Electrochemical flow-reactor for expedient synthesis of copper-N-heterocyclic carbene complexes

Article abstract of DOI:10.1039/c4cc08874c

An electrochemical flow-cell for highly efficient and selective generation of Cu^I-N-heterocyclic carbene complexes under neutral and ambient conditions is reported. The feasibility of the flow-cell is demonstrated through the electrochemical sy

Full text of DOI:10.1039/c4cc08874c

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Electrochemical flow-reactor for expedient
synthesis of copper–N-heterocyclic carbene
Cite this:DOI: 10.1039/c4cc08874c
complexes†
Received 6th November 2014,
Accepted 27th November 2014
a
a
b
a
Michael R. Chapman, Yarseen M. Shafi, Nikil Kapur,* Bao N. Nguyen* and
Charlotte E. Willans*
a
DOI: 10.1039/c4cc08874c
www.rsc.org/chemcomm
An electrochemical flow-cell for highly efficient and selective generation
I
of Cu –N-heterocyclic carbene complexes under neutral and ambient
conditions is reported. The feasibility of the flow-cell is demonstrated
through the electrochemical synthesis of [Cu(IMes)Cl] and subsequent
in situ flow directly into hydrosilylation reactions, with equal efficiency to
the purified catalyst.
Scheme 1 Electrochemical synthesis of metal–NHC complexes: (a) reduction
of imidazolium to a free NHC; (b) oxidation of metal; (c) combination of NHC
Since their isolation in 1991, N-heterocyclic carbenes (NHCs) have and metal.
1
become ubiquitous in organometallic chemistry and catalysis,
including hydrogenation, hydrosilylation, cross-coupling reactions
Practical issues associated with the electrochemical batch process
2
–5
and olefin metathesis. In recent years, metal–NHCs have also exist: (i) a large overpotential is required due to inefficient mass-
shown significant promise in biomedicine, particularly within transfer between the electrode surfaces; (ii) Faradaic efficiency tends
6
–8
the fields of antimicrobials and cancer chemotherapy.
The to be low (Q generally 42). These problems can be overcome by
most common synthetic methods to prepare metal–NHCs use moving into continuous mode, making the technology more
imidazolium salt precursors and often require the use of strong accessible for academic, industrial and clinical use. An electro-
bases and strict inert conditions, or the use of basic metal precursors chemical microreactor for the synthesis of organic compounds
9
–12
15
(
e.g. Ag O).
The major disadvantages of these routes include in flow has previously been reported. Herein, we report the
2
the generation of unstable intermediates, formation of undesirable design, construction and optimisation of an electrochemical
side-products and incompatibility with base-sensitive substituents. flow-reactor for the synthesis of both neutral heteroleptic and
I
Chen and co-workers reported a simple and practical procedure for cationic homoleptic Cu –NHC complexes. To the best of our
the production of metal–NHCs using N-pyridine or N-pyrimidine knowledge, this is the first example of the electrochemical
13
substituted imidazolium salts and metal plates. We reported a synthesis of metal complexes in continuous flow.
valuable extension to this model by using ligands that do not Our first prototype consists of a PTFE linear flow-channel
comprise a pendant donor arm, to produce selectively both neutral (190 ꢀ 4 ꢀ 3.5 mm), which supports two parallel copper electrodes
14
and cationic complexes. As basic conditions are not necessary, (190 ꢀ 4 ꢀ 0.5 mm) at a separation distance of 2.5 mm (see ESI†).
3
the route was found to be compatible with base-sensitive substi- The effective volume of the flow-channel is 1.9 cm . Preliminary
tuents, thus significantly widening the range of NHCs that may be experiments in MeCN under a N
developed. During the electrochemical reaction, an imidazolium significant amount of undesired [Cu(NHC)
ion (electrolyte) is reduced at the cathode, releasing H to form a likely due to the large distance between electrodes and conse-
free NHC. Concomitantly, oxidation of the sacrificial copper anode quently poor mixing between the carbene and [Cu(NCMe)
2
atmosphere indicated that a
2
][CuCl ] (3) was formed,
2
2
+
4
]
+
occurs, liberating Cu ions into solution. These two species com- (Scheme 2). Glass beads (dia. 2.0 mm) were packed into the flow
bine to deliver the desired Cu–NHC complex (Scheme 1).
channel in staggered formation to reduce the effective volume of
the reactor to 1.05 cm and increase flow velocity. Residence time
3
inside the cell was reduced and the formation of 3 was completely
suppressed. All subsequent data recorded in the first flow-cell was
therefore with the use of glass beads.
a
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
E-mail: c.e.willans@leeds.ac.uk
b
School of Mechanical Engineering, University of Leeds, LS2 9JT, UK
Flow-rate and applied potential were optimised for efficiency
†
Electronic supplementary information (ESI) available: Synthetic and catalytic
procedures, CV data and cell design and optimisation. See DOI: 10.1039/c4cc08874c and selectivity using a solution of [IMesH]Cl (6.6 mM) in MeCN
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Scheme 2 Concomitant electrochemical reduction/complexation of
[
IMesH]Cl 1 in flow.
Fig. 2 Photograph of the second-generation electrochemical flow-reactor
(left) and the shape of the reactor channel through a 1 mm thick Teflon spacer
(right).
To further increase the electrode surface area, a second
modular reactor design was developed. Six square copper plates
50 ꢀ 50 ꢀ 1 mm), separated by five PTFE spacers (1 mm
(
thickness cut with a 4 mm wide and 200 mm long flow channel)
were assembled as shown in Fig. 2. The copper plates alternate
between cathode and anode to provide five consecutive parallel-
plate electrochemical flow-reactors. This design allows reactor
metrics (channel length, width, electrode separation, interfacial
area and reactor volume) to be optimised as required. The short
distance between electrodes and the tailored channel shape
Fig. 1 Schematic diagram for the electrochemical synthesis of 2 in con-
tinuous mode.
(
Fig. 1). The reduction potential of [IMesH]Cl in MeCN was minimise the diffusive ion path-length and cell resistivity,
+
determined to be ꢁ2.32 V (versus Fc/Fc ) by cyclic voltammetry whilst optimising current density. The second flow-cell had a
(see ESI†). Maximum conversion in single-pass mode was achieved total volume of 4.0 mL, and the surface areas of the anode and
ꢁ
1
2
with an applied potential of 2.5 V and flow-rate of 0.5 mL min
cathode electrodes were 40 cm each.
(residence time = 126 seconds), giving Cu(IMes)Cl (2) in 36% yield.
Experimental evaluation of the revised flow-cell provided
An insoluble copper species was formed when a voltage Z3 V was significant improvements in both the electrochemical output
ꢁ
1
applied, with the current density at 2.5 V being calculated as and selectivity. At 1.94 V and 0.67 mL min (residence time =
ꢁ
2
0
.36 mA cm (Table 1). When the concentration of [IMesH]Cl 360 seconds), a yield of 94% of complex 2 was achieved in
was increased five-fold, a decrease in conversion (25% yield) was single-pass mode. Imidazolinone 4 was reduced to 3%, pre-
observed, indicating that the surface area of the electrode is the sumably due to reduced distance between the electrodes
limiting factor. Recirculation of the 6.6 mM solution (20 mL, increasing the rate of formation of Cu(IMes)Cl 2. The lower
0.132 mmol) allowed full conversion of 1 to give complex 2 in potential required highlights the improved efficiency of the
9
2% yield after 80 minutes, a significant improvement on the yield second flow-cell, and its capacity to selectively form desired
14
in batch (59%). A small amount of imidazolinone 4 (8%) was complexes in the presence of redox sensitive functional groups.
observed, presumably as a consequence of air being introduced The overall reaction time to convert 0.132 mmol of [IMesH]Cl to
ꢁ1
into the reactor during recirculation. Oxo-adducts of related NHCs complex 2 was reduced to 29.9 minutes (20 mL, 0.67 mL min
have previously been observed, and can be induced from the single-pass). A comparison between the performance of the two
,
16
imidazolium salt using CsOH. The overall Faradaic efficiency of electrochemical flow-cells is summarised in Table 1.
the cell was 98%.
The versatility of the second-generation flow-cell was examined
using a variety of imidazolium precursors (Table 2). These included
N-substituents with decreased steric bulk (entries 3–6), in addition
to base-sensitive allyl and ester N-substituents (entries 3–4) and a
macrocyclic imidazolium salt (entry 6). Furthermore, imidazolium
hexafluorophosphate salts were assessed (entries 2, 5 and 6), which
form exclusively cationic homoleptic complexes. A variety of
Table 1 Comparison of the electrochemical synthesis of Cu(IMes)Cl (2) in
first- and second-generation flow-reactors
1
st flow-cell 2nd flow-cell
2
Single electrode surface area (cm )
7.6
2.5
2.50
2.7
0.36
126
40
1.0
I
Cu –NHC complexes were prepared selectively and in high yields,
Distance between electrodes (mm)
Applied potential (V)
1.94
10.0
0.25
360
validating that the optimised cell is suitable for the efficient
a
Observed current (mA)
I
ꢁ2
synthesis of a broad range of Cu –NHCs.
Current density (mA cm
Residence time (s)
Time to convert 0.132 mmol of 1 to 2 (min) 80.0 (92%) 29.9 (97%)
)
To demonstrate the synthetic utility of our electrochemical
flow-cell, the output stream containing complex 2 (i.e. formed
in entry 1) in MeCN was introduced directly from the flow-cell
into catalytic hydrosilylation reactions of functionalised ketones
b
c
a
b
c
Registered at steady-state. In recirculation mode. In single-pass
mode.
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I
Table 2 Scope of Cu –NHC complexes prepared under continuous
In conclusion, two simple and effective electrochemical
flow-reactors have been reported which perform highly selec-
tive and efficient syntheses of Cu –NHC complexes in excellent
electrochemical conditions in the second-generation flow-cell
I
yields under neutral and ambient conditions. This was
achieved through rational design and construction of a flow-
cell to maximise interfacial area and mixing of species gener-
ated from the two electrodes, which resulted in much more
controlled electrochemical conditions. The synthetic utility of
0
ꢁ
c
d
R
R
X
E
appl (V)
I
(mA)
t
R
(min) Yield (%) the cell has been demonstrated through the preparation of a
I
a
range of Cu -mono- and bis-NHCs comprising varying
1
2
3
4
5
6
Mesityla Mesityl
Mesityla Mesityl
Cl 1.94
PF 2.54
10.0
20.1
19.3
31.0
28.7
74.4
29.9
20.0
6.7
13.3
20.0
94
93
91
95
94
95
6
N-substituents. In addition, the flow-cell can be used to ‘dis-
pense’ Cu(IMes)Cl 2 as catalyst directly into catalytic hydro-
silylation reactions with virtually no difference in catalytic
activity when compared to isolated catalyst.
Picolyl Allyl
Br 2.20
Bu Cl 2.40
a
t
Methyla CH
2
CO
2
Benzyl Benzyl
PF
PF
6
2.95
4.90
b
Cyclophane
6
300
a
b
c
We would like to thank AstraZeneca for funding towards the
first-generation flow-cell and the High Value Chemical Manu-
facturing Hub at Leeds for funding the second-generation flow-
cell.
In single-pass mode. In recirculation mode. Registered at steady-
d
1
state. Analysed by H NMR spectroscopy.
Table 3 Hydrosilylation reactions using catalyst 2 directly from the
electrochemical flow-cell
Notes and references
1
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a
a,b
c
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(h)
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0
R
R
2014, 510, 485–496.
Cyclohexyl
Cyclohexyl
Methyl
Methyl
Methyl
Methyl
2
6
6
6
5
97
95
97
94
97
2
6
6
6.5
6
98
94
97
90
98
4
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a
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c
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3
to those reported by Nolan using CuCl/[IMesH]Cl as pre-catalyst,
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1
1
7
Identical reaction conditions using our
2
‘
2
dispensed’ catalyst were reproduced using isolated and purified 11 I. J. B. Lin and C. S. Vasam, Coord. Chem. Rev., 2007, 251, 642–670.
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1
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generated catalysts are likely to be a consequence of the formation
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much more reactive, highlighting the importance of selective
complex formation. Our results demonstrate the potential of
the electrochemical flow-reactor as an ‘on-demand dispenser’
of high purity catalyst directly into a reaction without the need
for isolation and work-up.
I
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