Simple and versatile selective synthesis of neutral and cationic copper(i) N-heterocyclic carbene complexes using an electrochemical procedure

Article abstract of DOI:10.1039/c2cc30862b

An electrochemical approach for the preparation of copper(i) N-heterocyclic carbene complexes has been developed to include a diverse range of ligand precursors. Importantly, the method is effective for a ligand precursor that contains several acidic prot

Full text of DOI:10.1039/c2cc30862b

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COMMUNICATION
Simple and versatile selective synthesis of neutral and cationic copper(I)
N-heterocyclic carbene complexes using an electrochemical procedurew
a
a
b
b
Benjamin R. M. Lake, Emma K. Bullough, Thomas J. Williams, Adrian C. Whitwood,
a
a
Marc A. Little and Charlotte E. Willans*
Received 7th February 2012, Accepted 6th March 2012
DOI: 10.1039/c2cc30862b
An electrochemical approach for the preparation of copper(I)
N-heterocyclic carbene complexes has been developed to include a
diverse range of ligand precursors. Importantly, the method is effective
for a ligand precursor that contains several acidic protons and for
which traditional methods of carbene formation are not suitable.
To make them viable, however, routes to their synthesis should be
developed to eliminate the strict use of inert conditions, in addition
to producing minimum side-products and complexes of high purity.
Synthetic routes should also be compatible with a wide array of
ligand precursors. A procedure involving the reaction of copper(I)
oxide with imidazolium salts has been developed for the prepara-
24–27
tion of various copper(I)-NHCs (Fig. 1).
The route avoids the
Over the past two decades, metal complexes of N-heterocyclic
carbenes (NHCs) have become extremely important in catalytic
processes such as cross-coupling, metathesis, C–H bond activation
requirement of inert conditions, with the only side-product being
water. Imidazolium chloride/bromide salts are used to prepare
neutral complexes, though there are many ligand precursors for
which this route is not suited, particularly those containing less
bulky nitrogen substituents. More recently, an electrochemical
method for the preparation of copper(I)-NHC complexes has been
reported which uses an imidazolium hexafluorophosphate salt as
both the electrolyte and the reactant, and a copper plate as the
1–7
and polymerisation. To a much lesser extent they have been
investigated in biomedical applications, showing promise as anti-
8–10
microbial and as antitumour agents.
The most common
methods for the preparation of metal-NHCs are (i) deprotonation
of an imidazolium salt followed by coordination of the free NHC
to a metal centre, (ii) deprotonation of an imidazolium salt and
coordination in situ using a basic metal precursor and (iii) transfer
2
8
sacrificial anode. To the best of our knowledge, this methodology
is limited to ligands bearing N-pyridine or N-pyrimidine substitu-
ents, with cationic complexes of copper being formed. Herein, we
report an improved, cheaper and versatile electrochemical method
that allows controlled access to copper(I)-NHC complexes where
the NHC ligands do not possess a pendant donor arm (Fig. 2). We
have prepared both neutral and cationic copper(I)-NHCs using a
range of ligand precursors.
11–14
of an NHC ligand from silver.
The major disadvantages of
these routes are the requirement of strong bases and the generation
of unstable intermediates which require strict inert conditions, in
addition to the generation of undesirable side-products such as
silver salts. Furthermore, these routes are not compatible with
many ligand precursors, particularly those that possess nitrogen
substituents which are base-sensitive. A recently developed route
to NHC complexes which does not require base or silver salts
involves template synthesis, though this is limited to palladium,
The imidazolium chloride salts 1–3 were prepared through
glyoxal condensation with N-substituted amines followed by
2
9
cyclisation with paraformaldehyde (Fig. 2). Imidazolium
15
platinum and gold.
chloride 4 is commercially available, and imidazolium bromide
NHC complexes of copper(I) have significant roles in several
important catalytic processes such as cross-coupling reactions,
hydrosilylation, amination and reduction of carbonyl
5
was prepared through reaction of benzimidazole with benzyl
3
bromide in the presence of a base. Ligand precursor 6
0
16–19
was prepared by addition of 1-methylimidazole to benzyl
compounds.
Copper(I)-NHCs have also shown significant
3
bromide. Imidazolium bromide 7 was prepared through
1
20
cytotoxic profiles against various cancer cell lines. The develop-
ment of these materials for catalysis and biomedicine is of
great interest due to the relatively low cost of copper. In addition,
it has been shown that copper(I)-NHCs can act as ligand
0
0
reaction of a,a -dibromo-meta-xylene with a,a - diimidazole-
meta-xylene, and ligand precursor 8 was prepared by reaction
3
2
21–23
transfer reagents in a manner comparable to silver(I)-NHCs.
a
b
School of Chemistry, University of Leeds, Woodhouse Lane,
Leeds, LS2 9JT, UK. E-mail: c.e.willans@leeds.ac.uk
Department of Chemistry, University of York, Heslington, York,
YO10 5DD
w Electronic supplementary information (ESI) available: Experimental
procedures and crystallographic data. CCDC 865136–865140. For ESI
and crystallographic data in CIF or other electronic format see DOI:
24–27
O.
10.1039/c2cc30862b
Fig. 1 Copper(I)-NHCs prepared using imidazolium salts with Cu
2
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4887–4889 4887

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Table 1 Electrochemical synthesis of Cu(I)-NHC complexes
Time Time Current Yield
Ligand
Complex
(mins) (Q) (mA)
(%)
1
2
3
4
5
6
8
1
2
3
5
6
7
a X = Cl 1c Cu(NHC)Cl
120
80
19
60
45
60
60
200
300
220
330
150
880
4
3
1
2
50
60
50
60
44
62
a X = Cl 2c Cu(NHC)Cl
a X = Cl 3c Cu(NHC)Cl
a X = Cl 4c Cu(NHC) Cl
59
a
2
a X = Br 5c Cu(NHC)Br
a X = Br 6c Cu(NHC)Br
a X = Cl 8c Cu(NHC)Cl
1.5 50
2
2
68
67
48
36
42
74
64
58
72
50
50
40
50
100
50
50
+
+
+
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
b X = PF
b X = PF
b X = PF
b X = PF
b X = PF
b X = PF
6
6
6
6
6
6
1d [Cu(NHC)
2d [Cu(NHC)
3d [Cu(NHC)
5d [Cu(NHC)
6d [Cu(NHC)
2
2
2
2
2
]
]
]
]
[PF
[PF
[PF
[PF
6
6
6
6
6
]
]
]
]
]
5
10
14
11
5
]2+[PF
ꢁ
7d [Cu(NHC)]
2
2[PF
6
]
5.5 10
a
Due to the air sensitive and oily/sticky nature of 4c, an accurate yield
could not be obtained.
Fig. 2 Imidazolium salts used in the electrochemical study (a X = Cl/Br,
b X = PF ).
6
of 1-methylimidazole and tert-butyl 2-chloroacetate. The ligand
precursors were fully characterised using NMR spectroscopy and
mass spectrometry. A characteristic resonance at B9 ppm in the
H NMR spectra (DMSO-d ) is indicative of the (benz)imida-
1
6
zolium C2-proton. The anion was exchanged for hexafluoropho-
4 6
sphate using NH PF in either water or methanol. The
hexafluorophosphate salts precipitated and the isolated solids
were fully characterised.
The ligands shown in Fig. 2 were used in the electrochemical
synthesis of copper(I)-NHC complexes. The chloride/bromide or
hexafluorophosphate imidazolium salts in acetonitrile (1 mmol)
were used as the electrolyte. Copper plates (1 ꢀ 3 cm) were used as
both the sacrificial anode and cathode. At the anode the copper was
oxidised to copper(I) and at the cathode the imidazoliums were
reduced to free carbenes. The moieties combined in solution to
+
ꢁ
form either Cu(NHC)X, Cu(NHC) X, or [Cu(NHC) ] X ,
2
2
with the only side-product being hydrogen. The reactions were
1
monitored by H NMR spectroscopy and stopped when 495%
conversion was attained. The mixtures were filtered to remove small
amounts of copper oxide and metallic copper, and the products
were isolated as white or off-white solids. All the complexes
shown in Table 1 were characterised by NMR spectroscopy, mass
spectrometry and elemental analysis. Solid state structures for
several of the novel complexes have been obtained using X-ray
crystallographyw (Fig. 3). Reaction times are reported in minutes,
and in approximate number of Q (total charge) based upon the
reported current being maintained throughout the reaction period.
This shows that the reactions to prepare cationic complexes take
longer than those to prepare neutral complexes.
˚
Fig. 3 Solid-state structures with selected bond distances (A) and angles (1)
+
of 1d [Cu(NHC)
2
]
(C(9)–Cu(1) 1.8918(17), C(9)–Cu(1)–C(28) 177.55(7)),
(C(1)–Cu(1) 1.914(3), C(1)–Cu(1)–Br(1) 125.58(8)),
(C(1)–Cu(1) 1.9066(15), C(1)–Cu(1)–C(1) 180.00(7)),
2
(C(1)–Cu(1) 1.932(6), C(1)–Cu(1)–Br(1) 127.94(18)) and
5
c
[Cu(NHC)Br]
2
+
5d [Cu(NHC)
2
]
6
c [Cu(NHC)Br]
2+
7d [Cu(NHC)]
2
(C(1)–Cu(1) 1.8966(17), C(1)–Cu(1)–C(12) 178.45(7))
6ꢁ
(
ellipsoids are shown at 50% probability, hydrogen atoms and PF anions
are omitted for clarity).
Using the electrochemical method, we have established that the
use of imidazolium salts with a coordinating anion (chloride or
bromide) results in the formation of a neutral Cu(NHC)X complex,
expected near-linear geometry around the copper centre, with a
C–Cu–C bond angle of 177.551 (Fig. 3). Complex formation using
non-bulky nitrogen substituents is generally more problematic
due to the instability of the ‘unprotected’ carbene centre. Using
ligand precursors 4–8, we have shown that copper(I)-NHCs with
non-bulky nitrogen substituents can be easily prepared using this
methodology. Ligand 4 possesses the particularly small methyl
and ethyl substituents. The mass spectrometry data for 4c
indicates that two NHC ligands coordinate to the metal centre.
whereas a non-coordinating anion (hexafluorophosphate) gives a
+
cationic [Cu(NHC)
2
]
complex. Although complexes 1c–3c and
2d–3d are known, we have used these ligands to demonstrate that
the electrochemical route is compatible with imidazolium salts
bearing bulky nitrogen substituents, and with both coordinating
and non-coordinating anions. Complex 1d is novel and exhibits the
4
888 Chem. Commun., 2012, 48, 4887–4889
This journal is c The Royal Society of Chemistry 2012

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The procedure is simple, clean and generally high-yielding and will
be attractive as a general method for the preparation of copper(I)-
NHCs, including with the use of base-sensitive ligand precursors.
The methodology is being extended to other metals in our
laboratory through the use of different metal electrodes.
The authors gratefully acknowledge the Royal Society, the
School of Chemistry in Leeds and BP for financial support.
Notes and references
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2
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exhibits the expected bis-NHC cation with a linear copper centre.
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ꢁ
1
¨
¨
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Cu(NHC)]
2[PF ] (7d) has been prepared via the electro-
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copper centre on the opposite side.
The copper centres are near-
1
2
linear with normal copper-carbene bond lengths.
Imidazolium salts bearing ester substituents are of interest to our
group for the preparation of NHC complexes for biomedical
applications. Traditional routes to complex formation (deproton-
ation using various bases, reaction with different basic metal
precursors etc.) using ligand 8 have, however, been unsuccessful
to date (Scheme 1). Under basic conditions, the imidazolium
C2-proton remains protonated, and it appears that the base reacts
with the protons of the methylene bridge. This is indicative of
the methylene protons being more acidic than the imidazolium
C2-proton. Using the electrochemical method, we have prepared
a neutral copper(I) complex of the ester-substituted ligand 8.
Deprotonation occurs only at the C2-site to prepare complex 8c
in high-purity. This finding will significantly extend the range of
NHC ligands that can be explored in the field to include nitrogen
substituents that are base-sensitive.
2
2
2
2
0, 2027.
2
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In summary, we have reported the versatility of an electro-
chemical method for the preparation of both neutral and cationic
copper(I)-NHC complexes. We have used a range of monodentate
and bidentate imidazolium and benzimidazolium salts with differ-
ent nitrogen substituents (bulky and non-bulky) to prepare both
known and novel complexes. Crucially and for the first time, we
have shown that the method is compatible with an imidazolium
salt that contains a range of acidic protons. Traditional methods
of metal-NHC formation are not possible with these types
of ligand due to the necessary requirement for basic conditions.
2
2
2
3
3
3
3
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4887–4889 4889