Simple and versatile synthesis of copper and silver N-heterocyclic carbene complexes in water or organic solvents

Article abstract of DOI:10.1039/c0dt00128g

A novel synthetic route leading to N-heterocyclic carbene copper complexes has been developed by using air-stable and commercially available copper(i) oxide and imidazolium salts starting materials.

Full text of DOI:10.1039/c0dt00128g

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Simple and versatile synthesis of copper and silver N-heterocyclic carbene
complexes in water or organic solvents†
Ce´cilia A. Citadelle, Erwan Le Nouy, Fabrice Bisaro, Alexandra M. Z. Slawin and Catherine S. J. Cazin*
Received 13th January 2010, Accepted 24th March 2010
First published as an Advance Article on the web 19th April 2010
DOI: 10.1039/c0dt00128g
A novel synthetic route leading to N-heterocyclic carbene
copper complexes has been developed by using air-stable and
commercially available copper(I) oxide and imidazolium salts
starting materials.
Most often the development of catalytic processes strongly
depends on the accessibility and cost of the pre-catalyst. The
synthesis of catalysts based on inexpensive metals such as
iron1 and copper2 has been the topic of recent reports. For
the latter case, several studies have demonstrated the effective
role of N-heterocyclic carbene (NHC) copper species of the
type [CuX(NHC)] (X = halide) in catalytic transformations.
These include reduction of carbonyl compounds,3 reductive aldol
condensation,4 carbene transfer reactions,5 amination reactions,6
trifluoromethylation reaction in a cross-coupling type process,7
hydrosilylation8,9 and Huisgen [3+2] cycloaddition.10 These com-
plexes have also exhibited interesting biological activity as anti-
tumour agents.11 The most common synthetic pathways leading
Fig. 1 Complexes obtained from Cu2O.
to [CuX(NHC)] complexes involve the reaction of CuX with
the pre-formed or in situ-formed NHC.12 Drawbacks of such
methodologies are the use of a strong base under strictly inert
conditions and the generation of inorganic waste by-products.9,13
Danopoulos14 and more recently Douthwaite15 have synthesised
neutral chelating NHC copper complexes by reaction of copper
oxide and imidazolium salts (Fig. 1). In such reactions, the only
side-product is H2O.
To the best of our knowledge, this methodology is limited
to the complexes shown in Fig. 1, and no investigation on the
possible versatility of such a straightforward route has been
disclosed. Herein, we report the development of such an elegant
Fig. 2 N-Heterocyclic Carbenes (NHC) used in this study.
synthetic strategy for the high yield generation of linear neutral
[CuCl(NHC)] complexes.‡ Six ligands were selected for this study
(Fig. 2) bearing saturated or unsaturated C4-C5 backbone, and
aryl or alkyl substituents on the nitrogen atoms. This selection was
made in order to test the scope and limitations of the approach.
Initial efforts were focused on the reaction of the imidazolium
and imidazolinium chlorides with Cu2O in dichloromethane, a
solvent commonly used for the synthesis of silver analogues
(Scheme 1).16 This strategy proved successful at room temperature
with IMes and SIPr as clearly indicated by the 1H NMR spectra
Scheme 1 Synthesis of [CuCl(NHC)] complexes in CH2Cl2.
that show the loss of the imidazolium proton NCHN. In contrast,
all other NHCs studied led to poor conversions despite harsher
reaction conditions (reflux CH2Cl2).
EaStCHEM School of Chemistry, University of St Andrews, St Andrews,
KY16 9ST, UK. E-mail: cc111@st-andrews.ac.uk; Fax: +44 1334 463 808;
Tel: +44 1334 463 698
This disparity in reactivity cannot be rationalised by steric
or electronic reasons. For instance, despite the fact that SIPr
is bulkier than IPr,17 [CuCl(SIPr)] is formed relatively easily at
room temperature whilst [CuCl(IPr)] is formed in less than 5% in
refluxing dichloromethane. No general trend could be found and
† Electronic supplementary information (ESI) available: Synthesis and
purification of all complexes and their 1H NMR spectra. 1H and 13C-
1
{ H} NMR spectra of A. CCDC reference number 761660. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0dt00128g
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Dalton Trans., 2010, 39, 4489–4491 | 4489
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systematic studies were hence conducted in order to optimise the
reaction conditions to produce [CuCl(NHC)] complexes.
To avoid the use of chlorinated solvents, that are toxic and
not desirable for industrial applications, toluene was employed
to allow higher reaction temperatures. This proved an efficient
methodology as all NHCs described here led to the corresponding
complex in good to quantitative conversions and moderate to
excellent isolated yields (Scheme 2).
1670 cm-1). Therefore, the reaction of SICy·HCl with Cu2O would
form the corresponding ketone, 1,3-dicyclohexylimidazolidin-2-
one, A, instead of the expected Cu-NHC complex (Scheme 4).
Scheme 4 Synthesis of 1,3-dicyclohexylimidazolidin-2-one, A.
In order to confirm this hypothesis, single crystals suitable
for X-ray diffraction were grown by slow evaporation of a
saturated CH2Cl2, solution of A. The X-ray analysis permitted
to unambiguously confirm the identity of A (Fig. 3).
Scheme 2 Synthesis of [CuCl(NHC)] complexes in toluene.
The viability of such a reaction has been demonstrated on 25 g
scale for one of these complexes, [CuCl(IPr)]. We then reasoned
that if higher operating temperatures were the only factor of
importance in this reaction, then the possibility of employing
water as a reaction medium should be considered. Imidazolium
salts are soluble in water, whilst copper(I) oxide is insoluble in
virtually all solvents. Therefore, using water as solvent might lead
to increased reaction yields as the imidazolium salts would be
completely solubilised. In addition, the [CuCl(NHC)] complexes
should precipitate from water, which could be a driving force for
the reaction and facilitate product isolation. On the other hand, the
use of water as solvent in a reaction releasing a molecule of water
seems counter-intuitive as removal of the water formed during the
reaction is also a way to drive it to completion. As can be seen in
Scheme 3, the use of water as a solvent for this reaction proved
viable for NHCs bearing aryl groups. For alkyl N,N¢-substituted
salts, the formation of the Cu-complex seemed somehow impeded
(Scheme 3).
Fig. 3 X-ray crystal structure of the imidazolidin-2-one (A).
The structure clearly shows the product to be 1,3-dicyclo-
˚
=
hexylimidazolidin-2-one with a C O bond distance of 1.244(4) A
in agreement with a classical carbonyl bond. This heterocy-
cle, initially described in 195019 has never been examined by
X-ray diffraction. Imidazolidinones were originally synthesised
by heating a slight excess of urea with a 1,2-diamine.20 These
molecules have attracted attention in the development of polymers
used as synthetic fibres as shown by DuPont. These cyclic ureas
are also of interest as respiratory stimulants.21
At this point, the mechanism of formation of the imidazolidi-
none remains obscure. It might involve the transfer of oxygen
from copper oxide after deprotonation of SICy·HCl. Studies are
currently underway in our laboratory to establish the mechanistic
pathway by which this reaction occurs.
Cu-NHC systems are not the only NHC complexes of interest
in Group 10, indeed, the silver analogues have also attracted
increasing interest for different applications. For instance, Ag-
NHC complexes are nowadays commonly used as NHC transfer
agents in transition metal chemistry22 and have displayed interest-
ing antimicrobial23 activity. Facile synthetic routes leading to high
yields of these complexes continues to be highly desirable. Reaction
conditions reporting the synthesis of Ag-NHC complexes from
Ag2O oftentimes make use of chlorinated solvents under anhy-
drous conditions.24 To the best of our knowledge, there are only
a few examples of such reactions performed in water.25 With the
copper results in hand, we reasoned that silver complexes would
be worthy of investigation under these simple aqueous synthetic
conditions. These studies proved the methodology quite successful
when the reactions are carried out at reflux (Scheme 5).
Scheme 3 Synthesis of [CuCl(NHC)] complexes in water.
Surprisingly, in the case of SICy, when the reaction is carried
out in toluene, the disappearance of a substantial amount of the
starting material SICy·HCl was observed with the concomitant
clean formation of a new compound, A. Whilst the 1H NMR data
obtained for A could easily be mistaken for the data expected for
1
Cu-complex bearing SICy, the 13C{ H} NMR spectrum leaves no
doubt that [CuCl(SICy)] has not been formed. This assertion is
based on the absence of the characteristic signal for the carbene
carbon atom that is expected to be shifted to low field (typically
ca. 200 ppm).18 On the other hand, a quaternary carbon atom
with a chemical shift of 160 ppm was observed. This chemical
It must be mentioned that the complexation of SICy on silver
is, as for copper, problematic since a mixture of products was
obtained under both reaction conditions (RT and reflux).
In summary, we have developed a versatile, efficient, and
inexpensive synthetic route to [CuCl(NHC)] complexes. Notewor-
thy, the synthesis can be performed in non-chlorinated solvents
=
shift is consistent with the presence of a C O group, which
was further confirmed by IR spectroscopy (signal observed at
4490 | Dalton Trans., 2010, 39, 4489–4491
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Scheme 5 Synthesis of [AgCl(NHC)] complexes in H2O.
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as well as in water! The aqueous synthetic methodology has
been extended to the silver congeners. As the most frequently
encountered members of the NHC ligand family can now be easily
appended to copper, ongoing studies in our laboratory are aimed at
investigating these compounds as catalysts and bioactive entities.
Finally, work is being carried out on the potential exploitation of
copper for the synthesis of imidazolidin-2-ones. Results of these
studies will be reported in due course.
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The authors gratefully acknowledge the School of Chemistry of
St Andrews for financial support as well as the EPSRC National
Mass Spectrometry Service Centre for analyses.
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Notes and references
‡ General protocol for the synthesis of the complexes: A glass vial equipped
with a magnetic stirring bar was charged with Cu2O (1.52 mmol, 95%
purity) and the NHC·HCl (2.34 mmol). The vial was purged with Argon
prior to addition of degassed solvent and the reaction mixture was stirred at
the required temperature for 24 h. The conversion was determined by NMR
and the complexes were purified and isolated as colourless solids. Synthesis
of 1,3-dicyclohexylimidazolidin-2-one, A: In a glass vial, copper oxide
(0.217 g, 1.52 mmol) and 1,3-dicyclohexylimidazolinium chloride (0.634 g,
2.34 mmol) were dissolved in Argon purged toluene (4.8 mL). The reaction
mixture was heated at reflux for 24 h. The crude solid obtained after
removal of the solvent, was dissolved in CH2Cl2, filtered and dried under
vacuum. 1,3-Dicyclohexylimidazolidin-2-one was obtained as a colourless
solid in 45% yield (0.263 g). 1H NMR (CDCl3, 300 MHz) d (ppm) 3.64 (m,
2H, CH), 3.18 (s, 4H, NCH2), 1.73-0.84 (m, 20H, CH2). 13C{ H} NMR
1
=
(CDCl3, 75 MHz) d (ppm) 160.13 (C O), 51.35 (CH), 38.48 (NCH2), 30.15
18 To the best of our knowledge, [CuCl(SICy)] has not been reported to
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19 A. E. Martell and A. E. Frost, J. Am. Chem. Soc., 1950, 72, 1032.
20 Du Pont de Nemours, GB530267, 1940.
(CH2), 25.89 (CH2). IR (NaCl) nC= 1670 cm-1. HRMS (NSI) [M+H]+
O
Calcd for C15H27N2O: 251.2118, found: 251.2120.
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Dalton Trans., 2010, 39, 4489–4491 | 4491
©