A general electrochemical strategy for the Sandmeyer reaction

Article abstract of DOI:10.1039/c8sc03346c

Herein we report a general electrochemical strategy for the Sandmeyer reaction. Using electricity as the driving force, this protocol employs a simple and inexpensive halogen source, such as NBS, CBrCl₃, CH₂I₂, CCl₄, LiCl and NaBr for the halogenation of aryl diazonium salts. In addition, we found that these electrochemical reactions could be performed using anilines as the starting material in a one-pot fashion. Furthermore, the practicality of this process was demonstrated in the multigram scale synthesis of aryl halides using highly inexpensive graphite as the electrode. A series of detailed mechanism studies have been performed, including radical clock and radical scavenger study, cyclic voltammetry analysis and in situ electron paramagnetic resonance (EPR) analysis.

Full text of DOI:10.1039/c8sc03346c

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A General Electrochemical Strategy for Sandmeyer Reaction
Qianyi Liu,a Beiqi Sun,a Zheng Liu,b Yi Kao,b Bo-Wei Dong,b Shang-Da Jiang,b Feng Li,c Guoquan Liu,c
Yang Yang d and Fanyang Mo *a
Received 00th January 20xx,
Accepted 00th January 20xx
Herein we report a general electrochemical strategy for the Sandmeyer reaction. Using electricity as the driving force, this
protocol employs simple and inexpensive halogen source, such as NBS, CBrCl3, CH2I2, CCl4, LiCl and NaBr for the
halogenation of aryl diazonium salts. In addition, we found these electrochemical reactions could be performed using
anilines as the starting material in a one-pot fashion. Furthermore, the practicality of this process was demonstrated in the
multigram scale synthesis of aryl halides using highly inexpensive graphite as the electrode. A series of detailed mechanism
studies has been performed, including radical clock and radical scavenger study, cyclic voltammetry analysis and in situ
electron paramagnetic resonance (EPR) analysis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
radical intermediate can react with an arene or another aryl radical
to give a biaryl side product (Scheme 1Bb).35 Third, the well-
documented reaction of diazonium salts with the electrode can
Introduction
The Sandmeyer reaction represents a fundamentally important
method to convert an aryl amine to an aryl halide via the
alter its properties and reduce the efficiency of electrochemical
processes (Scheme 1Bc).36-38 We envision that the regulation of
electric current to control the rate of aryl radical generation and the
judicious choice of halogenation reagents to rapidly intercept the
nascent aryl radical would be the key to this electrochemical
Sandmeyer reaction (Scheme 1Bd). In this report, we demonstrate a
general electrochemical strategy for the Sandmeyer halogenation of
intermediacy of a diazonium salt.1 Discovered in 1884,2, this
3
century-old transformation is still being extensively used in modern
organic synthesis in both academic and industrial settings.4-8 To
date, many synthetically useful variants of Sandmeyer reaction have
been reported, including copper metal mediated process
(Gattermann reaction),9 diazotization in organic phases (Doyle
diazotization),10, 11 Cu(I)-catalyzed process12 and acetate-facilitated aryl diazonium salts.
metal-free halogenation.13 Despite these valuable advances,9-15 the
A. Electrochemical Sandmeyerreaction
development of new strategy for Sandmeyer reaction is still of great
importance.
Cathode
reduction
Halogen
abstraction
N2X
X
R
R
R
The past decade has witnessed a resurging interest in organic
electrochemistry that dramatically improved organic chemists’
ability for green and sustainable synthesis.16-29 Our laboratory has
been engaged in the development of organic electrochemistry to
overcome unmet synthetic challenges.30, 31 In this context, we have
recently become interested in electrocatalytic transformations of
diazonium salts (Scheme 1A). An efficient electrochemical method
for Sandmeyer reaction is hampered by several factors. First,
diazonium salts can engage in undesired two-electron reduction,32,
+e, -N2
[X]
[X]: NBS, CBrCl3, NIS, CH2I2, NCS, TCCA, LiCl, CaCl2, etc.
Cl
O
O
O
O
N
O
N
Br
N
I
N
Cl
N
N
Cl
Cl
O
O
O
O
NBS
NIS
NCS
TCCA
Ar
33
B. Challenge and solution
e-
leading to the formation of an aryl anion that could be easily
ArH
a. two-electron
protonated to give the reduction product (Scheme 1Ba). Second,
known as the Gomberg-Bachmann reaction,34 the transient aryl
reduction
b. ArH or
dimerization
Ar Ar
Ar
e-
Ar
Ar
ArN2BF4
transient
radical
Ar
Ar
c. electrografting
electrode surface
modification
d. radical-reactive
reagent
Ar
X
[X]
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Scheme 1 Electrochemical Sandmeyer halogenation reaction.
could be efficiently chlorinated using LiCl as the electrochemical
chlorine reagent. For instance, sulfone substituted product 4m was
obtained in 64% isolated yield.
Results and discussion
The
electrochemical
bromination
of
aryldiazonium
Table 1 Reaction development and optimization
tetrafluoroborate 1a was selected as the model reaction with N-
bromosuccinimide (NBS) as the halogen source. The results are
depicted in Table 1 (entries 1-7). Acetonitrile and DMF were first
evaluated due to the good solubility of substrates and electrolytes
in these solvents. Under these conditions, the desired product ethyl
4-bromobenzoate (2a) formed in low yields (entry 1-2). The major
byproduct was found to be ethyl benzoate as indicated by GC-MS
analysis of the crude reaction mixture, showing that protonation or
hydrogen abstraction11 was the major undesired pathway. We then
evaluated other solvents, and the use of a mixed solvent system
consisting of MeOH and DMF (entries 3-6) provided higher yield of
2a. Under the optimized reaction conditions using a 5:1 (v:v)
mixture of MeOH/DMF as the solvent, Bu4NClO4 as the electrolyte
and a constant current of 10 mA and time of 3 h (3.7 F/mol
electricity), the desired bromination product (2a) formed in 83%
yield. Finally, control experiments were conducted without current
(entry 7), and significantly lower yield of 2a was observed. This
demonstrated that the desired product was predominantly
obtained from the electrochemical process.
entrya
solvent
MeCN
I (mA)
10
yield (%)b
trace
34
1
2
3
4
5
6
7
DMF
10
10
25
MeOH/DMF 10:1
MeOH/DMF 10:1
MeOH/DMF 10:1
MeOH/DMF 5:1
MeOH/DMF 5:1
51
73
50
10
58
83 (73)
20, 31c
0
The iodination of 1a was next examined (entries 8-10).
Compared with N-iodosuccinimide (NIS) (entry 8), CH2I2 was found
to be a better iodinating agent in this electrochemical reaction. The
desired product (3a) was obtained in 87% isolated yield under the
optimized conditions (entry 9). Again, this iodination was
unambiguously driven by electricity as revealed by the control
experiment (entry 10).
entry
[I]
I (mA)
10
10
yield (%)b
8
9
10
NIS
CH2I2
CH2I2
37
(87)
14
0
Compared with bromination and iodination, the electrochemical
chlorination of diazonium salts was more challenging. Due to the
higher electronegativity of chlorine, NCS39 and TCCA40 behaved
more like oxidants rather than chlorine donors. Inspired by Lin’s
recent work on the electrocatalytic chlorination of alkenes,41, 42 we
used anodic oxidation to generate chlorine radical from chloride
anion. A series of alkali chlorides, cathode materials and solvents
were evaluated. Ultimately, LiCl was found to be the optimal
chlorine source with nickel as the cathode and acetonitrile as the
solvent (entries 13-15).
entry
[Cl] (equiv)
electrolyte
I (mA)
yield (%)b
16
11
12
13d
14d
15d
NCS (3)
TCCA (3)
LiCl (6)
Bu4NClO4
Bu4NClO4
LiClO4
10
10
20
10
0
18
49
CaCl2 (5)
LiCl (6)
LiClO4
LiClO4
trace
11
a
Reaction conditions: 1a (0.3 mmol), halogenation reagent [X],
electrolyte (0.25 mmol, 0.83 equiv), solvent (3 mL), 20 oC, 3 h. cc,
constant current. Pt mesh electrodes (1 cm2 each, 52 mesh) were
used. b GC-FID yields using decane as an internal standard. Isolated
With the optimal reaction conditions, we then surveyed the
substrate scope (Table 2). For bromination using NBS, aryl
diazonium salts with an electron-withdrawing group, including an nickel foam (1 cm2) as the cathode.
c
d
yields in parentheses. 15 h. MeCN (3 mL) as the solvent and
ester (2a-2c), a nitro (2d-2g), a cyano (2h and 2i), a halogen (2j-2l), a
Anilines are broadly available starting materials for organic
trifluoromethyl (2m) and a sulfonyl group (2n), furnished the
corresponding brominated products in good to excellent yields. For
electron-neutral or electron-rich diazonium salts, the use of NBS led
to polybromination as revealed by GC-MS analysis. In these cases,
CBrCl3 proved to be a better brominating agent using DMF as the
solvent (2o-2t).
synthesis. Thus, it is highly desirable to perform in situ
diazotization/electrochemical reaction to directly employ anilines as
the precursors for halogenation. As shown in Table 3, a diverse
array of aryl amines was successfully transformed to the
corresponding halogenated products in good to excellent yields (42-
83%). This one-pot protocol tolerated a number of functional
groups, such as a boronic ester (3aa), an amide (3ab-3ad) and an
indole (3ae). In general, aryl amines with an electron-withdrawing
group gave relatively higher yield. For instance, bromination of 4-
cyanoaniline under the one-pot protocol gave 83% GC yield (2h);
iodination of N-(4-aminophenyl)acetamide gave 78% isolated yield
(3ab). Moreover, it is noteworthy that the aniline derived from
Vitamin E was also iodinated in 59% isolated yield (3af).
Moreover, under analogous electrochemical conditions, the
iodination of aryl diazonium salts bearing an electron-withdrawing
group, such as an ester (3a-3c), a cyano (3h and 3i), a halogen (3j-
3l), a trifluoromethyl (3m), a sulfonyl (3n) and an acetyl (3u, 3v),
gave good yields (63-96%). Additionally, electron-neutral aryl
diazonium salts were also suitable substrates for this procedure
(3o-3q, 3s). Last, a range of diazonium salts (4a, 4k, 4m, 4n and 4o)
2 | J. Name., 2012, 00, 1-3
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Table 2 Scope of Diazonium Salts Electrochemical Sandmeyer Reactiona
ARTICLE
Bu4NClO4 (0.83 equiv)
MeOH/DMF 5:1 (0.15 M)
N2BF4
X
[X]
+
R
R
20 oC, 10 mA, 3 h
(-)Pt/(+)Pt
1
undivided cell, in air
2, 3, 4
NBS (2.0 equiv)
EtO2C
Br
EtO2C
Br
Br
Br
Br
O2N
Br
Br
O2N
Br
O2N
NO2
CO2Et
2a, 73% (83%)
2b, 42% (53%)
2d, 84% (86%)b,c
2e, 54%b
2f, 61%b
2g, 75%
2c, 30% (52%)
(NBS 3.0 equiv)
Br
Br
Br
Br
Br
Br
F3C
MeO2S
NC
CN
2i, 84%
Cl
Br
I
2h, 84%
2j, 52% (64%)
2k, 81%b
2l, 68%b
2m, 93%d
2n, 85%
(NBS 3.0 equiv)
(NBS 3.0 equiv)
(NBS 3.0 equiv)
NaBr (3.0 equiv)
CBrCl3 (3.0 equiv)
Br
Br
Br
Br
Br
Br
Br
Br
O2N
F
MeO
MeO
2s, (75%)e
2t, 37%d, e
2d, (49%)h
2o, (66%)h
2r, (37%)h
2s, (62%)h
2o, (66%)e,f
2r, (55%)e,g
CH2I2 (3.0 equiv)
I
I
I
I
I
I
I
EtO2C
I
EtO2C
CO2Et
O2N
NC
CN
Cl
3j, 60% (81%)
3d, (45%)g
3h, 93%
3i, 76%
3a, 87%
3b, 87%
3c, 74%
I
I
I
I
I
I
F3C
MeO2S
Br
I
3m, 96%d
3q, (53%)
3p, (47%)
3l, 56% (77%)
3n, 63%
3o, (71%)
3k (2l), 61% (89%)
O
I
I
I
I
I
I
I
N
N
MeO
F
Ac
Ac
O
3t, 48%c
3u, 87%
3v, 70%
3w, 68%
3x, 39%
3r, (37%)
3s, (78%)
LiCl (6.0 equiv)
Cl
Cl
Cl
Cl
Cl
EtO2C
4a, (36%)h,i
F3C
MeO2S
4n, 64%h,i
Br
4k (2j), (37%)h,i
4m, 31%d,h,i
4o, (49%)h,i
a
o
Reaction conditions: 1 (0.3 mmol), Bu4NClO4 (0.25 mmol, 0.83 equiv), CH3OH (2.5 mL) and DMF (0.5 mL), 20 C, 3 h, constant current 10
mA. Pt mesh electrodes (1cm × 1cm) were used. Isolated yields were given. GC-FID yields in parentheses were given due to either product
b
c
volatility or difficulty in isolation with by-product (e.g. ArH). CH3OH/DMF 20:1 (total 3.0 mL). 1 h. d 19F NMR yields determined using 4-
(trifluoromethoxy)anisole as an internal standard. DMF (3 mL). f 4.5 h. 2 h. MeCN (3 mL), LiClO4 (0.5 mmol) as electrolyte. 20 mA, Ni
e
g
h
i
foam cathode.
electrochemical reduction of diazonium salts takes place at the
To further demonstrate the utility of this electrochemical
cathode, we applied inexpensive graphite plate electrodes with a
protocol, gram-scale experiments were next carried out. Since the
large size to lower the current density (J = 2.78 mA/cm2). By using
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the cyclized product 6 in 37% yield as determined by 1H NMR
spectroscopy, and the acyclic product was not detected by GC-MS
and 1H NMR analysis. Next, electrochemical reaction of 1a with
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was conducted,
affording arylated product 7 in 62% isolated yield (Scheme 3B). This
is well in accord with the Studer’s report.43 In their paper, they have
demonstrated that TEMPONa is capable of reducing diazonium salt
to its aryl radical, thus facilitating the following transformation.
the setup shown in Scheme 2, 2h was prepared from 1h on a three-
gram scale (15 mmol) in 76% yield. Similarly, 3h was prepared on a
three-gram scale in 80% yield.
Table 3 One Pot Diazotization/Electrochemical Reaction.a
1) tBuONO (1.1 equiv), solvent
acid, 0 oC, 0.5 h
Ar NH2
Ar
X
2) [X], Bu4NClO4 (0.83 equiv)
(-)Pt/(+)Pt, 10 mA, 20 oC, 3 h
100 mA, 10 h
(-)Graphite/(+)Pt
MeOH/DMF
N2BF4
X
Br
Br
Br
[X]
+
J = 2.78 mA/cm-2
NC
NC
at cathode
EtO2C
NC
1h, 15 mmol
3.26 gram
2a, (60%)
2h, X = Br, 76%, with NBS (2.0 equiv)
3h, X = I, 80%, with CH2I2 (3.0 equiv)
2h, (83%)
2o, (57%)
NBS (2.0 equiv)
NBS (2.0 equiv)
CBrCl3 (3.0 equiv)
Pt anode
Br
Br
Br
MeO
tBu
Ph
2r, (61%)
CBrCl3 (3.0 equiv)
2y, (53%)
2z, (42%)
CBrCl3 (3.0 equiv)
CBrCl3 (3.0 equiv)
I
Graphite cathode
I
I
O
B
Scheme 2 Gram-Scale Electrochemical Sandmayer Reactions. A Pt
mesh electrode (1cm × 1cm, 52 mesh) as the anode, and 4 graphite
plates (4 × 3 cm × 3 cm immersed in the solution) as the cathodes.
EtO2C
O
AcHN
3a, (76%)
3aa, 72%
3ab, 78%
A. Electrochemical clock reaction
CH2I2 (3.0 equiv)
CH2I2 (3.0 equiv)
CH2I2 (3.0 equiv)
I
Bu4NClO4
N2BF4
MeOH/DMF 5:1
20 oC, 10 mA, 3 h
CH2I2
+
I
I
I
O
H
O
3.0 equiv
O
EtO2C
N
N
N
5
6, 37% (NMR)
I
Ts
O
O
not detected
23% (ISO)
3ac, 71%
CH2I2 (3.0 equiv)
3ad, 53%
3ae, 45%
O
CH2I2 (3.0 equiv)
CH2I2 (3.0 equiv)
B. Reaction with TEMPO
N2BF4
I
Bu4NClO4
MeOH/DMF 5:1
O
+
TEMPO
2 equiv
(-)Pt/(+)Pt
20 oC, 10 mA, 3 h
EtO2C
O
O
1a
O
N
3af, 59%
CH2I2 (3.0 equiv)
EtO2C
a
t
Reaction conditions: aryl amine (0.3 mmol), BuONO (0.33 mmol,
7, 62% (ISO)
1.1 equiv), HCl (5 M in Et2O, 90 µL, 0.45 mmol, 1.5 equiv), CH3OH
2.5 mL, DMF 0.5 mL, 0 oC, 0.5 h; then Bu4NClO4 (0.25 mmol, 0.83 Scheme 3 Control experiments.
o
equiv), [X], 20 C, 3 h, constant current 10 mA. Pt mesh electrodes
(1cm × 1cm) were used. Isolated yields were given. GC-FID yields
were shown in parentheses. For details, see ESI.
To probe this electrically generated aryl radical species, we carried
out a range of mechanistic experiments. First, a radical clock
experiment was performed by using diazonium salt 5 derived from
2-(allyloxy)aniline as the substrate (Scheme 3A). We obtained only
4 | J. Name., 2012, 00, 1-3
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Figure 1 Cyclic Voltammetry Curves.
B
A
1a
1a
NBS
-0.120 V
TEMPO
(1a+TEMPO)
0.214 V
0.269 V
1a+NBS
The mechanism of electrochemical reduction of diazonium salt
has been studied by means of polarography.44 Here we further
apply this technics in our reaction system. Thus, cyclic voltammetry
(CV) measurements of 1a with a series of radical-reactive reagents
were taken. The CV curve of 1a gave two waves, corresponded to
the reduction of aryl diazonium to aryl radical and further to aryl
anion, respectively. This is in good agreement with literature
report.45 Whereas the CV curves of 1a with reagents (TEMPO, NBS,
CH2I2 and CCl4 in these cases, respectively) give only one reduction
peak, indicating that the nascent aryl radical reacts with these
reagents, thus likely has no chance to be further reduced on the
cathode (Figure 1). These experimental results are consistent with
the hypothesis shown in Scheme 1Bd.
-0.120 V
0.495 V
0.269 V
0.574 V
1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 -0.4
1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 -0.4
E / V vs SCE
E / V vs SCE
C
D
1a
CH2I2
1a
CCl4
1a+CH2I2
-0.120 V
1a+CCl4
-0.120 V
-0.019 V
0.395 V
0.269 V
0.269 V
1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 -0.4
1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 -0.4
E / V vs SCE
E / V vs SCE
Figure 2 (A) Four in situ EPR electrochemical reactions. Photograph of EPR flat cell with home-made electrolysis setup is shown. (B) Time
dependent EPR profile of reaction b. For the EPR profile of reactions a, c and d, see Figure S5 in Electronic Supplementary Information. (C)
EPR signal at different time of reactions a-d. (D) Time evolution of double-integrated intensity of the signals of in situ EPR electrochemical
reactions a-d. a. u., arbitrary unit.
Electron paramagnetic resonance (EPR) is
a
spectroscopic utilized to study the electrochemically generating organic radicals.46
technique capable of detecting and identifying paramagnetic Here, we applied EPR spectroelectrochemistry to study the current
species, such as organic radicals, thus providing essential electrochemical Sandmeyer reaction. In our setup, we combined a
information on the nature of reactive intermediates in single common Bruker Elexsys E580 spectrometer with a Super-high
electron transfer reactions. EPR spectroscopy has been extensively sensitivity probe head (ω = 9.80 GHz) and a standard flat cell (0.3
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mm in depth) with ultrathin Pt wires (Φ 0.2 mm) for this in situ
study (Figure 2A). Using this setup, electrolysis experiments and in
situ EPR measurements were first performed on samples containing
diazonium salt 1a and NBS in MeOH/DMF with n-Bu4NClO4 as the
electrolyte. EPR signals were not observed, presumably due to the
high reactivity and low concentration of these radical intermediates.
Consequently,
N-benzylidene-tert-butylamine N-oxide (PBN) was
introduced to the experiments as a spin-trap.47 Spin-traps react
with short-living radicals and convert them to more stable, EPR
detectable radical species. The choice of PBN is based on Bard’s
report,48 where they found that PBN is electroinactive between 1.5
and -2.4 V (vs. SCE). Thus, four electrochemical reactions a-d were
followed by in situ EPR spectroscopy using PBN as the spin-trap
(Figure 2A). The EPR spectrum was acquired in an interval of 30 s
over the course of 100 min. These EPR signals were then compiled
as a time dependent 2D profile (for reaction b, see Figure 2B; for
reactions a, c and d, see Figure S5). Figure 2C shows the EPR signals
of these reactions at different reaction time, and figure 2D shows
time dependent double-integrated intensity of these in situ EPR
signals.
In these reactions, no major EPR signal is observed until
electricity is on. The isotropic
g factor and hyperfine coupling
constants of these radical EPR signals were simulated using the
least-squares fitting method with EasySpin’s function garlic (For
details, see ESI). As expected, radicals in reactions a, b and c are
different and in d resembles c (Figure 2C). The contrasting growth
rates of intensity shown in Figure 2D provided valuable mechanistic
information. By comparing reaction a and b, a rapid growth
observed in reaction b indicated that diazonium salt 1a was rapidly
reduced to an aryl radical upon electrolysis. The resulting aryl
radical was trapped by PBN to afford an EPR active species. Based
Scheme 4 Proposed reaction events on both electrodes and in
solvent bulk.
Conclusion
In summary, we have developed a general electrochemical protocol
for the Sandmeyer halogenation process. A diverse range of
functional groups were compatible with this electrochemical
reaction. Anilines can be directed employed as the starting material,
further expanding utility of this method. Moreover, this method is
amenable to the large-scale synthesis of aryl halides, and very
inexpensive graphite can be employed instead of platinum as the
cathode material for these large-scale preparation. Importantly,
detailed mechanism studies, including the application of rarely used
in situ EPR measurements, supports a single electron reduction
mechanism for the halogenation of diazonium salts upon
on a six-line EPR spectrum (
g
= 2.0039, aN = 13.02 G, aH = 2.37 G) 47,
and HRMS data, this radical could be likely attributed as
compound . In reactions c and d, the intensity grow slowly as
48
8
compared with reaction b, indicating that the addition of NBS
changes the reaction pathway of electrically generated radicals. In
reaction d, the intensity rapidly decayed when the current was
turned off, also demonstrating an electricity driving radical
generation process. These in situ EPR electrochemical experiments
and previous cyclic voltammetry studies demonstrated that
diazonium salts can readily undergo single electron reduction
processes on the cathode, and the resulting aryl radical is a highly
reactive species that can be trapped by many radical trapping
reagents, such as NBS, CH2I2, PBN and TEMPO. Meanwhile, the
solvents (e.g. MeOH) can be oxidized on anode49 to balance the
overall transformation (Scheme 4).
electrolysis. This electrochemical process could be
a
complementary method for the existing Sandmeyer halogenation
reactions, and might inspire other Sandmeyer type transformations
(e.g. noble metal free trifluoromethylation50-52) in the near future.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The project is supported by the Natural Science Foundation of
China (Grants 21502003 and 21772003). We also thank the
“1000-Youth Talents Plan” and Peking University for start-up
funds. Y.Y. thanks the Miller Institute for Basic Research in
Science at UC Berkeley for a post-doctoral fellowship.
Notes and references
6 | J. Name., 2012, 00, 1-3
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Page 7 of 8
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Journal Name
ARTICLE
1.
2.
3.
L. Kurti and B. Czakó, Strategic applications of named 36.
D. Belanger and J. Pinson, Chem. Soc. Rev., 2011, 40
3995-4048.
G. L. C. Paulus, Q. H. Wang and M. S. Strano, Acc. Chem.
Res., 2013, 46, 160-170.
A. Berisha, M. M. Chehimi, J. Pinson and F. Podvorica,
Electroanalytical Chemistry, A Series of Advances, 2015,
26, 115-224.
S. C. Virgil, T. V. Hughes, D. Qiu and J. Wang, in
Encyclopedia of Reagents for Organic Synthesis, John
,
reactions in organic synthesis, Elsevier, 2005.
T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 1633- 37.
1635.
T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 2650- 38.
2653.
4.
5.
6.
7.
H. H. Hodgson, Chem. Rev., 1947, 40, 251-277.
C. Galli, Chem. Rev., 1988, 88, 765-792.
E. B. Merkushev, Synthesis, 1988, 1988, 923-937.
F. Mo, G. Dong, Y. Zhang and J. Wang, Org. Biomol. Chem.
2013, 11, 1582-1593.
F. Mo, D. Qiu, Y. Zhang and J. Wang, Acc. Chem. Res.
2018, 51, 496-506.
L. Gattermann and A. Cantzler, Ber. Dtsch. Chem. Ges.
1892, 25, 1086-1091.
M. P. Doyle, J. F. Dellaria, B. Siegfried and S. W. Bishop, J.
Org. Chem., 1977, 42, 3494-3498.
M. P. Doyle, B. Siegfried and J. F. Dellaria Jr, J. Org. Chem.
1977, 42, 2426-2431.
I. P. Beletskaya, A. S. Sigeev, A. S. Peregudov and P. V.
Petrovskii, Synthesis, 2007, 2007, 2534-2538.
D. A. Leas, Y. Dong, J. L. Vennerstrom and D. E. Stack, Org.
Lett., 2017, 19, 2518-2521.
39.
,
,
,
Wiley
&
Sons,
Ltd,
2001,
DOI:
10.1002/047084289X.rc145.pub3.
8.
40.
G. A. Hiegel, G. Pozzi and AnuMahadevan, in Encyclopedia
of Reagents for Organic Synthesis, John Wiley & Sons, Ltd,
2001, DOI: 10.1002/047084289X.rt209.pub3.
N. Fu, G. S. Sauer and S. Lin, J. Am. Chem. Soc., 2017, 139,
15548-15553.
K.-Y. Ye, G. Pombar, N. Fu, G. S. Sauer, I. Keresztes and S.
Lin, J. Am. Chem. Soc., 2018, 140, 2438-2441.
M. Hartmann, Y. Li and A. Studer, J. Am. Chem. Soc., 2012,
134, 16516-16519.
R. M. Elofson and F. F. Gadallah, J. Org. Chem., 1969, 34
854-857.
E. R. Atkinson, H. H. Warren, P. I. Abell and R. E. Wing, J.
Am. Chem. Soc., 1950, 72, 915-918.
Peter Rapta, Evgenia Dmitrieva, Alexey A. Popov and L.
Dunsch, in Organic Electrochemistry: Revised and
Expanded, eds. Ole Hammerich and B. Speiser, CRC Press,
5 edn., 2016, ch. 3, pp. 169-190.
G. R. Buettner, Free. Radical. Bio. Med, 1987, 3, 259-303.
A. J. Bard, J. C. Gilbert and R. D. Goodin, J. Am. Chem. Soc.
1974, 96, 620-621.
9.
41.
42.
43.
44.
45.
46.
10.
11.
12.
13.
14.
15.
,
,
J. G. Lee and H. T. Cha, Tetrahedron Lett., 1992, 33, 3167-
3168.
H. Yang, L. Fu, L. Wei, J. Liang and B. P. Binks, J. Am. Chem.
Soc., 2015, 137, 1362-1371.
K. D. Moeller, Tetrahedron, 2000, 56, 9527-9554.
16.
17.
J. B. Sperry and D. L. Wright, Chem. Soc. Rev., 2006, 35
605-621.
,
47.
48.
,
18.
19.
A. Jutand, Chem. Rev., 2008, 108, 2300-2347.
J.-i. Yoshida, K. Kataoka, R. Horcajada and A. Nagaki, 49.
G. Sundholm, Acta Chem. Scand., 1971, 25, 3188-3189.
Chem. Rev., 2008, 108, 2265-2299.
50.
X. Wang, Y. Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang,
20.
21.
22.
23.
24.
25.
26.
R. Francke and R. D. Little, Chem. Soc. Rev., 2014, 43
2492-2521.
E. J. Horn, B. R. Rosen and P. S. Baran, ACS Cent. Sci.
2016, 2, 302-308.
R. Feng, J. A. Smith and K. D. Moeller, Acc. Chem. Res.
2017, 50, 2346-2352.
Y. Jiang, K. Xu and C. Zeng, Chem. Rev., 2017, DOI:
10.1021/acs.chemrev.7b00271.
M. Yan, Y. Kawamata and P. S. Baran, Chem. Rev., 2017,
117, 13230-13319.
W. Anton, G. Tile, M. Sabine, R. Eduardo, Z. Michael and
W. S. R., Angew. Chem. Int. Ed., 2018, 57, 5594-5619.
M. Sabine, Z. Michael, R. Eduardo, G. Tile, W. Anton and
W. S. R., Angew. Chem. Int. Ed., 2018, 57, 6018-6041.
,
,
,
Y. Zhang and J. Wang, J. Am. Chem. Soc., 2013, 135,
10330-10333.
J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu, L. Liu
and Y. Fu, J. Am. Chem. Soc., 2013, 135, 8436-8439.
G. Danoun, B. Bayarmagnai, M. F. Grünberg and L. J.
Gooßen, Angew. Chem. Int. Ed., 2013, 52, 7972-7975.
51.
52.
27.
28.
29.
G. S. Sauer and S. Lin, ACS Catal., 2018,
S. Tang, Y. Liu and A. Lei, Chem, 2018,
S. R. Waldvogel, S. Lips, M. Selt, B. Riehl and C. J. Kampf,
Chem. Rev., 2018, 118, 6706-6765.
8
, 5175-5187.
4
, 27-45.
30.
31.
32.
L. Zhang, Z. Zhang, J. Hong, J. Yu, J. Zhang and F. Mo, J.
Org. Chem., 2018, 83, 3200-3207.
L. Zhang, Z. Zhang, J. Zhang, K. Li and F. Mo, Green Chem.
2018, 20, 3916-3920.
,
E. R. Atkinson, C. E. Garland and A. F. Butler, J. Am. Chem.
Soc., 1953, 75, 983-984.
33.
34.
J. K. Kochi, J. Am. Chem. Soc., 1955, 77, 3208-3211.
M. Gomberg and W. E. Bachmann, J. Am. Chem. Soc.
1924, 46, 2339-2343.
,
35.
E. R. Atkinson, C. R. Morgan, H. H. Warren and T. J.
Manning, J. Am. Chem. Soc., 1945, 67, 1513-1515.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C8SC03346C
Electrochemical Sandmeyer Reaction
NH2 N2BF4
Halogen
Abstraction
X
R
R
R
R
NBS, CH2I2,
LiCl, NaBr...
In situ EPR electrochemical experiments
reaction a
7
6
5
4
3
2
1
0
reaction b
reaction c
reaction d
1
0
0
5
0
)
.
u
.
a
(
0
y
t
i
s
n
e
t
current off
(only for d)
n
-
5
0
I
-
1
0
0
current on
)
n
i
m
(
e
m
i
T
0
0
20
40
60
80
6
4
3
Time (min)