CV-driven Optimization: Cobalt-Catalyzed Electrochemical Expedient Oxychlorination of Alkenes via ORR

Article abstract of DOI:10.1002/adsc.201901260

Instead of screening reaction conditions by yield-based chemical trial-and-error, potential-based cyclic voltammetry was alternatively employed for optimization of electrochemical oxychlorination of alkenes. With this unconventional screening method, the catalyst system including catalysts, molar ratio of chloride sources and solvents were identified in a rational, time- and energy-efficient manner. The optimal catalytic system in combination with oxygen reduction reaction enabled broad substrate scopes for the desired transformation by taking advantages of persistent radical effect. UV-vis and CV titration experiments confirmed the in-situ formed catalytic species [CoCl₅]. Moreover, cyclic voltammetry was applied to obtain mechanistic insights in our reaction system. (Figure presented.).

Full text of DOI:10.1002/adsc.201901260

Title: CV-driven optimization: cobalt-catalyzed electrochemical
expedient oxychlorination of alkenes via ORR
Authors: Siyu Tian, Shide Lv, Xiaofei Jia, Li Ma, Baoying Li, Guofeng
Zhang, Wei Gao, Yingqin Wei, and Jianbin Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901260
Link to VoR: http://dx.doi.org/10.1002/adsc.201901260

10.1002/adsc.201901260
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201901260
CV-driven optimization: cobalt-catalyzed electrochemical
expedient oxychlorination of alkenes via ORR
Siyu Tian[a]†, Shide Lv[a]†, Xiaofei Jia[b], Li Ma[a], Baoying Li[a], Guofeng Zhang[a], Wei
Gao[a], Yingqin Wei[a], and Jianbin Chen*[a]
a
Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Pharmaceutical Engineering
Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, P R China
E-mail: jchen@qlu.edu.cn
Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and
b
Molecular Engineering.Qingdao University of Science and Technology, Qingdao 266042, P. R. China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Instead of screening reaction conditions by yield-based chemical trial-and-error, potential-based cyclic
voltammetry was alternatively employed for optimization of electrochemical oxychlorination of alkenes. With this
unconventional screening method, the catalyst system including catalysts, molar ratio of chloride sources and solvents were
identified in a rational, time- and energy-efficient manner. The optimal catalytic system in combination with oxygen
reduction reaction enabled broad substrate scopes for the desired transformation by taking advantages of persistent radical
effect. UV-vis and CV titration experiments confirmed the in-situ formed catalytic species [CoCl5]. Moreover, cyclic
voltammetry was applied to obtain mechanistic insights in our reaction system.
Keywords: cyclic voltammetry; chemical trial-and-error; electrochemistry; oxygen reduction reaction; persistent radical
effect; screening method
Introduction
Cyclic voltammetry (CV) serves as one of the most
important electroanalytical tools and, in principle, it
is ideally suitable for illuminating redox-involved
reaction mechanisms.[1] For instance, CV can be used
in manipulation of oxidation states of organic and/or
organometallic molecules. Characterizing the
composition of specific redox-active scaffolds in
solution and investigating the kinetics and properties
of the corresponding intermediates are also feasible
by CV.[2] In addition, data are generally obtained
within a few minutes with a small amount of material
highlighting the cost- and time- efficient nature.
However, CV has scarcely been used for optimization
of conditions. At present, condition screening
intensively relies on conventional yield-based
chemical trial-and-error which consumes tremendous
time, labor and energy. In order to overcome this
dilemma, one is trying to seek the assistance of
Impressively, Gansäuer and co-workers in 2018
demonstrated that CV could be employed for the
optimization of titanocene-catalyzed radical arylation
of epoxides.[3] Nevertheless, the chemical version for
Scheme
chloroacetophenones.
1.
Representative
Procedures
to
the same procedure is known and CV is mainly used
to recognize the halogen abstractor.[4] Hence, we
envision that utilization of CV as a rational, time- and
1
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10.1002/adsc.201901260
Advanced Synthesis & Catalysis
energy-efficient screening method to identify novel
catalytic system for new protocols.
Chloroacetophenones play a pivotal role in
modern organic chemistry and are frequently treated
as versatile intermediates in drug-related heterocyclic
synthesis.[5] Thus, the development of facile protocols
for its preparation remarkably attracts numerous
interests in organic community. Nevertheless, the
available approaches at present primarily depend on
two types of transformations, i.e. oxidation of
acetophenones[6] and halogen-exchange from
phenacyl bromides[7] (Eq. 1 & 2, Scheme 1).
Considering of the cost of feedstock, styrenes are
easily accessible comparing with acetophenones and
phenacyl bromides especially at large-scale. However,
only few methods have been reported with styrenes
as the building blocks. Recently, Tang and co-
Figure 1. CV screening of MCln in different solvents.
Conditions: glassy carbon as working electrode,
Ag/AgNO3 reference electrode, and a platinum wire
counter electrode. LiClO4 (1.2 mM), a) CrCl36H2O (0.12
mM), FeCl2 (0.12 mM), CoCl26H2O (0.12 mM), CoCl2
(0.12 mM), NiCl26H2O (0.12 mM), CuCl22H2O (0.12
mM) in acetone-DCM; b) CoCl26H2O (0.12 mM) in DCM
(balck), acetone (red), and acetone-DCM (blue). Scan rate:
100 mV/s.
workers developed
a
iron-catalyzed two-step
procedure for the construction of the titled
compounds. However, oxybenzotriazolation of
styrene and acidolysis was needed (Eq. 3, Scheme
1).[8] Loginova and Muathen independently reported
the synthesis of chloroacetophenones in the presence
of stoichiometric strong chemical oxidants, e. g.
chlorine dioxide (ClO2) or chlorous acid (Eq. 4,
Scheme 1).[9] Notably, other existing approaches
showed several drawbacks, for example, requiring
heavy metal reagents[10], low atom-efficient organic
compounds[11] and excessive amount of halogen
sources[12]
Analysis of the structure of chloroacetophenone
questions us that whether Cl and O motif could be
derived from very inexpensive feedstocks, inorganic
chloride salts and dioxygen, in the presence of
styrenes (Eq. 5, Scheme 1). Delightfully, both of the
nucleophilic chloride salts and oxygen molecule are
active species under electrochemical conditions.
Specifically, oxygen reduction reaction (ORR)
Table 1. CV features of varied transition metal chlorides
and the correlation with the corresponding yields.
Ep / V
Entry
Catal.
vs
Reversibility Yielda)
Ag/Ag+
1
2
3
4
5
1.28 V
1.31 V
1.27 V
1.29 V
0.5 V
NO
NO
Yes
NO
NO
18%
40%
88%
45%
8%
CrCl36H2O
FeCl2
CoCl26H2O
NiCl26H2O
CuCl22H2O
Co(NO3)26H2O
1 equiv.
6
0.89 V
Yes
90%
+
TBACl 5 equiv.
Yield was obtained in the condition of entry 2, table 2
unless otherwise noted.
a)
as the fundamental criteria for CV optimizing.
Initially, we put our attention on screening a series of
redox-active first-row transition metals except
manganese since we want to explore all new system.
After intensively scanning the first-row transition
metals (Cr, Fe, Co, Ni, Cu) by CV in various solvents
(see supporting information Figure S1-S60), cobalt
chloride hexahydrate in acetone-dichloromethane
(DCM) was identified as the most promising
candidate due to the reversibility (Figure 1) of CV
and good solubility. The representative cyclic
voltammograms and the corresponding first oxidation
potential were listed in Figure 1 and Table 1,
respectively.
generates highly reactive intermediate-superoxide ion
•[13]
O2
which has been employed in organic
electrosynthesis in very limited examples.[14]
Electrocatalysis of chloride by redox-active Mn salts
providing chlorine radical at a controlled manner was
elegantly described by Lin’s group.[15] Inspired by
those investigations, we report the CV-driven
optimization for Co-electrocatalyzed construction of
chloroacetophenones with abundant and cheap
feedstocks.
Then we turned our attention to the chloride
source. Surprisingly, the cyclic voltammogram of
CoCl26H2O was profoundly changed when
magnesium chloride hexahydrate (MgCl26H2O) was
added. So as to gain the effect of the concentration of
MgCl26H2O, we conducted the cyclic voltammetric
titration experiments. As we can see, the current
intensity of the reversible redox couple was
significantly enhanced (Figure 2a) and the oxidation
potential was remarkably decreased (from 1.27 V to
0.86 V, Figure 2b) when 3 equivalent of MgCl6H2O
Results and Discussion
As stated in Lin’s work, the real catalytic species was
in situ formed chlorine bound [MnCln] complex. The
cyclic voltammogram of the mixture of Mn(OTf)2
and MgCl2 displayed a reversible pattern with lower
oxidation potential (Ep = 0.81 V vs Fc+/0) than that of
pure chloride anion (Ep = 1.1 V vs Fc+/0).
Consequently, we chose the reversibility of CV and
the relative low oxidation potential of active complex
2
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10.1002/adsc.201901260
Advanced Synthesis & Catalysis
Figure 2. CV screening of molar ratio of chloride salts.
Conditions: glassy carbon as working electrode,
Ag/AgNO3 reference electrode, and a platinum wire
counter electrode. LiClO4 (1.2 mM), a) CoCl26H2O (0.04
mM), MgCl26H2O (0.2 to 2 mM) in acetone-DCM; b)
CoCl26H2O (0.04 mM), MgCl26H2O (1.2 mM) in
acetone-DCM (red), CoCl26H2O (0.04 mM), MgCl26H2O
(1.2 mM) in acetone (blue), CoCl26H2O (0.12 mM) in
acetone-DCM (black). Scan rate: 100 mV/s.
Figure 4. UV-vis spectra for the titration experiments of
Co(NO3)26H2O with TBACl in acetone-DCM. a)
Co(NO3)26H2O (0.12 mM), TBACl (0.6 to 0.96 mM); b)
CoCl26H2O (0.12 mM) (black line), CoCl26H2O (0.04
mM), MgCl26H2O (1.2 mM) (red line), Co(NO3)26H2O
(0.12 mM), TBACl (0.6 mM) (blue line), Co(NO3)26H2O
(0.12 mM), TBACl (0.96 mM) (pink line).
Figure S99-S106). Furthermore, the color change
(from blue to colorless transparent) of the above
solutions was clear (supporting information Figure
S107). Those data indicated that [CoCl5] was most
likely the real active catalytic species and that the
concentration of [CoCl5] was highly sufficient in the
standard conditions (Figure 4b & supporting
information Figure S108-S116). In fact, the
CoCl26H2O with MgCl26H2O system could be
mimic by the Co(NO3)26H2O with nBu4NCl system
(Entry 6, Table 1).
Subsequently, with this CV-indicated promising
system in hand, we setup the bulk electrolysis with
the commercially available pencil lead as both anode
and cathode at room temperature. Delightfully, 63%
isolated yield of the desired product was obtained
was added to 10 mol % CoCl26H2O (supporting
information Figure S61-S66).[16] In order to confirm
the optimal system, we conducted the CV
experiments in various solvents. Undoubtedly, the
superior current intensity was observed in acetone-
DCM again (Figure 2b, red vs blue line, &
supporting information Figure S67-S80).
However, the solubility of MgCl26H2O was
poor neither in acetone nor in the mixture of acetone-
DCM. This scenario questions us what was the real
catalyst in solution. Considering the fact that
tetrabutylammonium chloride (TBACl) is fully
dissolved in organic solvents, the titration
[17]
experiments of cobalt nitrate Co(NO3)2
with
TBACl were conducted by CV (Figure 3 &
supporting information Figure S81-S88). Obviously,
with the increased concentration of Cl, a new
reversible redox couple was observed when the molar
ratio of Co metal to Cl located in the range of 1:4 to
1:6. These results can be further corroborated by the
ultraviolent-visible absorbance spectrum (UV-vis).
Evidently, a new species was formed since three new
peaks at 634 nm, 668 nm, and 692nm appeared when
the molar ratio of Co metal to Cl located in the range
of 1:5 to 1:8 (Figure 4a & supporting information
Table 2. Screening the chemical essential parametersa).
Yield of
Yield of
Entry
1
Temp.
r.t.
Sol.
2
3
Acetone-
DCM
Acetone-
DCM
Acetone-
DCM
Acetone-
DCM
Acetone-
DCM
Acetone-
DCM
63%
88%
3%
4%
6%
0%
55%
3%
0%
2
40 oC
40 oC
40 oC
40 oC
40 oC
3b)
4c)
5d)
6e)
40%
89%
0%
a) Unless otherwise noted, pencil lead used as anode and
cathode, constant current I = 5 mA, CoCl26H2O (10
mol %), MgCl26H2O (3 equiv.), LiClO4 (3 equiv.), 5 h, O2
Figure 3. Cyclic voltammogram for titration experiments
of Co(NO3)26H2O with TBACl. Conditions: glassy carbon
as working electrode, Ag/AgNO3 reference electrode, and
a platinum wire counter electrode. LiClO4 (1.2 mM),
Co(NO3)26H2O (0.12 mM), TBACl (0.48 to 0.72 mM) in
acetone-DCM. Scan rate: 100 mV/s.
b)
balloon, acetone (6 mL) or acetone-DCM (5.9-0.1 mL).
c)
No CoCl26H2O CoCl26H2O (3 equiv.), no MgCl26H2O
d) RVC as anode and cathode 12 h, with H2SO4 (2 equiv.) e)
No electricity.
3
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10.1002/adsc.201901260
Advanced Synthesis & Catalysis
Table 3. Substrate scopesa).
a)
Unless otherwise noted, entry 6 in table 1 was employed as the reaction conditions: RVC used as anode and cathode,
constant current I = 5 mA, CoCl2·6H2O (10 mol %), MgCl2·6H2O (3 equiv.), LiClO4 (3 equiv.), H2SO4 (2 equiv.), 12 h, O2
balloon, 40 oC, acetone-DCM (5.9-0.1 mL). b) Acetone-DCM (5-1 mL) c) Pencil lead as anode and cathode, 5h d) No H2SO4.
(Entry 1, Table 2). Increasing the temperature to 40
oC resulted in 88% yield (Entry 2, Table 2). Then
the chemical essential parameters were recognized.
Cobalt metal and electricity were both necessary
(Entries 3 & 7, Table 2). Importantly, mixture of
compounds 2 and 3 were obtained when the reaction
was ran with soluble stoichiometric cobalt chloride in
electron- withdrawing substitutes, for instance, fluoro
(10-11), chloro (12-14), bromo (15), trifluoromethyl
(16), and cyano (17) were tolerated well. Furthermore,
1,2-substituted olefins could also be transformed into
the final scaffolds in good to excellent yields (18-19).
Regarding the site substituted pattern, para-pendent
analogues showed superior efficiency than meta- and
lieu of partially soluble magnesium chloride (Entry 4, ortho-ones resulting from the steric hindrance (4 vs 5
Table 2). These findings indicated that the
& 6; 12 vs 13 & 14).
One of
chemoselectivity depended on the concentration of
the
appealing
features
of
chlorides. Considering the reproducibility[18]
,
electrosynthesis[19] is robust scalability. Hence, gram-
scale reaction of the model substrate was conducted
in satisfied efficiency (Eq. 1, Scheme 2). In order to
reticulated vitreous carbon (RVC) was utilized
instead, although prolonged duration was required to
obtain high yield originating from the low current
density (Entry 5, Table 2). Most importantly, in
order to test the correlation between yield-based trial-
and-error and CV-based screening method, the
reaction with different metals was setup, and the
yields were in line with the prediction highlighting
the feasibility of our CV-driven optimization (Table
1).
After achieving the optimal conditions, we
focused on the substrate scopes (Table 3). First, we
tested the electron-releasing groups such as methyl
(4-6), tertiary butyl (7), methoxyl (8), and phenolic
ester (9). Delightly, most of them worked smoothly
under our standard conditions. Substrates with
Scheme 2. Gram-scale synthesis and control expriments.
4
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10.1002/adsc.201901260
Advanced Synthesis & Catalysis
it’s conceivable to initiate the reaction via anodically
oxidation of [Co(II)Cl5] to [Co(III)Cl5] releasing
chlorine radical at controlled manner. This step was
confirmed by entry 3 in table 2 since almost no
product was formed without cobalt catalyst. In order
to gain some insights into the mechanism, CV
analysis was employed once again to investigate the
interaction of electrogenerated [Co(III)Cl5] with
styrene. Obviously, the reduction peak of the
reversible redox-couple was completely disappeared
during the backward scanning when styrene was
presented in the optimal catalytic system (Figure 5 &
supporting information Figure S93-S96). This result
Figure 5. Cyclic voltammogram for investigation of
optimal system with styrene. Conditions: glassy carbon as
working electrode, Ag/AgNO3 reference electrode, and a
platinum wire counter electrode. LiClO4 (1.2 mM),
CoCl26H2O (0.04 mM), MgCl26H2O (0.12 mM), styrene
(0.12 mM) in acetone-DCM. Scan rate: 100 mV/s.
indicated that
a
fast interaction between
electrogenerated [Co(III)Cl5] and styrene via inner-
sphere or out-sphere mechanism delivered radical A.
When enough chlorine was presented (or without
oxygen in the system), dichlorination took place. This
proposal was in agreement with entries 4 & 6 in table
gain insights into the mechanism, a variety of control
experiments were performed. Addition of radical
scavengers, e.g. 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or 1,1-diphenylethylene, resulted in
remarkable decrease of the eventual product 3 which
strongly implied a radical pathway (Eq. 2, Scheme 2).
Moreover, the chlorohydroxylated intermediate 20
was fully transformed into the desired molecule under
the standard conditions whereas no conversion was
observed in the absence of electricity (Eq. 3, Scheme
2). Those phenomena indicated that structure 20 may
serve as one of the intermediates en route to the
desired product 3 According to the oxidative potential
of the each component (Ep = 0.89 V vs Ag/Ag+ for
[CoCl5] complex; Ep= 1.1 V vs Ag/Ag+ for Cl-; Ep=
1.1 V vs Ag/Ag+ for Cl-; Ep= 1.78 V vs Ag/Ag+ for
styrene, see supporting information Figure S89-S92),
2 (route 1). Cross-coupling of radical A with
[20]
cathodically generated persistent radical
-
superoxide ion (half-life, 30 mins at ambient
temperature)[21] produced intermediate B which
decomposed to 20; then electrochemically or
chemically further oxidation delivered product 2
(route 2). This proposal was corroborated by the
control experiments (Eq. 3 in Scheme 2). Oxygen
reduction reaction (ORR) or proton reduction (HER)
was believed to take response for the cathodic half-
reaction which could be determined by the
corresponding reductive potential (see supporting
information Figure S97-S98).
Scheme 3. Proposed mechanism.
However, the major disadvantage is that the
developed system was not suitable to the electronic
unbiased alkyl alkenes. Efforts are paying on this
topic in our lab and the related results will be
reported in due time.
Conclusion
In summary, we developed a CV-assisted
screening method to facilitate the condition
optimization processes in a rational manner. Thus
catalyst (CoCl2 6H2O), chloride source (MgCl2 6H2O)
and solvent (acetone and/or acetone-DCM) were
acknowledged step by step. By combining with the
chemical optimization, the best system was
successfully applied to expand the substrate scope.
.
.
Experimental Section
General procedure for the external oxidant-free
electrooxidative difunctionalization for the synthesis
5
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10.1002/adsc.201901260
Advanced Synthesis & Catalysis
of 2-chloroacetophenone: To an oven-dried undivided
glass vial (10 mL), string bar, CoCl2·6H2O (4.7 mg,
0.02 mmol. 10 mol%), MgCl2·6H2O (121.9 mg, 0.6
mmol, 3.0 equiv.), LiClO4 (63.8 mg, 0.6 mmol, 3.0
equiv.) was added. The bottle was equipped with a
rubber septum and graphite rod (ϕ 2 mm, about 10
mm immersion depth in solution) as the anode and
cathode. The cell was sealed and flushed with oxygen
for 15 minutes, followed by the sequential addition of
olefin substrates (23 μL, 0.20 mmol, 1.0 equiv.),
acetone (5.9 mL) and DCM (0.1 mL) via syringe.
Then the bulk electrolysis was started at a constant
current of 5 mA at 40 ˚C for 5 h. When the reaction
completed as indicted by TLC, the pure product
(white solid 27 mg, 88% Yield.) was obtained by
flash column chromatography on silica gel
(Petroleum ether:ethyl acetate = 20:1). Regarding
reticulated vitreous carbon (RVC, 100 PPI, 10 mm 
10 mm  2 mm) as the electrode, the sheet of RVC
was connected by the graphite rod with a sharpened
head and the reaction was run for 12 h unless
otherwise stated.
Liedtke, T. Hilche, S. Klare, A. Gansäuer,
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Acknowledgements
We greatly appreciate financial support from Qilu University of
Technology (Shandong Academy of Sciences; no. 0412048811,
81110326), Shandong Provincial Natural Science Foundation
(no. ZR2018BB017), the National Natural Science Foundation of
China (nos. 21801144, 81872744, 51602164), and Program for
Scientific Research Innovation Team in Colleges and Universities
of Shandong Province.
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CV-driven optimization: cobalt-catalyzed
electrochemical expedient oxychlorination of
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