of 99
S
1
Investigation
of the
C
N
B
ond
-
F
orming
S
tep
in
a
P
hotoinduced,
C
opper
-
C
atalyzed
E
nanti
oconvergent
N
Alkylatio
n:
Characterization and Application of a Stabilized Organic
Radical as a Mechanistic Probe
Heejun Lee, Jun Myun Ahn, Paul H. Oyala, Cooper Citek, Haolin Yin, Gregory C. Fu*, Jonas C.
Peters*
Division of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125, United States
Supporting Information
Table of Contents
I.
General information
II.
Preparative syntheses of NP(H) and NP
-
ligated copper
complexes
III.
Preparative syntheses and characterization of metal carbazolides
IV.
Procedures for freeze
-
quench EPR studies of the catalytic reactions
V.
Pulse EPR experiments
VI.
X
-
band
continuous wave (CW)
EPR studies of organic
radicals
VII.
Stoichiometric C
N coupling reactions
VIII.
DFT calculations
IX.
X
-
ray crystallography
X.
NMR Spectra
I
. General Information
Unless otherwise noted, all materials were purchased from commercial suppliers and used as
received. All manipulations of air-sensitive materials were carried out in oven
-
dried glassware
using standard Schlenk or glovebox techniques under an N
2
atmosphere. Solvents were
deoxygenated and dried by thoroughly sparging with N
2
followed by passage through an
activated alumina column in a solvent purification system
1
supplied by SG water, LLC.
Silicycle
Silia
Flash
®
P60 Silica gel (particle size 40
63 μm) was used for flash chromatography.
Analytical thin layer chromatography was
conducted with glass TLC plates (silica gel 60 F254)
and spots were visualized under UV light or after treatment with standard TLC stains.
Carbazole was recrystallized from hot ethanol. Deuterated solvents were purchased from
Cambridge Isotope Laboratorie
s, Inc., degassed, and dried over activated 3 Å molecular sieves
before use. Mesitylcopper(I)
,
2
3,6
-
di
-
tert
-
butylcarbazole
,
3
titanium(III) tris(
N
-
tert
-
butyl
-
3,5
-
dimethylanilide)
, and
4
tris(4
-
tert
-
butyl
-
phenyl)methyl bromide
5
were prepared according to
literature procedures. Indoline (Aldrich), NEt
3
(EMD), PBr
3
(Acros) were distilled prior to use.
The chiral monodentate phosphine ligand
(
R
)
-
L*
(see Figure 1 in the main text)
was purchased
S
2
from Strem and used without further purification.
15
N
-
labeled ani
line (98%+) was purchased
from Cambridge Isotope Laboratories and used as received. All other reagents were purchased
from commercial vendors and used without further purification unless otherwise stated.
Concentration under reduced pressure was performed
by rotary evaporation at 25
30 ºC at
reduced
pressure. SFC analyses were carried out using Daicel CHIRALPAK® columns
(internal diameter 4.6 mm, column length 250 mm, particle size 5 μm). Purified compounds
were further dried under high vacuum (0.01
0.05 To
rr). Yields refer to purified and
spectroscopically pure compounds.
X
-
ray crystallography.
X
-
ray diffraction (XRD) measurements were carried out in the Beckman
Institute Crystallography Facility. XRD measurements were collected using a dual source
Bruker D8 Venture, four
-
circle diffractometer with a PHOTON CMOS detector. Structures
were solved using SHELXT and refined against
F
2
on all data by full
-
matrix least squares with
SHELXL and OLEX2. Hydrogen atoms were added at calculated positions and refi
ned using a
riding model. The crystals were mounted on a glass fiber or a nylon loop with Paratone N oil.
Infrared and UV
-
vis Spectroscopy.
IR measurements were recorded on a Bruker ALPHA
Diamond ATR. Absorbance spectroscopy measurements were acquired on
a Cary 50 UV
-
vis
spectrophotometer using a 1 cm quartz cell with a Unisoku Scientific Instruments cryostat to
maintain temperature.
NMR spectroscopy.
1
H,
2
H,
13
C,
31
P NMR spectra were recorded on a Bruker Ascend 400, a
Varian 300 MHz, a Varian 400 MHz, a
Varian 500 MHz, or a Varian 600 MHz spectrometer.
1
H
NMR
chemical shifts are reported in ppm, relative to tetramethylsilane
,
using residual proton
resonances from solvent as internal standards.
31
P
NMR
chemical shifts are reported in ppm
relative to 85% aq
ueous H
3
PO
4
.
15
N
NMR
chemical shifts are reported in ppm relative to NH
3
.
Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad
CW EPR spectroscopy.
All
X
-
band
continuous
-
wave
(
CW
)
EPR spectra were obtained on a
Bruker EMX spectrometer using a quartz liquid nitrogen immersion dewar
on solutions
prepared as frozen glasses in toluene, unless otherwise noted.
Pulse EPR spectroscopy.
All pulse EPR and electron nuclear double resonance (ENDOR)
experiments were aquired using a Bruker (Billerica, MA) ELEXSYS E580 pulse EPR
spectromete
r
.
All Q
-
band data
were
acquired using a Bruker D2 resonator. Temperature
control was achieved using an ER 4118HV
-
CF5
-
L Flexline Cryogen
-
Free VT cryostat
manufactured by ColdEdge (Allentown, PA) equipped with an Oxford Instruments Mercury
ITC.
S
3
Q
-
band HYSCORE
spectra were acquired using the 4
-
pulse sequence (
!
/
2
%
!
/
2
'
!
!
'
"
!
/
2
echo), where
%
is a fixed delay, while
'
!
and
'
"
are independently incremented by
Δ
'
!
and Δ
'
"
, respectively. The time domain data was baseline
-
corrected (third
-
order
polynomial) to eliminate the exponential decay in the echo intensity, apodized with a
Hamming window function, zero
-
filled to eight
-
fold points, and fast Fourier
-
transformed to
yield the 2
-
dimensional frequency domain.
In general, the ENDOR spectrum for a given nucleus with spin
(
= ½ (
1
H,
31
P) coupled to the
S
=
½ electron spin exhibits a doublet at frequencies
)
±
=
+
,
2
±
)
$
+
(1)
Where
)
$
is the nuclear Larmor frequency and
,
is the hyperfine coupling. For nucle
i with
(
1
(
14
N,
2
H), an additonal splitting of the
)
±
manifolds is produced by the nuclear quadrupole
interaction (P)
)
±
,
&
!
=
+
)
$
±
3
1
(
2
3
'
1
)
2
+
(2)
In HYSCORE spectra, these signals manifest as cross
-
peaks or ridges in the 2
-
D
frequency
spectrum which are generally symmetric about the diagonal of a given quadrant. This
technique allows hyperfine levels corresponding to the same electron
-
nuclear submanifold to
be differentiated, as well as separating features from hyperfine coupl
ings in the weak
-
coupling
regime (
|
,
|
<
2
|
)
'
|
) in the (+,+) quadrant from those in the strong coupling regime (
|
,
|
>
2
|
)
'
|
) in the (−,+) quadrant. The (−,−) and (+,−) quadrants of these frequency spectra are
symmetric to the (+,+) and (−,+) quadrants, thus typ
ically only two of the quadrants are
typically displayed in literature.
For systems with appreciable hyperfine anisotropy in frozen solutions or solids, HYSCORE
spectra typically do not exhibit sharp cross peaks, but show ridges that represent the sum of
cross peaks from selected orientations within the excitation bandwidth of the MW pulses at
the magnetic field position at which the spectrum is collected. The length and curvature of
these correlation ridges can allow for the separation and estimation of t
he magnitude of the
isotropic and dipolar components of the hyperfine tensor, as shown in Fig
ure
S1.
S
4
Figure S1.
a) HYSCORE powder patterns for an
S
=
½
,
I
=
½
spin system with an isotropic
hyperfine tensor
A. b) HYSCORE powder patterns for an
S
=
½
,
I
=
½
spin system with an
axial
hyperfine tensor that contains isotropic (
8
()*
) and dipolar (
9
) contributions. Blue correlation
ridges represent the strong coupling case; red correlation ridges represen
t the weak coupling
case.
EPR Simulations.
Simulations of all CW and pulse EPR data were achieved using the
EasySpin
6
simulation toolbox (release 5.2.21) with Matlab 2018b using the following Hamiltonian:
:
;
=
<
+
=
>
,
@
A
B
+
<
$
@
$
=
>
,
(
B
+
A
B
F
(
B
+
(
B
G
(
B
(3)
In this expression, the first term corresponds to the electron Zeeman interaction term where
<
+
is the Bohr magneton, g is the electron spin g
-
value matrix with
principal
components g = [g
xx
g
yy
g
zz
], and
A
B
is the electron spin operator; the se
cond term corresponds to the nuclear Zeeman
interaction term where
<
$
is the nuclear magneton,
@
$
is the characteristic nuclear g
-
value for
each nucleus (e.g.
1
H,
2
H,
31
P) and
(
B
is the nuclear spin operator; the third term corresponds to the
electron
-
nu
clear hyperfine term, where
F
is the hyperfine coupling tensor with
principal
components
F
= [A
xx
, A
yy
, A
zz
]; and for nuclei with
(
1
, the final term corresponds to the
nuclear quadrupole (NQI) term which arises from the interaction of the
nuclear quadrupole
moment with the local electric field gradient (efg) at the nucleus, where
G
is
the
quadrupole
S
5
coupling tensor. In the
principal
axis system (PAS),
G
is traceless and parametrized by the
quadrupole coupling constant
H
"
IJ
/
and the as
ymmetry parameter
K
such that:
G
=
L
1
--
0
0
0
1
..
0
0
0
1
//
N
=
H
"
IJ
/
4
(
(
2
(
1
)
P
(
1
K
)
0
0
0
(
1
+
K
)
0
0
0
2
Q
(4)
where
0
"
12
3
=
2
(
(
2
(
1
)
1
//
and
K
=
4
##
5
4
$$
4
%%
. The asymmetry parameter may have values
between 0 and 1, with 0 corresponding to an electric field gradient with axial symmetry and 1
corresponding to a fully rhombic efg.
The orientations between the hyperfine and NQI tensor
principal
axis systems and
the g
-
matrix
reference frame are defined by the Euler angles (α, β, γ).
S
6
I
I
. Preparative syntheses of N
P
(H)
and N
P
-
ligated copper complexes
3,6
-
di
-
tert
-
butyl
-
1
-
(hydroxymethyl)carbazole
To a suspension of
1
-
bromo
-
3,6
-
di
-
tert
-
butylcarbazole (15 g, 42 mmol) in 400 mL Et
2
O in a 500
mL Schlenk flask,
n
-
BuLi
in hexanes (42.
5
mmol) was added at 0 °C under
a
nitrogen atmosphere
slowly over a period of 5 min. After 30 min, the mixture was cooled to
78 °C, and
tert
-
BuLi in
pentane (84 mmol, 2 equiv) was added slowly over a period of 15 min. The reaction mixture was
stirred for an additional 2 h, at
78 °C. Next, paraformaldehyde (2 g) was added in one portion
under a positive flow of nitrogen, and the suspension
was allowed to warm to room temperature
overnight. The resulting red solution was carefully quenched with saturated NH
4
Cl(aq) (100
mL) under
a
nitrogen atmosphere and transferred to a separatory funnel, and the resulting
yellow organic layer was washed wi
th NaCl(aq) (200 mL), dried over Na
2
SO
4
and concentrated
to yield pale yellow residue which
,
upon washing with cold hexanes
,
afforded a
spectroscopically pure, off
-
white solid (11 g, 85% yield). This material can be carried forward
as
is
,
or
additional pur
ification by column chromatography on silica gel can also be performed,
eluting with DCM
3% DCM/MeOH.
1
H NMR (600 MHz, CDCl
3
) δ 8.63 (br, 1H), δ 8.09 (d,
J
= 1.9 Hz, 1H), 8.05 (d,
J
= 1.8 Hz, 1H), 7.45
(dd,
J
= 8.5, 2.0 Hz, 1H), 7.37 (d,
J
= 8.5 Hz, 1H
), 7.28 (d,
J
= 1.8 Hz, 1H), 4.95 (s, 2H), 2.24 (s, 1H),
1.47 (s, 9H), 1.45 (s, 9H).
13
C NMR (151 MHz, CDCl
3
) δ 142.27, 141.96, 138.29, 137.08, 123.93, 123.80, 123.14, 122.00, 121.96,
116.26, 116.10, 110.46, 64.77, 34.81, 34.77, 32.17.
FT
-
IR (film):
3332, 2961, 2904, 2867, 1493, 1363, 1241, 1006, 873 cm
1
.
MS (ESI) m/z (M)+ calcd for C
21
H
27
NO: 309.2, found: 309.2.
8
-
bromo
-
3,6
-
di
-
tert
-
butyl
-
1
-
(hydroxymethyl)carbazole
A 250 mL flask was charged with 3,6
-
di
-
tert
-
butyl
-
1
-
(hydroxymethyl)carbazole (7.5 g, 24 mmol,
1 equiv) and a magnetic stir bar, before the addition of chloroform (150 mL). The solution was
S
7
then cooled to 0 °C and
N
-
bromosuccinimide (4.3 g, 24 mmol, 1 equiv) was added in portions.
After warming to r
oom temperature overnight, the white solid was collected by filtration and
washed with cold dichloromethane, yielding the title compound in spectroscopically pure form.
To recover the target compound in the filtrate, the filtrate was concentrated and the r
esidue was
purified by column chromatography, eluting with 10%
50% EtOAc/hexanes (8.4 g, 90% yield).
1
H NMR (300 MHz, CDCl
3
)
δ
8.67 (s, 1H), 8.00 (s, 2H), 7.60 (s, 1H), 7.33 (s, 1H), 5.11 (d,
J
= 6.1 Hz,
2H), 1.44 (s, 18H).
13
C NMR (101 MHz, CDCl
3
)
δ
144.2, 142.8, 136.9, 136.8, 126.1, 124.5, 124.3, 122.6, 116.5, 115.6,
104.0, 100.1, 64.9, 35.0, 34.9, 32.1.
FT
-
IR (film): 3548, 3221, 2958, 1560, 1362, 1007, 950, 875 cm
1
.
MS (ESI) m/z (M)
+
calcd
for C
21
H
26
BrNO: 387.1, found: 387.1.
3,6
-
di
-
tert
-
butyl
-
1
-
(hydroxymethyl) 8
-
mesitylcarbazole
To
a
250
mL
Schlenk
flask
was
charged
with
8
-
bromo
-
3,6
-
di
-
tert
-
butyl
-
1
-
(hydroxymethyl)carbazole (1.0 g, 2.5
8
mmol, 1 equiv), mesityl boronic acid (1.2
7
g, 7.7 mmol, 3
equiv), and Pd(PPh
3
)
4
(300 mg, 0.13 mmol, 0.10 equiv) was added degassed toluene (25 mL),
ethanol (12 mL), and 2 M K
2
CO
3
(aq) (10 mL) under an N
2
atmosp
here. The reaction mixture was
heated to 90 °C for 15 h. After cooling to room temperature, the mixture was extracted with
EtOAc (3 × 50 mL), and the combined organic layer was dried over Na
2
SO
4
, filtered, and
concentrated. The residue was purified by colu
mn chromatography (eluting with 10%
30%
EtOAc/hexanes) to afford 0.9 g of the title compound (80 % yield).
1
H NMR (300 MHz, CDCl
3
) δ 8.08 (d,
J
= 1.6 Hz, 1H), 8.07 (br, 1H), 8.05 (d,
J
= 1.7 Hz, 1H), 7.28
(d,
J
= 1.7 Hz, 1H), 7.23 (d,
J
= 1.8 Hz, 1H), 7
.03 (s, 2H), 4.94 (d,
J
= 4.6 Hz, 2H), 2.39 (s, 3H), 1.98
(s, 6H), 1.45 (s, 9H), 1.45 (s, 9H)
13
C NMR (101 MHz, CDCl
3
) δ 142.71, 141.97, 137.43, 137.41, 137.29, 137.04, 136.69, 135.36, 128.48,
125.03, 124.27, 123.18, 122.91, 122.25, 122.08, 116.32, 114.72
, 64.56, 34.92, 34.81, 32.23, 32.19, 21.32,
20.38.
FT
-
IR (film): 3534, 3306, 2961, 1610, 1494, 1362, 1242, 1002, 870 cm
1
.
MS (ESI) m/z (M+Na)
+
calcd for C
30
H
37
NONa: 450.3, found: 450.3.
3,6
-
di
-
tert
-
butyl
-
1
-
(bromomethyl)
8
-
mesitylcarbazole
S
8
A 100 mL round
-
bottom
ed
flask was charged with 3,6
-
di
-
tert
-
butyl
-
1
-
(hydroxymethyl) 8
-
mesitylcarbazole (0.85
5
g, 2.0 mmol, 1 equiv
) and a magnetic stir bar. The flask was placed under
a
nitrogen atmosphere and the starting material was dissolved in degassed DCM (20 mL, 0.1 M).
After cooling to 0 °C, phosphorus tribromide (0.19 mL, 2.0 mmol, 1 equiv) was added dropwise,
and the result
ing solution was stirred for an additional 30 min at 0 °C. Next, the mixture was
transferred to a separatory funnel containing NaHCO
3
(aq) (30 mL). The organic layer was
washed with brine (30 mL), dried over Na
2
SO
4
, filtered, and concentrated
in vacuo
to af
ford 0.95
g
(
97% yield
)
of the title compound as
a
pale yellow solid. This material can be directly used for
the next step but can be further purified by recrystallization in pentane
.
1
H NMR (400 MHz, CDCl
3
) δ 8.11 (d,
J
= 2.2 Hz, 1H), 8.05 (d,
J
= 2.2 Hz
, 1H), 7.70 (br, 1H), 7.39
(d,
J
= 1.8 Hz, 1H), 7.27 (d,
J
= 1.8 Hz, 1H), 4.75 (s, 2H), 2.42 (s, 3H), 2.03 (s, 6H), 1.46 (s, 9H), 1.45
(s, 9H).
13
C NMR (101 MHz, CDCl
3
) δ 143.34, 142.59, 137.54, 137.36, 136.79, 136.61, 134.78, 128.74, 125.48,
124.77, 123.9
0, 123.32, 123.13, 118.70, 117.64, 114.93, 34.97, 34.83, 32.39, 32.16, 32.15, 21.30, 20.44.
MS (ESI) m/z (M)
+
calcd for C
30
H
36
BrNO: 489.2, found: 489.2.
3,6
-
di
-
tert
-
butyl
-
1
-
((
di
-
isopropylphospino)methyl) 8
-
mesitylcarbazole
(NP(H))
To the 3,6
-
di
-
tert
-
butyl
-
1
-
(bromomethyl) 8
-
mesitylcarbazole (0.49 g, 1.0 mmol) in
dichloromethane (10 mL), a solution of di
-
iso
-
propylphosphine
7
(0.12 g, 1.0 mmol, 1 equiv
) in
DCM (10 mL) was added in one portion. The solution was stirred overnight and concentrated
in vacuo
to afford yellow residue. The residue was washed with
n
-
pentane, re
-
suspended in
DCM (10 mL), and stirred for 30 min after adding dry, degassed triethyl
amine (2 mL). Next,
volatiles were removed
in vacuo
and the residue was extracted in benzene (10 mL). The resulting
white precipitate (NH
4
Br) was removed by filtration and the filtrate was concentrated and
layered with either
n
-
pentane or CH
3
CN to precipit
ate the title compound as off
-
white solid
(0.44 g, 84% yield).