Coupling of Alternating Current to Transition-Metal Catalysis: Examples of Nickel-Catalyzed Cross-Coupling

Article abstract of DOI:10.1021/acs.joc.0c02350

The coupling of transition-metal to photoredox catalytic cycles through single-electron transfer steps has become a powerful tool in the development of catalytic processes. In this work, we demonstrated that transition-metal catalysis can be coupled to al

Full text of DOI:10.1021/acs.joc.0c02350

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Coupling of Alternating Current to Transition-Metal Catalysis:
Examples of Nickel-Catalyzed Cross-Coupling
Evgeniy O. Bortnikov and Sergey N. Semenov*
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Supporting Information
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ABSTRACT: The coupling of transition-metal to photoredox catalytic cycles
through single-electron transfer steps has become a powerful tool in the
development of catalytic processes. In this work, we demonstrated that
transition-metal catalysis can be coupled to alternating current (AC) through
electron transfer steps that occur periodically at the same electrode. AC-assisted
Ni-catalyzed amination, etherification, and esterification of aromatic bromides
showed higher yields and selectivity compared to that observed in the control
experiments with direct current. Our mechanistic studies suggested the importance
of both reduction and oxidation processes in the maintenance of the AC-assisted
catalytic reactions. As described in presented examples, the AC assistance should be well-suited for catalytic cycles involving
reductive elimination or oxidative addition as a limiting step.
INTRODUCTION1
that both oxidation and reduction processes are essential for
■
maintaining the sustainable catalytic pathway.3a,d,4a,b These
Ni-based catalysis has attracted much attention as an effective
tool for forming the C(aryl)−heteroatom bond,2 which is
mechanistic considerations led us to the idea of merging
alternating current (AC) with Ni-catalyzed cross-coupling
reactions (Figure 1C). AC authentically fits the idea of a
catalytic cycle assisted by a pair of redox processes. Because of
frequently found in drug-like molecules, dyes, and conjugated
polymers. However, Ni-catalytic systems are often inferior to
more prevalent but expensive Pd-catalytic systems. Unfavor-
the periodical polarity switch, both redox steps can successfully
able reductive elimination from Ni(II) species and the
occur at the same electrode with a tunable delay between them
instability of the Ni(I) species are among the factors causing
(Figure 1D). In this work, we performed AC-assisted Ni-
this inferiority. Nevertheless, Ni catalysis is susceptible to
catalyzed amination, etherification, and esterification of
facilitation by energy inputs from light or electricity because of
the availability of redox states of nickel ranging from 0 to +4
aromatic bromides. For all reactions, AC displayed advantages
over DC in our electrochemical cell.
(Figure 1A,B).
Currently, AC has a significantly more modest application in
By merging photoredox and nickel catalysis, MacMillan and
organic synthesis compared with DCgenerally, it is used for
others enabled previously elusive Ni-catalyzed C−C, C−N,
and C−O coupling reactions under batch and flow conditions.3
preventing electrode fouling. Notable works showed that AC
can be successfully applied in the electrosynthesis of phenol,12
In most situations, the coupling between photoredox and
trifluoromethylated arenes,13 or in accelerating S−S bond
nickel catalysis involves single-electron oxidation and reduction
metathesis through reversible redox steps.14
of nickel catalytic species by a photoredox catalyst (Figure
1A).4 Thus, oxidation to Ni(III) species enables reductive
RESULTS AND DISCUSSION
elimination, whereas reduction to Ni(0) species accelerates
oxidative addition. Later, Baran’s group, regarding the example
of C−N coupling, showed that the photocatalytic approach
might be successfully replaced with assistance by direct current
(DC) electrolysis.5 Here, nickel species are oxidized on one
electrode, enabling reductive elimination, and reduced on
another electrode, accelerating oxidative addition (Figure 1B);
the current-assisted catalytic cycle involving nickel species in
oxidation states +1, +2, and +3 was suggested.6 This approach
was effective for the C−S,7 C−P,8 Heck,9 and C−O coupling
reactions.10
■
We performed reactions in an electrochemical cell equipped
with two glassy carbon (GC) rod electrodes. A commercial
waveform generator supplied sinusoidal voltage to the
electrodes; we used an oscilloscope to measure both the
voltage and current in our experiments (Figures 2A and S3).
Received: October 4, 2020
Although some disagreements exist regarding key reaction
intermediates,6,11 mechanistic studies of both electrochemically
and photochemically enabled nickel cross-coupling suggest
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solvents [dimethylformamide (DMF) and dimethylacetamide
(DMA)] worked, but combining DMA with di-tBuBipy
provided better stability to the nickel complex in the solution
and more reproducible results than the other systems did. The
frequency of the applied voltage is a unique parameter for AC-
assisted catalysis. Interestingly, the dependency of yield on
frequency has a maximum of around 2 Hz (87%). The increase
in frequency to 25 Hz caused a steep drop in yield, most likely
because of the increased contribution of charging and
discharging of the electrical double layer (see Figure S6 for
quantitative analysis) and of nonproductive reversible Ni(II)/
Ni(I) and Ni(II)/Ni(0) oxidation/reduction cycles to the
current at high frequencies. At the same time, the decrease in
frequency as well as the use of DC also led to diminished
yields. We can speculate at this point that in case of the use of
AC assistance, some optimum “resonance” frequency exists
which is defined by the complex combination of the
parameters such as rates of chemical and electron-transfer
steps, rate of diffusion of the catalytic and non-catalytic species
from and to the surface of the electrodes, and stirring rate.
However, we expect that under specific conditions, the value of
“resonance” frequency may provide valuable data related to the
kinetics of the discussed reactions.
In contrast to amination, the base is an essential component
in esterification (Figure 2C). We achieved the best results
using a suspension of potassium carbonate unlike in photo-
activated esterification;17 organic bases were found to be less
effective. The increase of the ligand concentration or the use of
more sterically hindered ligands than bipyridine resulted in
diminished yields. The choice of NBu4PF6 as a supporting
electrolyte was instrumental for getting good yields of esters;
we suggest two possible reasons for that. First, carboxylate is a
relatively weak ligand; thus, eliminating the competition of
carboxylate with bromide at the nickel center increases the
efficiency of a catalytic cycle. Second, carboxylate is a more
electronegative group than amine or alcoholate; thus, the
oxidation potential of the [NiL(Ar)(RCOO)] species (e.g., 0.9
V vs SCE for [Ni(C6H3(CF3)2)(OAc)]) is expected to be
higher than that of [NiL(Ar)(OR)] and the [NiL(Ar)-
(NHR2)] species.3d,16 Avoiding excessive anodic oxidation of
Br− allows one to achieve higher oxidation potentials in
experiments with NBu4PF6 than with LiBr (Figure S19), which
might be necessary for the oxidation of the [NiL(Ar)-
(RCOO)] species. The optimum frequency for the ester-
ification reaction was 2 Hz. The control DC experiments at
potentiostatic (2.8 V) and galvanostatic (2, 4, and 6 mA)
conditions demonstrated low yields (13−26%) and high
amounts (22−53%) of the biaryl side product (see Table S2).
As esterification, etherification also requires the addition of a
base (Figure 2D); we tested 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) as
bases; however, the best results were achieved with
quinuclidine, analogously to photoredox-assisted etherifica-
tion.3d Interestingly, the use of non-cyclic tertiary amines led to
the formation of the homocoupling product in considerable
amounts (Table S3)presumably, they serve as sacrificial
reductants in this case. Comparing the results of AC- and DC-
assisted (both in the potentiostatic and galvanostatic modes)
etherification further highlights that AC assistance demon-
strates higher selectivity toward the formation of cross-
coupling products versus homocoupling products than DC
assistance. Moreover, the decrease in the amount of the biaryl
product occurs gradually with an increase in the frequency.
Figure 1. Some methods for activating Ni-based catalytic cycles by
sequential oxidation and reduction: (A) photoredox-assisted; (B) DC-
assisted; and (C) AC-assisted couplings. (D) Working hypothesis of
the mechanism underlying the coupling of AC to the nickel catalytic
cycle for cross-coupling reactions.
The combinations of NiBr2·DME (DMEdimethoxyethane)
with 2,2′-dipyridyl (Bipy) or 4,4′-Di-tert-butyl-2,2′-dipyridyl
(di-tBuBipy) were chosen as catalysts because they were
successfully employed in various catalytic systems.3d,6
To perform the catalytic cycle based on both reduction and
oxidation of the catalyst, the voltage should be sufficient to
perform the reduction on one of the electrodes, whereas the
oxidation occurs on another electrode. We proposed that
reduction of [Ni(Bipy)x]2+ to [Ni(Bipy)x]0 [for x = 3, −1.25 V
vs saturated calomel electrode (SCE) in CH3CN] is most likely
to be a process that would favor oxidative addition.15 Similarly,
oxidation of [NiL(Ar)(Nu)] to [NiL(Ar)(Nu)]+ (Lligand,
Araryl, Nunucleophile) would favor the reductive
elimination of Ar−Nu.16 Considering that the potential for
oxidation of [Ni(C6H3(CF3)2)(OCH2CF3)] to [Ni-
(C6H3(CF3)2)(OCH2CF3)]+ is 0.83 V versus SCE in
CH3CN, which is at the high end of the expected oxidation
potentials for the [NiL(Ar)(Nu)] species,3d a voltage higher
than ∼2.1 V is required to simultaneously perform the desired
oxidation and reduction of nickel species. We found a peak
voltage of 3 V to be effective in most of our experiments; in
such conditions the peak value of current varied from 10 to 20
mA in different experiments.
In the initial screening, we aimed to optimize the conditions
for amination, etherification, and esterification of aryl bromides
(Figure 2B−D and Tables S1−S3). We used the reaction
between bromobenzene (1) (50 mM) and morpholine (150
mM) for optimization of the amination conditions because 1
being a less reactive substrate than 4-bromobenzotrifluoride
(3) offered more room for the optimization (Figure 2B).
Different combinations of ligands (di-tBuBipy and Bipy) and
B
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Figure 2. (A) Experimental setup for the AC-assisted cross-coupling reactions. (B−D) Optimization of conditions for AC-assisted amination,
esterification, and etherification reactions, respectively. The comparison of the results of the experiments with AC assistance (using optimized
conditions) and DC-assistance (using potentiostatic and galvanostatic conditions) is given in red boxes.
Two hypotheses could explain these observations: (i) the
shorter lifetime of [NiL(Ar)(Nu)] species in the AC than in
the DC experiments and (ii) fewer chances for the second
oxidative addition in the AC than in the DC experiments. With
a short lifetime, [NiL(Ar)(Nu)] does not have time to
disproportionate appreciably to the [NiL(Ar)2] intermediate
with two aryl groups at one nickel center, which affords diaryl
coupling products by reductive elimination.18 In the DC
C
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Figure 3. Scope of AC-assisted nickel-catalyzed amination (A), esterification (B), and etherification (C). Isolated yields are shown. NMR yields are
shown in parentheses. DC-assisted control experiments were performed under potentiostatic or galvanostatic conditions. For details of the
a
experimental protocols, see the Supporting Information. Boctert-butyloxycarbonyl. A mixture of the corresponding amine hydrochloride (3
equiv) and K2CO3 (5 equiv) was used instead of amine. bSodium acetate (5 equiv) was used instead of a mixture of carboxylic acid and K2CO3. c2
mmol scale reaction was performed using a setup with four GC rod electrodes (see the Experimental Section and Supporting Information for
details).
experiments, a continuous strongly reducing environment near
the cathode increases chances that the oxidative addition
product [NiL(Ar)Br] will undergo reduction to Ni(I) species
and subsequently a second oxidative addition, resulting in
[NiL(Ar)2Br] intermediates that eliminate diaryl products.18,19
Next, we studied the substrate scope of the discussed
coupling reactions (Figure 3). Amination appears to be the
most robust reaction in relation to the activity of the
substratescouplings with non-activated (1), sterically
hindered aryl halides (o-bromotoluene), and halides bearing
electron-donor groups (m-bromoanisole) exhibited good yields
(61−74%) (Figure 3A). The amine scope is not limited only to
secondary and primary aminesthe hydrochlorides of amines
successfully reacted in the presence of the suspension of
K2CO3.
Esterification of 3 resulted in 48−75% yields for aliphatic-,
aromatic-, and Boc (tert-butyloxycarbonyl)-protected amino
acids (Figure 3B). Other electron-deficient aryl bromides (i.e.,
4-bromobenzonitrile and methyl 4-bromobenzoate) and 2-
bromonaphthalene also reacted smoothly with Boc-L-proline
with 45−79% yields. As expected, the highest yields (66−79%)
in etherification were achieved in reactions with electron-
deficient aryl bromides and primary alcohols (Figure 3C). The
reactions with secondary alcoholscyclohexanol and iso-
propanolgave 50 and 62% yield, respectively, but required a
6-fold instead of a 3-fold excess of alcohol and a prolonged
reaction time. Larger-scale etherification (2 mmol) showed
D
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Figure 4. Mechanistic studies of the cross-coupling reactions. (A) GC electrode potential versus Ag+/Ag in a typical amination experiment [3 (50
mM), morpholine (150 mM), NiBr2·DME (5 mM), and di-tBuBipy (7.5 mM) in LiBr (0.2M) DMA solution]. (B) CV curves of a NiBr2·DME
(2mM) and a Bipy (2mM) solution before (blue) and after (gray) the addition of 3 (2mM) (0.1M TBAPF6, DMA). (C) Amination in the divided
cell without stirring. The concentrations of the reagents are identical to A. (D) Control experiment of amination with the DC and Zn sacrificial
anode. The concentrations of the reagents are identical to A. (E) Kinetics of the amination reaction between 3 (50 mM) and morpholine (150
mM), NiBr2·DME (5 mM), and Bipy (7.5 mM) in LiBr (0.2M) DMA solution) with ON/OFF cycles of AC. Conversion of 3 to 7 was determined
by HPLC. See the Supporting Information for details.
70% (353.5 mg) of yield of 25, demonstrating the scalability of
AC-assisted catalytic reactions.
To better understand the basic mechanistic features of AC-
assisted nickel-catalyzed cross-coupling, we performed electro-
chemical studies of the discussed reactions. First, we measured
the potentials of the electrodes (GC rods), relatively standard
nonaqueous silver electrode (Ag+/Ag), in typical amination,
etherification, and esterification experiments. As Figure 4A
shows, the potential changes from 0.8 to −2.2 V (vs Ag+/Ag)
in the amination reaction. This interval remains the same for
the etherification (Figure S20); however, for esterification, it is
shifted to slightly higher potentials because of the absence of
Br− in the electrolyte (Figure S21). To better understand what
electrochemical processes occur within these potentials in the
reactions under investigation, we performed cyclic voltamme-
try (CV) studies (Figure 4B and Supporting Information). The
voltammogram of Ni(DME)Br2 (2 mM) and Bipy (2 mM)
showed two partially separated quasi-reversible reduction
waves with peaks at −1.42 and −1.57 V (Figure 4B). The
It is worth mentioning that additional control DC-assisted
experiments of amination, esterification, and etherification,
performed using the potentiostatic mode(for substrates 7, 17,
23, 24, 28, and 29), demonstrated lower NMR yields and
higher quantities of side products compared to the results
achieved in identical AC-assisted reactions (Figure 3 and
Experimental Section). These observations highlight the
crucial impact of AC assistance on the efficiency of the
discussed reactions.
Overall, the advantage of AC over DC assistance is the most
pronounced for esterification and etherification and, to a less
extent, for amination. This observation is in agreement with
the literature data: while a very broad scope was demonstrated
for DC-assisted amination,5,6 only a humble scope with 32−
43% yields was shown for etherification.6 DC-assisted
esterification was enabled only using a specific microfluidic
flow cell with a narrow (≤0.5 mm) gap between the
electrodes.10 This close distance between the electrodes
allowed researchers to perform reactions that involve short-
living intermediates existing between reduction and oxidation
steps. AC provides an alternative way to conduct reactions that
require a short interval between reduction and oxidation.
coulometric studies20 and the combination of the voltammo-
18,20b,21
grams for [Ni(Bipy)3]2+ and Ni(Bipy)Br2
strongly
indicate that these waves represent the sequential reduction
of Ni(II) to Ni(0) through a Ni(I) intermediate. When 3 (2
mM) was added to a solution of Ni(Bipy)Br2, the original
reduction waves could still be detected, but they became less
resolved and fully irreversible; two new reduction waves
E
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appeared with peak potentials of −1.71 and −1.89 V. We
hypothesized that oxidative addition occurs after the reduction
of nickel to a zero oxidation state, making the reduction waves
irreversible, and that these additional waves (−1.71 and −1.89
V) correspond to the sequential reduction of the [NiL(Ar)Br]
species.22 Nevertheless, the voltammetry under conditions as
close as possible to the synthetic experiments (GC rods as
working and counter electrodes, a scan rate of 24 V/s, and the
concentrations of reagents as in synthesis) indicated that in
synthetic experiments, the reduction of the [NiL(Ar)Br]
species might be less significant than in analytical CV because
of the higher surface area of the electrode, the higher
concentration of nickel ions, and the higher scan rate (Figures
S8, S12, and S16). These data imply that NiL(Ar)Br is the
most probable species to undergo further ligand exchange and
oxidation to afford the product of cross-coupling (Figure 1D).
The anodic area of the CV curves of the amination and
etherification reaction mixtures is dominated by the oxidation
Overall, our mechanistic studies are consistent with the
proposal shown in Figure 1D. Likely, the catalytic cycle is
initiated by the reduction of Ni(II), which is abundant in the
solution, to the Ni(0) species, which undergo oxidative
addition. During the low-voltage phase, when neither oxidation
nor reduction processes are expected, the oxidative addition
product undergoes ligand exchange. The further oxidation of
[NiL(Ar)Nu] species to a Ni(III) state favors reductive
elimination, which would furnish the desired coupling product
and release Ni(I) species. There are at least two ways by which
Ni(I) could be reduced to Ni(0): (i) direct reduction at the
electrode and (ii) reversible disproportionation to Ni(II) and
Ni(0) with the subsequent reduction of Ni(II) to Ni(0) at the
electrode. At the same time, current-assisted catalytic cycles
involving oxidative addition to Ni(I) species (Figure 5B)6 may
coexist with the proposed cycle (Figure 1D).
CONCLUSIONS
■
of Br− (Figure S18); therefore, Br3 and Br2 are probably
−
To summarize, we demonstrated the coupling of AC to
transition-metal catalysis using three examples of related
nickel-catalyzed coupling reactions, but the idea of enabling
new catalytic cycles by periodically oxidizing and reducing
catalytic intermediates by AC could be applied to various
catalytic systems, especially to ones that involve oxidative
addition or reductive elimination as a rate-limiting step. The
use of AC provides two important advantages: (i) the absence
of the need to transfer reactive intermediates between
electrodes, which prevents their dilution and allows working
with short-living intermediates; (ii) the frequency and the
waveform of AC are easily tunable experimental parameters
that can be used to achieve the selectivity of reactions.
Moreover, side electrochemical reactions might be tolerated in
experiments with AC if they are fully reversible. We hope that
further development of synthetic methods based on the
coupling of transition-metal catalysis to AC will enable new
efficient transformations.
mediators of the electrochemical oxidation of nickel species in
these experiments.
To confirm that processes at one electrode are sufficient to
perform the reactions, we conducted the AC-assisted reaction
between 3 and morpholine in a divided cell without stirring
(Figure 4C). This experiment resulted in a 77% yield,
confirming that the transfer of intermediates between electro-
des is unnecessary for this reaction to proceed. To probe the
possibility that only the reduction phase of the AC cycle is
essential for the coupling, we performed DC amination and
etherification of 3 with a Zn sacrificial anode and set the
potential of the GC cathode equal to the peak negative
potential in AC experiments (−2.2 V vs Ag+/Ag) (Figures 4D
and S23). Both experiments resulted in the formation of the
biaryl product (30) with 60−70% yields and only minor
quantities (2−8%) of the coupling products 7 and 5, thus
indicating the essential role of the oxidation phase of the AC
cycle in forming the coupling products. To probe the role of
self-sustainable catalysis by Ni(I) species in bulk solution
(Figure 5A),11 we performed kinetic experiments with the
In addition, this work demonstrates well how external
oscillations (not necessarily electrochemical ones) could
couple to catalytic cycles to perform otherwise unfavorable
chemical transformations. The oscillator pumps energy into
the catalytic cycle by periodically modifying its intermediates.
This point of view might be relevant for development of
catalytic processes enabled by various oscillatory fields.
EXPERIMENTAL SECTION
■
Materials and Methods. All reactions were performed under an
argon atmosphere according to the methods indicated in the general
procedures. Anhydrous solvents (Extra Dry over Molecular Sieve,
AcroSeal)DMF, DMA, and acetonitrile (MeCN)were purchased
from Acros Organics and stored under a positive pressure of argon.
CDCl3 was purchased from Cambridge Isotope Laboratories. All
other commercially available chemicals and reagents were used as
received from Sigma-Aldrich, Alfa Aesar, Acros Organics, and Fisher
chemicals unless otherwise noted. Flash column chromatography was
performed using Merck silica gel (60 mesh, particle size 0.043−0.063
mm).
Figure 5. Possible catalytic cycles involving oxidative addition to
Ni(I) species. (A) Self-sustainable Ni(III)/Ni(I) cycle.11 (B)
Current-assisted Ni(III)/Ni(I) cycle.6
ON/OFF cycles of AC (Figures 4E, S24 and S25). The
kinetics of the amination reaction between 3 and morpholine
as well as the data for similar esterification and etherification
experiments indicate that the reactions stop almost immedi-
ately when AC is OFF and start again when AC is ON,
demonstrating that the contribution of the long-living
(minutes timescale) self-sustainable Ni(III)/Ni(I) cycles to
the formation of the products (7, 5, and 18) is insignificant;
short-living Ni(III)/Ni(I) cycles that require constant
regeneration of Ni(I) remain possible.
GC rods (100 mm × 6 mm diameter) were purchased from Alfa
Aesar. Platinum wire (1 mm diameter) was purchased from Holland-
Moran. Ltd. (Israel). A GC disk (1 mm diameter) working electrode,
a platinum wire counter-electrode, and an Ag+/Ag reference electrode
were purchased from CH Instruments, Inc.
NMR spectra were measured on a Bruker AVANCE III-300
spectrometer at 300 MHz for 1H and 282.4 MHz for 19F, on a Bruker
1
AVANCE III-400 spectrometer at 400 MHz for H and 100.6 MHz
F
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for 13C{1H}, and on a Bruker AVANCE III HD-500 spectrometer at
bromide (0.2 mmol, 1 equiv) and K2CO3 (138 mg, 1 mmol, 5 equiv).
The following procedure is identical to the one described above.
General Procedure for Esterification Experiments. To an Ar-
flushed mixture containing NiBr2·DME (6.2 mg, 0.02 mmol, and 0.1
equiv), Bipy (3.1 mg, 0.02 mmol, and 0.1 equiv), carboxylic acid (0.3
mmol, 1.5 equiv) (unless otherwise noted), and Bu4NPF6 (155 mg)
in a screw-capped vial, 4 mL of DMA was added. The solution was
stirred until the reagents were completely dissolved; thereafter, the
mixture was transferred to a glass cell as much as possible with the
addition of aryl bromide (0.2 mmol, 1 equiv) and K2CO3 (276 mg, 10
equiv) (unless otherwise noted). The Teflon cap equipped with GC
rod electrodes was placed on top of the cell; then, the cap was sealed
tightly with parafilm; and the argon inlet and outlet (optional) were
inserted into the corresponding holes in the cap. The temperature of
the hotplate was set to 60 °C. Next, the argon inlet was immersed into
the solution, and argon was bubbled through the solution for at least 5
min with moderate stirring. Then, the Ar inlet was set above the
solution, and the position of the electrodes was adjusted to be as deep
in the solution as possible (ca. 1 cm). The electric circuit was
assembled, as described in the “Setup preparation” section of the
Supporting Information. The electrolysis was conducted for 4 h
(unless otherwise noted) with the following parameters of AC: sine
waveform, 2 Hz frequency, 3 V peak voltage, and a stirring rate of 200
rpm.
1
500 MHz for H, 125.8 MHz for 13C{1H}, and 470.6 MHz for 19F.
Chemical shifts for 1H and 13C are given in ppm relative to
1
tetramethylsilane and those for 19F relative to CFCl3. H and 13C
spectra were calibrated using a residual solvent peak as an internal
reference (1H NMR: δ = 7.26 ppm, 13C NMR: δ = 77.16 ppm). The
following abbreviations were used to explain NMR peak multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =
multiplet, and br = broad.
A B&K Precision 4053B dual channel function/arbitrary waveform
generator served as a tunable source for the AC. The measurements
and tracking of voltage drops over the electrochemical cell and the
resistor were performed using a Global Specialties DSC-5300 50 MHz
Digital Storage Oscilloscope. DC electrolysis, CV, and open-circuit
potential measurements were performed using a CH Instruments
600E potentiostat/galvanostat.
High-resolution mass spectra were recorded on a Waters Xevo G2-
XS QTof mass spectrometer (Manchester, UK) with an electrospray
ionization (ESI) source.
Analytical chromatographic separation was performed on a Waters
Acquity liquid chromatography system equipped with a 2998 PDA
Detector and a Waters QDa mass detector (a mass range of 85−1250
m/z) with ESI.
Synthesis of Compounds. General Procedure for Amination
Experiments. With Amines as Substrates. To an Ar-flushed mixture
containing NiBr2·DME (6.2 mg, 0.02 mmol, and 0.1 equiv),
di-tBuBipy (8.1 mg, 0.03 mmol, and 0.15 equiv), and LiBr (69.5
mg) in a screw-capped vial, 4 mL of DMA (unless otherwise noted)
was added. The solution was stirred until the reagents were
completely dissolved, and then amine(0.6 mmol, 3 equiv) was
added. Next, the mixture was transferred to a glass cell as much as
possible with the addition of aryl bromide (0.2 mmol, 1 equiv). The
Teflon cap equipped with GC rod electrodes was placed on top of the
cell; then the cap was sealed tightly with parafilm; the argon inlet and
outlet (optional) were inserted into the corresponding holes in the
cap. Thereafter, an argon inlet was immersed into the solution, and
argon was bubbled through the solution for at least 5 min with
moderate stirring. Then, the Ar inlet was set above the solution, and
the position of the electrodes was adjusted to be as deep in the
solution as possible (ca. 1 cm). The electric circuit was assembled, as
described in the “Setup preparation” section of the Supporting
Information. The electrolysis was conducted for 4 h with the
following parameters of AC: sine waveform, 2 Hz frequency, 3 V peak
voltage, and a stirring rate of 1400 rpm.
After the electrolysis, 0.5 mL of the solution was transferred to a
screw-capped vial, mixed with a small amount of Na2H2EDTA
(EDTAethylenediaminetetraacetate) water solution (for Ni com-
plexation), diluted with an aqueous solution of K2CO3 (0.1 M), and
extracted with a pentane/Et2O (1/1 ratio) mixture. The extract was
dried over Na2SO4, and the solvent was evaporated carefully under
vacuum (since some of the aryl bromides and products are quite
volatile, soft conditions are required). Then, the residue was used to
determine the NMR yield of the experiment. The remaining 3.5 mL
of the reaction mixture was diluted with an aqueous solution of
K2CO3 (0.1 M) and extracted four times with a pentane/Et2O (1/1
ratio) mixture. The combined organic fractions were washed with a
small amount of 0.1 M NaCl water solution and dried over Na2SO4.
Next, the solution was dried carefully under vacuum, and the residue
was dissolved in a minimum amount of hexane (with the addition of
dichloromethane if needed) and subjected to column chromatography
on SiO2 to afford the desired product. The isolated yield in each case
was calculated while considering the use of only 3.5 mL of solution for
the isolation.
After the electrolysis, 0.5 mL of the solution was transferred to a
screw-capped vial, mixed with a small amount of Na2H2EDTA water
solution (for Ni complexation), diluted with deionized water (DI)
water, and extracted with a pentane/Et2O (1/1 ratio) mixture. The
extract was dried over Na2SO4, and the solvent was evaporated
carefully under vacuum. Then, the residue was used to determine the
NMR yield of the experiment. The remaining 3.5 mL of the reaction
mixture was carefully diluted with an aqueous solution of KH2PO4 (1
M) and extracted four times with a pentane/Et2O (1/1 ratio) mixture.
The combined organic fractions were washed with a small amount of
0.1 M NaCl water solution and dried over Na2SO4. Next, the solution
was dried carefully under vacuum, and the residue was dissolved in a
minimum amount of hexane (with the addition of dichloromethane if
needed) and subjected to column chromatography on SiO2 to afford
the desired product. The isolated yield in each case was calculated
while considering the use of only 3.5 mL of solution for the isolation.
General Procedure for Etherification Experiments. To an Ar-
flushed mixture containing NiBr2·DME (6.2 mg, 0.02 mmol, and 0.1
equiv), Bipy (3.1 mg, 0.02 mmol, and 0.1 equiv), and LiBr (69.5 mg)
in a screw-capped vial, 4 mL of DMF was added. The solution was
stirred until the reagents were completely dissolved, and then
quinuclidine (44.5 mg, 0.4 mmol, and 2 equiv) and alcohol (0.6
mmol, 3 equivunless otherwise noted) were added. Next, the
mixture was transferred to a glass cell as much as possible with the
addition of aryl bromide (0.2 mmol, 1 equiv). The Teflon cap
equipped with GC rod electrodes was placed on top of the cell; then,
the cap was sealed tightly with parafilm; and the argon inlet and outlet
(optional) were inserted into the corresponding holes in the cap.
Thereafter, an argon inlet was immersed into the solution, and argon
was bubbled through the solution for at least 5 min with moderate
stirring. Then, the Ar inlet was set above the solution, and the position
of the electrodes was adjusted to be as deep in the solution as possible
(ca. 1 cm). The electric circuit was assembled, as described in the
“Setup preparation” section of the Supporting Information. The
electrolysis was conducted for 8 h (unless otherwise noted) with the
following parameters of AC: a sine waveform, 10 Hz frequency
(unless otherwise noted), 3 V peak voltage, and a stirring rate of 200
rpm.
After the electrolysis, 0.5 mL of the solution was transferred to a
screw-capped vial, mixed with a small amount of Na2H2EDTA water
solution (for Ni complexation), diluted with DI water, and extracted
with a pentane/Et2O (1/1 ratio) mixture. The extract was dried over
Na2SO4, and the solvent was evaporated carefully under vacuum.
Then, the residue was used to determine the NMR yield of the
experiment. The remaining 3.5 mL of the reaction mixture was diluted
with DI water and extracted four times with a pentane/Et2O (1/1
With Amine Hydrochlorides as Substrates. To an Ar-flushed
mixture containing NiBr2·DME (6.2 mg, 0.02 mmol, 0.1 equiv),
di-tBuBipy (8.1 mg, 0.03 mmol, 0.15 equiv), amine hydrochloride (0.6
mmol, 3 equiv), and LiBr (69.5 mg) in a screw-capped vial, 4 mL of
DMA (unless otherwise noted) was added. The solution was stirred
until the reagents were completely dissolved; the mixture was
transferred to a glass cell as much as possible, with the addition of aryl
G
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ratio) mixture. The combined organic fractions were washed with a
small amount of 0.1 M NaCl water solution and dried over Na2SO4.
Next, the solution was dried carefully under vacuum, and the residue
was dissolved in a minimum amount of hexane or pentane and
subjected to column chromatography on SiO2 to afford the desired
product. The isolated yield in each case was calculated while
considering the use of only 3.5 mL of solution for the isolation.
Synthetic Procedures and Compound Characterization
Data. Amination. 4-(4-(Trifluoromethyl)phenyl)morpholine (Figure
3, 7). Prepared according to the procedure described in the “General
procedure for amination experiments” section with morpholine (52.5
μL, 0.6 mmol, 3 equiv) as amine and 4-bromobenzotrifluoride (28.0
μL, 0.2 mmol, 1 equiv) as aryl bromide. Hexane−dichloromethane
mixture with gradient (from pure hexane to 1:1 ratio, respectively)
was used as an eluent. NMR yield98%, isolated yield75% (30.3
mg, white solid). Control DC-assisted experiment (potentiostatic
conditions2.8 V) demonstrated 66% NMR yield (9% of the diaryl
product was also observed). The spectra data matched with values
hydrochloride and 4-bromobenzotrifluoride (28.0 μL, 0.2 mmol, 1
equiv) as aryl bromide. Hexane−dichloromethane mixture with
gradient (from pure hexane to 1:1 ratio, respectively) was used as
an eluent. NMR yield71%, isolated yield35% (14.3 mg, white
solid). The spectra data matched with values reported in the
literature.6 Rf (dichloromethane)0.61. 1H NMR (500 MHz,
CDCl3): δ 7.43 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 4.61
(s, 1H), 3.95 (d, J = 5.2 Hz, 2H), 3.81 (s, 3H). 13C{1H} NMR (100.6
MHz, CDCl3): δ 171.1, 149.5, 126.9 (q, C−F, 3JC−F = 3.9 Hz), 125.0
(q, C−F, 1JC−F = 270.5 Hz), 120.0 (q, C−F, 2JC−F = 32.8 Hz), 112.3,
52.6, 45.2. 19F NMR (270.6 MHz, CDCl3): δ −62.18.
4-Phenylmorpholine (Figure 3, 2). Prepared according to the
procedure described in the “General procedure for amination
experiments” section with morpholine (52.5 μL, 0.6 mmol, 3 equiv)
as amine and bromobenzene (21.3 μL, 0.2 mmol, 1 equiv) as aryl
bromide. Hexane−dichloromethane mixture with gradient (from pure
hexane to 1:1 ratio, respectively) was used as an eluent. NMR yield
99%, isolated yield74% (21.1 mg, white solid). The spectra data
matched with values reported in the literature.3f Rf (dichloro-
methane)0.65. 1H NMR (500 MHz, CDCl3): δ 7.33−7.26 (m,
2H), 6.95−6.86 (m, 3H), 3.87 (t, J = 4.0 Hz, 4H), 3.17 (t, J = 4.0 Hz,
4H). 13C{1H} NMR (100.6 MHz, CDCl3): δ 151.4, 129.3, 120.2,
115.9, 67.1, 49.5.
4-Morpholinobenzonitrile (Figure 3, 12). Prepared according to
the procedure described in the “General procedure for amination
experiments” section with morpholine (52.5 μL, 0.6 mmol, 3 equiv)
as amine and 4-bromobenzonitrile (36.4 mg, 0.2 mmol, 1 equiv) as
aryl bromide. Hexane−dichloromethane mixture with gradient (from
pure hexane to 1:1 ratio, respectively) was used as an eluent. NMR
yield79%, isolated yield58% (19.1 mg, white solid). The spectra
data matched with values reported in the literature.3f Rf (dichloro-
methane)0.68. 1H NMR (400 MHz, CDCl3): δ 7.54−7.47 (m,
2H), 6.89−6.82 (m, 2H), 3.85 (t, J = 4.9 Hz, 4H), 3.27 (t, J = 4.9 Hz,
4H). 13C{1H} NMR (100.6 MHz, CDCl3): δ 153.6, 133.6, 120.0,
114.2, 101.0, 66.6, 47.4.
Methyl 4-morpholinobenzoate (Figure 3, 13). Prepared according
to the procedure described in the “General procedure for amination
experiments” section with morpholine (52.5 μL, 0.6 mmol, 3 equiv)
as amine and methyl 4-bromobenzoate (43.0 mg, 0.2 mmol, 1 equiv)
as aryl bromide. Hexane−dichloromethane mixture with gradient
(from pure hexane to 1:1 ratio, respectively) was used as an eluent.
NMR yield86%, isolated yield75% (29.0 mg, white solid). The
spectra data matched with values reported in the literature.3f Rf
(dichloromethane)0.4. 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J =
8.3 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 3.90−3.82 (m, 7H), 3.28 (m,
4H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 167.2, 154.4, 131.3,
120.5, 113.6, 66.7, 51.8, 47.9.
4-(Naphthalen-2-yl)morpholine (Figure 3, 14). Prepared accord-
ing to the procedure described in the “General procedure for
amination experiments” section with morpholine (52.5 μL, 0.6 mmol,
3 equiv) as amine and 2-bromonaphthalene (41.4 mg, 0.2 mmol, 1
equiv) as aryl bromide. Hexane−dichloromethane mixture with
gradient (from pure hexane to 1:1 ratio, respectively) was used as
an eluent. NMR yield75%, isolated yield52% (19.4 mg, white
solid). The spectra data matched with values reported in the
literature.24 Rf (dichloromethane)0.52. 1H NMR (500 MHz,
CDCl3): δ 7.77−7.68 (m, 3H), 7.45−7.40 (m, 1H), 7.34−7.39 (m,
1H), 7.27 (dd, J = 8.9 Hz, J = 2.5 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H),
3.92 (t, J = 4.8 Hz, 4H), 3.27 (t, J = 4.8 Hz, 4H). 13C{1H} NMR
(125.8 MHz, CDCl3): δ 149.2, 134.7, 129.0, 128.8, 127.6, 126.9,
126.5, 123.7, 119.0, 110.2, 67.1, 49.9.
4-(o-Tolyl)morpholine (Figure 3, 15). Prepared according to the
procedure described in the “General procedure for amination
experiments” section with morpholine (52.5 μL, 0.6 mmol, 3 equiv)
as amine and 2-bromotoluene (24.1 μL, 0.2 mmol, 1 equiv) as aryl
bromide. Hexane−dichloromethane mixture with gradient (from pure
hexane to 1:1 ratio, respectively) was used as an eluent. NMR yield
82%, isolated yield61% (18.9 mg, colorless liquid). The spectra
data matched with values reported in the literature.25 Rf (dichloro-
methane)0.57. 1H NMR (400 MHz, CDCl3): δ 7.23−7.17 (m,
reported in the literature.5 Rf (dichloromethane)0.59. H NMR
1
(500 MHz, CDCl3): δ 7.50 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.1 Hz,
2H), 3.87 (m, 4H), 3.24 (m, 4H). 13C{1H} NMR (125.8 MHz,
3
CDCl3): δ 153.5, 126.6 (q, C−F, JC−F = 3.8 Hz), 124.8 (q, C−F,
1JC−F = 269.9 Hz), 121.1 (q, C−F, 2JC−F = 33.4 Hz), 114.5, 66.8, 48.3.
19F NMR (282.4 MHz, CDCl3): δ −62.39.
N-Cyclohexyl-4-(trifluoromethyl)aniline (Figure 3, 8). Prepared
according to the procedure described in the “General procedure for
amination experiments” section with cyclohexylamine (68.6 μL, 0.6
mmol, 3 equiv) as amine and 4-bromobenzotrifluoride (28.0 μL, 0.2
mmol, 1 equiv) as aryl bromide in DMF. Hexane was used as an
eluent. NMR yield91%, isolated yield65% (27.7 mg, colorless
liquid). The spectra data matched with values reported in the
5
1
literature. Rf (hexane)0.17. H NMR (500 MHz, CDCl3): δ 7.37
(d, J = 8.5 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 3.88 (br, s, 1H), 3.29 (t,
J = 9.6, 1H), 2.05 (dd, J = 12.8, 3.2 Hz, 2H), 1.78 (dt, J = 13.6, 3.9
Hz, 2H), 1.69−1.65 (m, 1H), 1.43−1.34 (m, 2H), 1.28−1.14 (m,
3H). 13C{1H} NMR (100.6 MHz, CDCl3): δ 149.9, 126.6 (q, C−F,
1
3JC−F = 3.9 Hz), 125.2 (q, C−F, JC−F = 270.1 Hz), 118.2 (q, C−F,
2JC−F = 32.6 Hz), 112.1, 51.5, 33.3, 25.9, 25.0. 19F NMR (470.6 MHz,
CDCl3): δ −61.88.
N-Hexyl-4-(trifluoromethyl)aniline (Figure 3, 9). Prepared accord-
ing to the procedure described in the “General procedure for
amination experiments” section with 1-hexylamine (79.3 μL, 0.6
mmol, 3 equiv) as amine and 4-bromobenzotrifluoride (28.0 μL, 0.2
mmol, 1 equiv) as aryl bromide in DMF. Hexane was used as an
eluent. NMR yield82%, isolated yield75% (32.2 mg, colorless
liquid). The spectra data matched with values reported in the
literature.3a Rf (hexane)0.17. 1H NMR (500 MHz, CDCl3): δ 7.39
(d, J = 8.5 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 3.94 (br, s, 1H), 3.14
(m, 2H), 1.63 (p, J = 7.4, 2H), 1.43−1.30 (m, 6H), 0.92−0.89 (m,
3H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 151.0, 126.7 (q, C−F,
1
3JC−F = 3.8 Hz), 125.2 (q, C−F, JC−F = 269.9 Hz), 118.5 (q, C−F,
2JC−F = 32.4 Hz), 111.8, 43.7, 31.7, 29.4, 26.9, 22.8, 14.2. 19F NMR
(282.4 MHz, CDCl3): δ −61.90.
N,N-Dimethyl-4-(trifluoromethyl)aniline (Figure 3, 10). Prepared
according to the procedure described in the “General procedure for
amination experiments” section with dimethylamine hydrochloride
(48.9 mg, 0.6 mmol, 3 equiv) as amine hydrochloride and 4-
bromobenzotrifluoride (28.0 μL, 0.2 mmol, 1 equiv) as aryl bromide.
Hexane was used as an eluent. NMR yield86%, isolated yield71%
(23.5 mg, white solid). The spectra data matched with values reported
in the literature.23 Rf (hexane)0.24. 1H NMR (500 MHz, CDCl3):
δ 7.46 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H).
3
13C{1H} NMR (100.6 MHz, CDCl3): δ 152.4, 126.5 (q, C−F, JC−F
= 3.9 Hz), 125.3 (q, C−F, 1JC−F = 270.1 Hz), 117.7 (q, C−F, 2JC−F
=
32.6 Hz), 111.3, 40.3. 19F NMR (282.4 MHz, CDCl3): δ −61.81.
Methyl (4-(trifluoromethyl)phenyl)glycinate (Figure 3, 11).
Prepared according to the procedure described in the “General
procedure for amination experiments” section with glycine methyl
ester hydrochloride (75.3 mg, 0.6 mmol, 3 equiv) as amine
H
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2H), 7.07−6.98 (m, 2H), 3.87 (t, J = 4.5 Hz, 4H), 2.93 (t, J = 4.5 Hz,
4H), 2.34 (s, 3H). 13C{1H} NMR (100.6 MHz, CDCl3): δ 151.4,
132.7, 131.3, 126.8, 123.5, 119.1, 67.6, 52.4, 87.0.
bromobenzotrifluoride (28.0 μL, 0.2 mmol, 1 equiv) as aryl bromide.
Hexane−dichloromethane mixture with gradient (from pure hexane
to 1:1 ratio, respectively) was used as an eluent. NMR yield84%,
isolated yield70% (33.8 mg, colorless liquid). Rf (dichloro-
4-(Pyridin-3-yl)morpholine (Figure 3, 16). Prepared according to
the procedure described in the “General procedure for amination
experiments” section with morpholine (52.5 μL, 0.6 mmol, 3 equiv)
as amine and 3-bromopyridine (19.3 μL, 0.2 mmol, 1 equiv) as aryl
bromide. The whole mixture was extracted with ethyl acetate four
times. Combined organic fractions were washed with small amount of
0.1 M NaCl water solution and dried over Na2SO4. Next, the solution
was dried carefully under vacuum, the residue dissolved in the
minimum amount of dichloromethane and subjected to column
chromatography on SiO2 (dichloromethane/diethyl ether mixture
with gradientfrom pure dichloromethane to pure diethyl ether) to
furnish the product. Isolated yield65% (from the whole reaction
mixture, 21.3 mg, yellowish liquid). The spectra data matched with
values reported in the literature.3f Rf (diethyl ether)0.22. 1H NMR
(500 MHz, CDCl3): δ 8.29 (s, 1H), 8.14−8.10 (m, 1H), 7.19−7.14
(m, 2H), 3.90−3.83 (m, 4H), 3.22−3.15 (m, 4H). 13C{1H} NMR
(125.8 MHz, CDCl3): δ 147.0, 141.2, 138.4, 123.7, 122.3, 66.8, 48.7.
4-(3-Methoxyphenyl)morpholine (Figure 3, 17). Prepared accord-
ing to the procedure described in the “General procedure for
amination experiments” section with morpholine (52.5 μL, 0.6 mmol,
3 equiv) as amine and 3-bromoanisole (25.3 μL, 0.2 mmol, 1 equiv)
as aryl bromide. Hexane−dichloromethane mixture with gradient
(from pure hexane to 1:1 ratio, respectively) was used as an eluent.
NMR yield86%, isolated yield67% (22.7 mg, colorless liquid).
Control DC-assisted experiment (potentiostatic conditions2.8 V)
demonstrated 45% NMR yield. The spectra data matched with values
1
methane)0.67. H NMR (500 MHz, CDCl3): δ 7.65 (d, J = 7.8
Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 3.73 (s, 3H), 2.93−2.86 (m, 2H),
2.78−2.75 (m, 2H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 172.6,
170.6, 153.2, 128.3 (q, C−F, 2JC−F = 33.4 Hz), 126.9 (q, C−F, 3JC−F
=
3.8 Hz), 124.0 (q, C−F, 1JC−F = 271.8 Hz), 122.16, 52.17, 29.4, 28.9.
19F NMR (470.6 MHz, CDCl3): δ −63.26. HRMS (ESI) m/z: [M +
Na]+ calcd for C12H11O4F3Na 299.0507; found 299.0507.
4-(Trifluoromethyl)phenyl acetate (Figure 3, 21). Prepared
according to the procedure described in the “General procedure for
esterification experiments” section with the sodium acetate suspension
(82.0 mg, 1 mmol, 5 equiv) instead of the carboxylic acid and K2CO3
mixture, and 4-bromobenzotrifluoride (28.0 μL, 0.2 mmol, 1 equiv) as
aryl bromide. Hexane−dichloromethane mixture with gradient (from
pure hexane to 1/1 ratio, respectively) was used as an eluent. NMR
yield87%, isolated yield48% (17.1 mg, colorless liquid). The
spectra data matched with values reported in the literature.26 Rf
(dichloromethane)0.65. 1H NMR (500 MHz, CDCl3): δ 7.65 (d, J
= 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR
2
(125.8 MHz, CDCl3): δ 169.0, 153.3, 128.3 (q, C−F, JC−F = 32.4
3
1
Hz), 126.9 (q, C−F, JC−F = 3.8 Hz), 124.0 (q, C−F, JC−F = 271.8
Hz), 122.2, 21.2. 19F NMR (282.4 MHz, CDCl3): δ −63.25.
1-(tert-Butyl) 2-(4-(trifluoromethyl)phenyl) (S)-pyrrolidine-1,2-
dicarboxylate (Figure 3, 4). Prepared according to the procedure
described in the “General procedure for esterification experiments”
section with Boc-L-proline (64.6 mg, 0.3 mmol, 1.5 equiv) as
carboxylic acid and 4-bromobenzotrifluoride (28.0 μL, 0.2 mmol, 1
equiv) as aryl bromide. Hexane−dichloromethane mixture with
gradient (from pure hexane to 1/1 ratio, respectively) was used as
an eluent. NMR yield87%, isolated yield69% (43.4 mg, colorless
liquid). The spectra data matched with values reported in the
literature.27 Rf (dichloromethane)0.37. 1H NMR (500 MHz,
CDCl3): (rotameric mixture, resonances for minor rotamer are
enclosed in parenthesis) δ 7.67 (7.64) (d, J = 8.4 Hz, 2H), 7.25 (7.23)
(d, J = 8.7 Hz, 2H), 4.53 (4.47) (dd, J = 8.7, 4.4 Hz, 1H), 3.67−3.40
(m, 2H), 2.45−2.29 (m, 1H), 2.22−2.10 (m, 1H), 2.09−1.90 (m,
2H), (1.48) 1.46 (s, 9H). 13C{1H} NMR (125.8 MHz, CDCl3):
(rotameric mixture, resonances for minor rotamer are enclosed in
parenthesis) δ (171.4) 171.3, (154.6) 153.8, (153.5) 153.2, 128.4
reported in the literature.3f Rf (dichloromethane)0.43. H NMR
1
(500 MHz, CDCl3): δ 7.24−7.16 (m, 1H), 6.56−6.50 (m, 1H),
6.48−6.42 (m, 2H), 3.85 (t, J = 4.8 Hz, 4H), 3.80 (s, 3H), 3.15 (t, J =
4.8 Hz, 4H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 160.8, 152.9,
130.0, 108.6, 104.9, 102.4, 67.0, 55.4, 49.4.
Esterification. 4-(Trifluoromethyl)phenyl benzoate (Figure 3, 18).
Prepared according to the procedure described in the “General
procedure for esterification experiments” section with benzoic acid
(36.6 mg, 0.3 mmol, 1.5 equiv) as carboxylic acid and 4-
bromobenzotrifluoride (28.0 μL, 0.2 mmol, 1 equiv) as aryl bromide.
Hexane−dichloromethane mixture with gradient (from pure hexane
to 10:1 ratio, respectively) was used as an eluent. NMR yield81%,
isolated yield75% (34.9 mg, white solid). The spectra data matched
with values reported in the literature.17 Rf (hexane)0.11. 1H NMR
(500 MHz, CDCl3): δ 8.25−8.18 (m, 2H), 7.72 (d, J = 7.3 Hz, 2H),
7.69−7.64 (m, 1H), 7.57−7.51 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H).
13C{1H} NMR (125.8 MHz, CDCl3): δ 164.8, 153.6, 134.1, 130.4,
2
3
(128.2) (q, C−F, JC−F = 33.4 Hz), 127.0 (126.8) (q, C−F, JC−F
=
1
3.8 Hz), (123.8) 123.9 (d, C−F, JC−F = 271.8 Hz), (122.2) 121.8,
80.5 (80.4), 59.3 (59.2), (46.8) 46.6, 31.2 (30.1), 28.6, (24.7) 23.9.
19F NMR (282.4 MHz, CDCl3): (rotameric mixture, resonances for
129.1, 128.9, 128.3 (q, C−F, 2JC−F = 33.4 Hz), 127.0 (q, C−F, 3JC−F
=
minor rotamer are enclosed in parenthesis) δ −63.22 (−63.27).
1-(tert-Butyl) 2-(4-(methoxycarbonyl)phenyl) (S)-pyrrolidine-1,2-
dicarboxylate (Figure 3, 22). Prepared according to the procedure
described in the “General procedure for esterification experiments”
section with Boc-L-proline (64.6 mg, 0.3 mmol, 1.5 equiv) as
carboxylic acid and methyl 4-bromobenzoate (43.0 mg, 0.2 mmol, 1
equiv) as aryl bromide. Hexane−dichloromethane mixture with
gradient (from pure hexane to pure dichloromethane) was used as
an eluent. NMR yield89%, isolated yield79% (48.3 mg, white
solid). The spectra data matched with values reported in the
literature.27 Rf (dichloromethane)0.2. 1H NMR (500 MHz,
CDCl3): (rotameric mixture, resonances for minor rotamer are
enclosed in parenthesis) δ 8.08 (8.05) (d, J = 8.4 Hz, 2H), 7.2 (7.18)
(d, J = 8.5 Hz, 2H), (4.53) 4.46 (dd, J = 8.5, 4.3 Hz, 1H), 3.91 (3.90)
(s, 3H), 3.69−3.40 (m, 2H), 2.47−2.28 (m, 1H), 2.23−2.11 (m, 1H),
2.10−1.90 (m, 2H), (1.48) 1.45 (s, 9H). 13C{1H} NMR (125.8 MHz,
CDCl3): δ (rotameric mixture, resonances for minor rotamer are
enclosed in parenthesis) (171.3) 171.25, (166.5) 166.4, (154.6)
154.3, 153.8, 131.4 (131.3), 128.0 (127.8), (121.7) 121.3, 80.5
(80.3), 59.3 (59.2), 52.4 (52.3), (46.8), 46.6, 31.2 (30.1), 28.6, (24.7)
23.9.
1
3.8 Hz), 124.0 (q, C−F, JC−F = 271.8 Hz), 122.4. 19F NMR (282.4
MHz, CDCl3): δ −63.18.
5-(tert-butyl) 1-(4-(trifluoromethyl)phenyl) (tert-butoxycarbon-
yl)-L-glutamate (Figure 3, 19). Prepared according to the procedure
described in the “General procedure for esterification experiments”
section with Boc-L-glutamic acid 5-tert-butyl ester (61.0 mg, 0.3
mmol, 1.5 equiv) as carboxylic acid and 4-bromobenzotrifluoride
(28.0 μL, 0.2 mmol, 1 equiv) as aryl bromide. Hexane−dichloro-
methane mixture with gradient (from pure hexane to 1:1 ratio,
respectively) was used as an eluent. NMR yield82%, isolated
1
yield66% (51.7 mg, white solid). Rf (dichloromethane)0.45. H
NMR (500 MHz, CDCl3): δ 7.66 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.4
Hz, 2H), 5.20 (d, J = 7.6 Hz, 1H), 4.53 (m, 1H), 2.50−2.37 (m, 2H),
2.34−2.25 (m, 1H), 2.15−2.05 (m, 1H), 1.46 (m, 18H). 13C{1H}
NMR (125.8 MHz, CDCl3): δ 172.1, 170.9, 155.6, 153.1, 128.6 (q,
C−F, 2JC−F = 33.4 Hz), 127.0 (q, C−F, 3JC−F = 3.8 Hz), 123.9 (q, C−
F, 1JC−F = 272.8 Hz), 122.1, 81.3, 80.5, 53.6, 31.7, 28.4, 28.2, 27.3. 19
F
NMR (282.4 MHz, CDCl3): δ −63.27. HRMS (ESI) m/z: [M + Na]+
calcd for C21H28NO6F3Na 470.1766; found 470.1769.
Methyl (4-(trifluoromethyl)phenyl) succinate (Figure 3, 20).
Prepared according to the procedure described in the “General
procedure for esterification experiments” section with succinic acid
methyl ester (39.6 mg, 0.3 mmol, 1.5 equiv) as carboxylic acid and 4-
1-(tert-Butyl) 2-(4-cyanophenyl) (S)-pyrrolidine-1,2-dicarboxy-
late (Figure 3, 23). Prepared according to the procedure described
in the “General procedure for esterification experiments” section with
I
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Boc-L-proline (64.6 mg, 0.3 mmol, 1.5 equiv) as carboxylic acid and 4-
bromobenzonitrile (36.4 mg, 0.2 mmol, 1 equiv) as aryl bromide.
Hexane−dichloromethane mixture with gradient (from pure hexane
to pure dichloromethane) was used as an eluent. NMR yield65%,
isolated yield45% (24.9 mg, colorless liquid). Control DC-assisted
experiment (potentiostatic conditions2.8 V) demonstrated 23%
NMR yield (37% of the diaryl product was also observed). The
spectra data matched with values reported in the literature. The
spectra data matched with values reported in the literature.27 Rf
fluoride (28.0 μL, 0.2 mmol, 1 equiv) as aryl bromide. The electrolysis
was conducted for 8 h with the frequency of 5 Hz. Hexane was used
as an eluent. NMR yield65%, isolated yield50% (21.4 mg,
colorless liquid). The spectra data matched with values reported in
the literature.29 Rf (hexane)0.48. H NMR (500 MHz, CDCl3): δ
1
7.51 (d, J = 8.5 Hz, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 4.34−4.27 (m,
1H), 2.03−1.94 (m, 2H), 1.85−1.76 (m, 2H), 1.63−1.50 (m, 3H),
1.45−1.28 (m, 3H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 160.5,
3
1
127.0 (q, C−F, JC−F = 3.8 Hz), 124.7 (q, C−F, JC−F = 271.8 Hz),
1
2
122.5 (q, C−F, JC−F = 33.4 Hz), 115.7, 75.6, 31.7, 25.7, 23.8. 19F
(dichloromethane)0.2. H NMR (500 MHz, CDCl3): (rotameric
mixture, resonances for one of the rotamers are enclosed in
parenthesis) δ 7.70 (7.67) (d, J = 8.5 Hz, 2H), 7.26 (7.24) (d, J =
8.7 Hz, 2H), 4.51 (4.46) (dd, J = 8.5, 4.5 Hz, 1 H), 3.67−3.41 (m,
2H), 2.45−2.30 (m, 1H), 2.20−1.90 (m, 3H), 1.47 (1.44) (s, 9H).
13C{1H} NMR (125.8 MHz, CDCl3): (rotameric mixture, resonances
NMR (470.6 MHz, CDCl3): δ −62.42.
1-Isopropoxy-4-(trifluoromethyl)benzene (Figure 3, 27). Pre-
pared according to the procedure described in the “General procedure
for etherification experiments” section with 2-propanol (91.9 μL, 1.2
mmol, 6 equiv) as alcohol and 4-bromobenzotrifluoride (28.0 μL, 0.2
mmol, 1 equiv) as aryl bromide. The electrolysis was conducted for 16
h with the frequency of 5 Hz. Pentane was used as an eluent. NMR
yield73%, isolated yield62% (22.2 mg, colorless liquid). The
spectra data matched with values reported in the literature.29 Rf
(hexane)0.45. 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 8.7 Hz,
2H), 6.93 (d, J = 8.7 Hz, 2H), 4.61 (sept, J = 6.1 Hz, 1H), 1.36 (d, J =
6.1 Hz, 6H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 160.6, 127.03
for one of the rotamers are enclosed in parenthesis) δ (171.1) 171.0,
(154.6) 154.3, 154.0 (153.7) 133.9 (133.8), (122.8) 122.4, (118.4)
118.2, (110.1) 109.9, 80.6 (80.4), 59.3 (59.2), (46.8) 46.6, (31.2)
30.1, 28.5, (24.7) 23.9.
1-(tert-Butyl) 2-(naphthalen-2-yl) (S)-pyrrolidine-1,2-dicarboxy-
late (Figure 3, 24). Prepared according to the procedure described in
the “General procedure for esterification experiments” section with
Boc-L-proline (64.6 mg, 0.3 mmol, 1.5 equiv) as carboxylic acid and 2-
bromonaphthalene (41.4 mg, 0.2 mmol, 1 equiv) as aryl bromide.
Hexane−dichloromethane mixture with gradient (from pure hexane
to 1/1 ratio, respectively) was used as an eluent. NMR yield79%,
isolated yield54% (32.3 mg, yellowish liquid). Control DC-assisted
experiment (potentiostatic conditions2.8 V) demonstrated 4%
NMR yield (9% of the diaryl product was also observed). Rf
3
1
(q, C−F, JC−F = 3.8 Hz), 124.7 (q, C−F, JC−F = 270.8 Hz), 122.6
(q, C−F, 2JC−F = 32.4 Hz), 115.6, 70.3, 22.0. 19F NMR (282.4 MHz,
CDCl3): δ −62.44.
1-(Hexyloxy)-4-(trifluoromethyl)benzene (Figure 3, 5). Prepared
according to the procedure described in the “General procedure for
etherification experiments” section with 1-hexanol (75.3 μL, 0.6
mmol, 3 equiv) as alcohol and 4-bromobenzotrifluoride (28.0 μL, 0.2
mmol, 1 equiv) as aryl bromide. Hexane was used as an eluent. NMR
yield87%, isolated yield68% (29.3 mg, colorless liquid). The
spectra data matched with values reported in the literature.3d Rf
(hexane)0.56. 1H NMR (500 MHz, CDCl3): δ 7.53 (d, J = 8.4 Hz,
2H), 6.95 (d, J = 8.4 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 1.80 (tt, J =
7.3, 6.7 Hz, 2H), 1.51−1.45 (m, 2H), 1.39−1.32 (m, 4H), 0.95−0.87
(m, 3H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 161.7, 127.0 (q,
1
(dichloromethane)0.36. H NMR (300 MHz, CDCl3): (rotameric
mixture, resonances for minor rotamer are enclosed in parenthesis) δ
7.92−7.75 (m, 3H), 7.62−7.4 (m, 3H), 7.32−7.18 (m, 1H), 4.59
(4.51) (dd, J = 8.4, 4.0 Hz, 1H), 3.75−3.40 (m, 2H), 2.51−1.9 (m,
4H), 1.50 (m, 9H). 13C{1H} NMR (100.6 MHz, CDCl3): (rotameric
mixture, resonances for minor rotamer are enclosed in parenthesis)
(171.93) 171.89, (154.7) 153.9, (148.6) 148.4, 133.8, 131.6, 129.6
(129.5), 127.91 (127.87), 127.75, 126.8 (126.6), 125.9 (125.8),
(121.2) 120.7, (118.6) 118.2, 80.4 (80.2), 59.4 (59.3), 46.8 (46.6),
31.2 (30.2), 28.6, (24.7) 23.9. HRMS (ESI) m/z: [M + Na]+ calcd for
C20H23NO4Na 364.1525; found 364.1524.
3
1
C−F, JC−F = 3.8 Hz), 124.7 (q, C−F, JC−F = 270.8 Hz), 122.7 (q,
2
C−F, JC−F = 32.4 Hz), 114.6, 68.4, 31.7, 29.2, 25.8, 22.7, 14.2. 19F
NMR (282.4 MHz, CDCl3): δ −62.42.
Methyl 4-(hexyloxy)benzoate (Figure 3, 28). Prepared according
to the procedure described in the “General procedure for ether-
ification experiments” section with 1-hexanol (75.3 μL, 0.6 mmol, 3
equiv) as alcohol and methyl 4-bromobenzoate (43.0 mg, 0.2 mmol, 1
equiv) as aryl bromide. Hexane−dichloromethane mixture with
gradient (from pure hexane to 1/1 ratio, respectively) was used as
an eluent. NMR yield85%, isolated yield79% (32.7 mg, colorless
liquid). Control DC-assisted experiment (potentiostatic conditions
2.8 V) demonstrated only traces of product in NMR spectra. The
spectra data matched with values reported in the literature.3d Rf
(dichloromethane)0.7. 1H NMR (500 MHz, CDCl3): δ 7.97 (d, J =
8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.88
(s, 3H), 1.79 (m, 2H), 1.51−1.41 (m, 2H), 1.38−1.30 (m, 4H),
0.95−0.86 (m, 3H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 167.1,
163.1, 131.7, 122.5, 114.2, 68.4, 52.0, 31.7, 29.2, 25.8, 22.7, 14.2.
3-(Hexyloxy)pyridine (Figure 3, 29). Prepared according to the
procedure described in the “General procedure for etherification
experiments” section with 1-hexanol (75.3 μL, 0.6 mmol, 3 equiv) as
alcohol and 3-bromopyridine (19.3 μL, 0.2 mmol, 1 equiv) as aryl
bromide. Hexane−dichloromethane mixture with gradient (from pure
hexane to pure dichloromethane) was used as an eluent. NMR
yield66%, isolated yield61% (19.1 mg, yellowish liquid). Control
DC-assisted experiment (potentiostatic conditions2.8 V) demon-
strated 29% NMR yield. The spectra data matched with values
Etherification. 1-(Benzyloxy)-4-(trifluoromethyl)benzene (Figure
3, 25). Prepared according to the procedure described in the “General
procedure for etherification experiments” section with benzyl alcohol
(62.1 μL, 0.6 mmol, 3 equiv) as alcohol and 4-bromobenzotrifluoride
(28.0 μL, 0.2 mmol, 1 equiv) as aryl bromide. Hexane was used as an
eluent. NMR yield72%, isolated yield66% (29.1 mg, white solid).
A 2 mmol scale experiment was performed using a setup with four GC
rod electrodes and 20 ml vial as an electrochemical cell (see the
Supporting Information) with 4-bromobenzotrifluoride (280.0 μL, 2
mmol, 1 equiv), benzyl alcohol (620.9 μL, 6 mmol, 3 equiv), NiBr2·
DME (61.7 mg, 0.2 mmol, 0.1 equiv), Bipy (31.2 mg, 0.2 mmol, 0.1
equiv), and quinuclidine (444.7 mg, 4 mmol, 2 equiv) in 10 mL of
0.2M LiBr (174 mg) DMF solution. The electrolysis was conducted
for 20 h with the following parameters of AC: a sine waveform, 10 Hz
frequency, 3 V peak voltage, and a stirring rate of 300 rpm. The
preparation of the initial reaction mixture and the purification of the
product are identical to the procedure described in the “General
procedure for etherification experiments” section. The isolated yield
of 2 mmol scale experiment70% (353.5 mg). The spectra data
matched with values reported in the literature.28 Rf (hexane)0.2.
1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.6 Hz, 2H), 7.47−7.33
(m, 5H), 7.04 (d, J = 8.6 Hz, 2H), 5.12 (s, 2H). 13C{1H} NMR
(100.6 MHz, CDCl3): δ 161.3, 136.4, 128.9, 128.4, 127.6, 127.1 (q,
3
1
C−F, JC−F = 3.7 Hz), 124.7 (q, C−F, JC−F = 271.1 Hz), 123.3 (q,
C−F, 2JC−F = 32.6 Hz), 115.0, 70.3. 19F NMR (282.4 MHz, CDCl3):
δ −62.48.
reported in the literature.30 Rf (dichloromethane)0.27. H NMR
1
(500 MHz, CDCl3): δ 8.30 (d, J = 2.3, 1H), 8.20 (dd, J = 4.3, 1.5 Hz,
1H), 7.23−7.15 (m, 2H), 3.99 (t, J = 6.5 Hz, 2H), 1.83−1.75 (m,
2H), 1.51−1.42 (m, 2H), 1.40−1.29 (m, 4H), 0.91 (t, J = 7.0 Hz,
3H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 155.4, 142.0, 138.2,
123.9, 121.2, 68.5, 31.7, 29.3, 25.8, 22.7, 14.2.
1-(Cyclohexyloxy)-4-(trifluoromethyl)benzene (Figure 3, 26).
Prepared according to the procedure described in the “General
procedure for etherification experiments” section with cyclohexanol
(126.8 μL, 1.2 mmol, 6 equiv) as alcohol and 4-bromobenzotri-
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Side Products. 4,4′-Bis(trifluoromethyl)-1,1′-biphenyl (Figure 4D,
30). Separated as a minor product in the reactions of amination,
etherification, and esterification with 4-bromobenzotrifluoride or as a
major product in DC-assisted amination and etherification with a Zn
sacrificial anode. Purified by column chromatographyhexane was
used as an eluent. NMR yield73%, isolated yield66% (19.5 mg,
white solidfrom DC-assisted etherification with a Zn sacrificial
anode). The spectra data matched with values reported in the
literature.31 Rf (hexane)0.53. 1H NMR (400 MHz, CDCl3): δ 7.74
(d, J = 8.6 Hz, 4H), 7.70 (d, J = 8.6 Hz, 4H). 13C{1H} NMR (100.6
MHz, CDCl3): δ 143.4, 130.4 (q, C−F, 2JC−F = 32.6 Hz), 127.8, 126.1
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3
1
(q, C−F, JC−F = 3.9 Hz), 124.2 (q, C−F, JC−F = 272.2 Hz). 19F
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02350.
■
sı
Experimental procedures, electrochemical analysis data,
and compound characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
Sergey N. Semenov − Department of Organic Chemistry,
Weizmann Institute of Science, Rehovot 7610001, Israel;
orcid.org/0000-0002-5829-2283;
■
(5) Li, C.; Kawamata, Y.; Nakamura, H.; Vantourout, J. C.; Liu, Z.;
Hou, Q.; Bao, D.; Starr, J. T.; Chen, J.; Yan, M.; Baran, P. S.
Electrochemically Enabled, Nickel-Catalyzed Amination. Angew.
Chem., Int. Ed. 2017, 56, 13088−13093.
Email: sergey.semenov@weizmann.ac.il
Author
(6) Kawamata, Y.; Vantourout, J. C.; Hickey, D. P.; Bai, P.; Chen, L.;
Hou, Q.; Qiao, W.; Barman, K.; Edwards, M. A.; Garrido-Castro, A.
F.; deGruyter, J. N.; Nakamura, H.; Knouse, K.; Qin, C.; Clay, K. J.;
Bao, D.; Li, C.; Starr, J. T.; Garcia-Irizarry, C.; Sach, N.; White, H. S.;
Neurock, M.; Minteer, S. D.; Baran, P. S. Electrochemically Driven,
Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications. J.
Am. Chem. Soc. 2019, 141, 6392−6402.
Evgeniy O. Bortnikov − Department of Organic Chemistry,
Weizmann Institute of Science, Rehovot 7610001, Israel
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02350
Funding
(7) Wang, Y.; Deng, L.; Wang, X.; Wu, Z.; Wang, Y.; Pan, Y.
Electrochemically Promoted Nickel-Catalyzed Carbon−Sulfur Bond
Formation. ACS Catal. 2019, 9, 1630−1634.
This work was funded by Weizmann Institute of Science.
Notes
The authors declare the following competing financial
interest(s): Authors are inventors on the patent application
(277384) based on the results presented in this manuscript
(Israel patent office).
́
(8) Sengmany, S.; Ollivier, A.; Le Gall, E.; Leonel, E. A mild
electroassisted synthesis of (hetero)arylphosphonates. Org. Biomol.
Chem. 2018, 16, 4495−4500.
(9) Tian, J.; Moeller, K. D. Electrochemically Assisted Heck
Reactions. Org. Lett. 2005, 7, 5381−5383.
(10) (a) Mo, Y.; Lu, Z.; Rughoobur, G.; Patil, P.; Gershenfeld, N.;
Akinwande, A. I.; Buchwald, S. L.; Jensen, K. F. Microfluidic
electrochemistry for single-electron transfer redox-neutral reactions.
Science 2020, 368, 1352−1357.
(11) (a) Sun, R.; Qin, Y.; Nocera, D. G. General Paradigm in
Photoredox Nickel-Catalyzed Cross-Coupling Allows for Light-Free
Access to Reactivity. Angew. Chem., Int. Ed. 2020, 59, 9527−9533.
(b) Sun, R.; Qin, Y.; Ruccolo, S.; Schnedermann, C.; Costentin, C.;
Nocera, D. G. Elucidation of a Redox-Mediated Reaction Cycle for
Nickel-Catalyzed Cross Coupling. J. Am. Chem. Soc. 2019, 141, 89−
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ACKNOWLEDGMENTS
■
We thank E. Narevicius for the help with setting up equipment
for AC experiments. We thank R. Neumann and M. Somekh
for helpful discussions.
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