and stored in the glovebox. Mangan
ese powder (~325 mesh, 99.3%)
was purchased from Alfa Aesar. Zinc dust (97.5%) was purchased from Strem.
NaI (anhydrous
,
99%) was purchased from Strem and stored in a N
2
-
filed glovebox.
Flash column
chromatography was performed as described by Still et al.
using silica gel (230
-
400 mesh,
Silicycle).
1
Purified compounds were dried on a high vacuum line (0.2 torr) to remove trace
solvent.
1
H and
13
C NMR spectra were recorded on a Bruker Avance
III HD with Prodigy
cryoprobe (at 400 MHz and 101 MHz, respectively), a Varian 400 MR (at 400 MHz and 101
MHz, respectively), or a Varian Inova 500 (at 500 MHz and 126 MHz, respectively).
1
H and
19
F NMR spectra were also recorded on a Varian Inova 300 (at
300 MHz and 282 MHz,
respectively). NMR data is reported relative to internal CHCl
3
(
1
H, δ = 7.26) and CDCl
3
(
13
C,
δ = 77.0)
or C
6
F
6
(
19
F
-
164.9 ppm)
. HRMS were acquired from the Caltech
Center for Catalysis
and Chemical Synthesis
Facility using electrospray ionization (ESI
-
TOF)
. Analytical chiral
SFC was performed with a Mettler SFC supercritical CO
2
analytical chromatography system
with Chiralcel AD
-
H, OD
-
H, AS
-
H, OB
-
H, and OJ
-
H columns (4.6 mm x 25 cm). Analytical
achiral GC was
performed with an Agilent 6850 GC utilizing an HP
-
1 capillary column (methyl
siloxane, 30.0 m x 320 μm x 0.25 μm, Agilent) column with a splitless injection and a helium
flow of 7.3 mL/min. The temperature program began at 50 °C and was held for 2 min, in
creased
to 250 °C at 25 °C/min and then held at 250 °C for 3 min. X
-
band
perpendicular
mode
EPR
spectra were recorded on a Bruker EMX spectrometer
at 77 K using a LN
2
immersion dewar.
Parallel mode EPR were recorded at 5K using a LHe cryostat. EPR spectra
were simulated
with Easyspin (version 5.2.35)
2
.
Electronic absorption spectra were obtained using CARY 300
spectrophotometer.
Electroanalytical experiments were conducted in the Beckman Resource
Laser Resource Center at the California Institute of Technol
ogy
using a Bio
-
Logic SP300
potentiostat/galvanostat. Cyclic voltammetry experiments we conducted with a glassy carbon
S
4
disk working electrode, a platinum wire counter electrode, and a silver wire reference electrode
containing a 10 mM AgNO
3
solution with 0
.1 M TBAPF
6
in MeCN.
2.
Synthetic Procedures
Substrate and Catalyst Synthesis
Figure S
1
.
Substrates and catalysts used for mechanistic studies.
Catalysts:
(3a
R
,3a'
R
,8a
S
,8a'
S
)
-
2,2'
-
(Cyclopropane
-
1,1
-
diyl)bis(3a,8a
-
dihydro
-
8
H
-
indeno[1,2
-
d
]
-
oxazole)
(L1)
was synthesized according to our previously published procedure.
3
Complexation with NiBr
2
or NiCl
2
were prepared according to previously reported synthesis of
L1
NiCl
2
4
and
L1
N
iBr
2
.
5
Complexes were recrystallized once by vapor diffusion of pentane in
a saturated DCM solution for use in catalytic reactions and 3 times for use in electroanalytical
experiments.
Substrates
: Coupling partners
1a
,
1b
and
2b
were synthesized according to the procedure
described in the initial disclosure.
5
(
E
)
-
1
-
fluoro
-
4
-
(2
-
iodovinyl)benzene
(
2b
-
I
): To a 250 mL oven
-
dried round bottom flask with
a stir bar was added (
E
)
-
4
-
fluorocinnamic acid (831.6mg, 5.0 mmol, 1 equiv). The acid was
then suspended in 50 mL (0.1 M) DCM then triethylamine (105
μ
L, 0.75 mmol, 0.
15 equiv)
was added and the reaction was stirred under N
2
. To the stirring solution was then added
N
-
iodosuccinimide (1.41 g, 6.25 mmol, 1.25 equiv) in one portion. After 12 minutes, the reaction
solution had turned red and then deep black after 20 minutes
. After 1h the starting material was
consumed by TLC and the reaction mixture was concentrated
in vacuo
.
Residue was taken up
Br
MeO
Br
F
1a
1b
Me
O
O
N
O
O
2b
N
Ni
N
O
O
Cl
Cl
L1
NiCl
2
N
Ni
N
O
O
Br
Br
L1
NiBr
2
N
N
O
O
I
F
1b–I
Ph
Ph
Me
Me
4
L1
Substrates
Catalysts
F
O
OH
I
F
NIS (1.25 equiv)
Et
3
N (0.15 equiv)
DCM (0.1 M)
21 ºC
2b-I
45% yield
S
5
in 30 mL EtOAc and washed with 25 mL sat. Na
2
S
2
O
3
solution. The aqueous layer was then
extracted two more times and combined organ
ics were dried over MgSO
4
, filtered through
celite, rinsed with EtOAc then concentrated in vacuo to give a brown solid. The crude was then
purified by filtration through SiO
2
with pentane to give alkenyl iodide
2b
-
I
(558 mg, 2.3 mmol,
45% yield).
Note:
we observed significant discoloration and decomposition upon prolonged
exposure to light so storage at
-
20 ºC in the darkness under Ar is essential to prevent
decomposition.
Spectral data is in good agreement with literature reported data.
6
3.
Kinetics and Time Course Experiments
Methods of GC
-
FID Quantification
:
For each reaction component and product, authentic
samples were isolated to determine response factors for GC
-
FID analysis.
Three standards were
made
for each analyte
to normalize the GC
-
FID area counts and convert the obtained data into
reaction concentration (M) values. The analyte and dodecane standard were each added to a 20
mL vial and massed on a balance. The mixture was dissolved in 10 mL of EtOAc and
transferre
d to a GC vial for analysis. The density of dodecane (0.75 g/mL) was also used to
convert the area values to concentration.
3.1
Heterogenous Reaction Kinetics
General Procedure
1 (
Zn
0
powder
)
:
A 10 mL round bottom flask with a small magnetic
stirring ro
d was charged with the sodium iodide (22.5 mg, 0.15 mmol, 0.5 equiv) and zinc
powder (58.8 mg, 0.9 mmol, 3 equiv). The flask was sealed with a rubber septum, purged with
N
2
, and cooled to 0
°
C by being placed in an ice water bath. The alkenyl bromide
1a
(8
5.2 mg,
0.4 mmol) and
L
·NiCl
2
complex (19.4 mg, 0.04 mmol) were added to a 2 mL volumetric flask,
sealed with a rubber septum, and purged with N
2
. The benzyl chloride
2a
(53
μ
L, 0.4 mmol)
and dodecane (48
μ
L) as an internal standard were added via syringe to the volumetric flask.
Then
anhydrous DMA was added to the volumetric flask until it reached the 2 mL line. A small
stir bar was added to the volumetric flask and the solution was stirred until all of the
L
·NiCl
2
complex was dissolved. The solution was taken up into a 2 mL syringe t
o ensure homogeneity,
and then 1.5 mL of the solution was added to the round bottom flask. The reaction was stirred
under
N
2
by inlet needle attached to a Schenck line
by using an IKA stir plate set to a stirring
1a
2a
Br
MeO
Me
Ph
Cl
L1
NiCl
2
(10 mol %)
Zn
0
(3 equiv)
NaI (0.5 equiv)
DMA (0.2 M), 0 °C
Ph
MeO
Me
3a
S
6
speed of 1500 rpm. At appropriate time poin
ts, approximately 50
μ
L of the solution was
removed by syringe (syringe and needle were pre
-
flushed with N
2
), loaded onto a short silica
plug (1 cm) in a glass pipette packed with cotton. The crude mixture was flushed through the
silica plug with 2 mL of 1
0% EtOAc/hexane directly into GC vials and analyzed by GC
-
FID.
All data runs obtained from the GC
-
FID instrument were appropriately integrated for the
product and the dodecane standard. The integrated data points were further processed by
normalizing each
product area value by its corresponding standard area value. The normalized
areas were then converted to concentration by using calculated response factors obtained from
preparing known mixtures of the standard and purified reaction product. Each reaction
was
analyzed and graphed to show the product concentration (M) as a function of reaction time
(min). All data points were plotted with
black
markers (
) as shown below, while only the data
points included in the linear fit are shown with red markers (
).
The best
-
fit linear regression
line is also shown and the y=mx+b equation is given. Each reaction was run in duplicates as
indicated by Trial 1 and Trial 2.
Standard Reaction Conditions
Figure S
2
:
Results of s
tandard
r
eaction
c
onditions
runs with linear fit regions highlighted:
[
1a
]
0
= 0.2M, [
2a
]
0
= 0.2M, [
L1·
NiCl
2
] = 0.02M
.
Effect of Changing [L1
·
NiCl
2
]
The general procedure 1 was followed except varying the amounts of
L1
NiCl
2
were used to
give final loadings of 5%, 7%, 14%, and 20%.
y = 0.0051x
-
0.0318
R² = 0.9758
0
0.04
0.08
0.12
0.16
0.2
0
25
50
[
3a
] (M)
Time (min)
trial 2
fit2
y = 0.004976x
-
0.039119
R² = 0.974893
0
0.04
0.08
0.12
0.16
0.2
0
25
50
[
3a
] (M)
Time (min)
trial 1
fit
S
7
Figure S
3
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.0
1
M.
Figure S4
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.014M.
Figure S5
:
Kinetics runs
with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.028M.
y = 0.0021x
-
0.0296
R² = 0.9677
0
0.04
0.08
0.12
0.16
0
25
50
75
[
3a
] (M)
time (min)
trial 1
fit1
y = 0.0026x
-
0.027
R² = 0.9826
0
0.04
0.08
0.12
0.16
0.2
0
25
50
75
[
3a
] (M)
time (min)
trial 2
fit2
y = 0.0037x
-
0.0377
R² = 0.9967
0
0.04
0.08
0.12
0.16
0.2
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 1
fit1
y = 0.0035x
-
0.0254
R² = 0.9744
0
0.04
0.08
0.12
0.16
0.2
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 2
fit2
y = 0.0059x
-
0.0454
R² = 0.997
0
0.04
0.08
0.12
0.16
0.2
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trail 1
fit 1
y = 0.0061x
-
0.0484
R² = 0.999
0
0.04
0.08
0.12
0.16
0.2
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 2
fit 2
S
8
Figure S6
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.04M.
Effect of Changing Alkenyl Bromide 1a
Equivalents
The general procedure 1 was followed except varying the amounts of
1a
were used to give
final amounts of 1.5, 2, 3, and 4 equivalents.
Figure S7
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.3M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.02
M
Figure S8
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.4M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.02M.
y = 0.0099x
-
0.0589
R² = 0.992
0
0.04
0.08
0.12
0.16
0.2
0
10
20
30
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0105x
-
0.0646
R² = 0.9905
0
0.04
0.08
0.12
0.16
0.2
0
10
20
30
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.00300x
-
0.01540
R² = 0.98781
0
0.04
0.08
0.12
0.16
0.2
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0031x
-
0.0112
R² = 0.9717
0
0.04
0.08
0.12
0.16
0.2
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0025x
-
0.0055
R² = 0.978
0
0.04
0.08
0.12
0.16
0.2
0
25
50
75
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0024x
-
0.0116
R² = 0.9514
0
0.04
0.08
0.12
0.16
0.2
0
25
50
75
[
3a
] (M)
Time (min)
trial 2
fit 2
S
9
Figure S9
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.6M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.02M.
Figure S10
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.8M, [
2a
]
0
= 0.2M,
[
L1·
NiCl
2
] = 0.02M.
Effect of Changing Benzyl Chloride 2a Equivalents
The general procedure 1 was followed except varying the amounts of
2a
were used to give
final amounts of 1
.5, 2, 3, and 4 equivalents.
Figure S11
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.3M,
[
L1·
NiCl
2
] = 0.02M.
y = 0.0018x
-
0.0065
R² = 0.955
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0019x
-
0.0051
R² = 0.9663
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0018x
-
0.0129
R² = 0.9812
0
0.02
0.04
0.06
0.08
0.1
0.12
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0015x + 0.0032
R² = 0.9405
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0
20
40
60
80
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0069x
-
0.0671
R² = 0.9777
0
0.05
0.1
0.15
0.2
0.25
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0069x
-
0.0511
R² = 0.9481
0
0.05
0.1
0.15
0.2
0.25
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 1
fit 1
S
10
Figure S12
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.4M,
[
L1·
NiCl
2
] =
0.02M.
Figure S13
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.6M,
[
L1·
NiCl
2
] = 0.02M.
Figure S14
:
Kinetics runs with linear fit regions highlighted: [
1a
]
0
= 0.2M, [
2a
]
0
= 0.8M,
[
L1·
NiCl
2
] = 0.02M.
y = 0.0075x
-
0.0793
R² = 0.9749
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.2
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0085x
-
0.0703
R² = 0.9933
0
0.05
0.1
0.15
0.2
0.25
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0055x
-
0.0354
R² = 0.935
0
0.05
0.1
0.15
0.2
0.25
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 1
fit 1
y = 0.0059x
-
0.0483
R² = 0.9779
0
0.05
0.1
0.15
0.2
0.25
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0053x
-
0.053
R² = 0.9819
0
0.05
0.1
0.15
0.2
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 2
fit 2
y = 0.0053x
-
0.049
R² = 0.9907
0
0.05
0.1
0.15
0.2
0
10
20
30
40
50
[
3a
] (M)
Time (min)
trial 1
fit 1