Catalytic Rosenmund-von Braun reaction in halide-based ionic liquids

Article abstract of DOI:10.1016/S0040-4039(01)02168-2

Ionic liquids based on 1-n-butyl-3-methylimidazolium halide salts (bmiX) have been used as an effective reusable reaction media in the Rosenmund-von Braun reaction of aryl halides and NaCN using copper(I) salts as catalysts. Product isolation is achieved

Full text of DOI:10.1016/S0040-4039(01)02168-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 387–389
Catalytic Rosenmund–von Braun reaction in halide-based
ionic liquids
Jeff Xin Wu, Brandon Beck and Rex X. Ren*
Max Tishler Laboratory of Organic Chemistry, Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA
Received 12 October 2001; revised 7 November 2001; accepted 13 November 2001
Abstract—Ionic liquids based on 1-n-butyl-3-methylimidazolium halide salts (bmiX) have been used as an effective reusable
reaction media in the Rosenmund–von Braun reaction of aryl halides and NaCN using copper(I) salts as catalysts. Product
isolation is achieved by simple extraction using organic solvents. The copper catalysts immobilized in ionic liquid media can be
reused continuously. © 2002 Elsevier Science Ltd. All rights reserved.
Room-temperature ionic liquids, particularly those
based on 1,3-dialkylimidazolium cations such as 1-n-
butyl-3-methylimidazolium tetrafluoroborate (bmiBF4)
and 1-n-butyl-3-methylimidazolium hexafluorophos-
phate (bmiPF6), have been shown as the promising new
reaction media for organic synthesis. Their utility in
alkylation, acylation, hydrogenation, Diels–Alder and
Heck reactions as well as other organic transformations
has been demonstrated.1 On the other hand, 1,3-
dialkylimidazolium halide-based ionic liquids have
received little attention as reaction media, even though
they have been known for at least 80 years.2
Rosenmund–von Braun reaction is needed for contem-
porary chemical synthesis with less waste and more
facile isolation of products, perhaps with reuse of the
catalysts and reaction media as well.
We initially set out to investigate the feasibility of using
ionic liquids, especially 1-n-butyl-3-methylimidazolium
halides (bmiX, X=I, Br, Cl)5 as reaction media to
replace DMF and pyridine in the Rosenmund–von
Braun reaction. We reasoned that because of the non-
volatility of ionic liquids, the products could be distilled
directly from the reaction mixture. On the other hand,
owing to the limited solubility of these ionic liquids in
certain organic solvents such as hexanes, ethyl acetate
and toluene, isolation of products could be achieved
directly via simple extraction using common organic
solvents.
The Rosenmund–von Braun reaction has been known
for almost the same length of time, which gives rise to
aryl nitriles from the coupling of copper cyanide
(CuCN) with aryl halides.3 This reaction is usually
carried out in polar solvents such as nitrobenzene,
DMF and pyridine using excess of CuCN at 150–
250°C. The product isolation is a tedious process,
involving washings with water followed by extensive
silica gel column chromatography. Most recently, the
Rosenmund–von Braun reaction has experienced a
rekindled interest in the synthetic community for the
preparation of nitrile-containing aromatics as photo-
genic materials4 and as intermediates for pharmaceuti-
cal industry. However, the use of excess of CuCN and
high boiling point organic solvents may not be the
preferred choices. Hence, a more realistic catalyzed
A mixture of 2 mmol of CuCN, 1 mmol of iodobenzene
in 0.5 mL of 1-n-butyl-3-methylimidazolium iodide
(bmiI) sealed in a vial was heated at 90°C with stirring
for 24 h. A complete conversion of iodobenzene to
benzonitrile was observed (Table 1, entry 1). The
product was extracted using either hexanes or a mixture
of 2:1 hexanes:EtOAc (3×) and characterized based on
GC/MS and NMR after removal of organic solvents.6
Table 1 shows the Rosenmund–von Braun reaction of
iodobenzene with CuCN in various ionic liquids such as
bmiI, bmiBr and bmiCl. It was found that 2 equiv. of
CuCN was necessary to complete the reaction (entries
1b and c, 2b and c and 3b and c). When 1 equiv. of
CuCN was used, the conversion only reached 50%, and
addition of a catalytic amount of palladium chloride
(PdCl2) to the reaction mixture resulted in essentially
the same conversion rate. Other aryl iodides also gave
Keywords: Rosenmund–von Braun reaction; copper catalysts; aryl
nitrile; ionic liquids.
* Corresponding author. Fax: 1-860-685-2211; e-mail: rren@
wesleyan.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02168-2

388
J. X. Wu et al. / Tetrahedron Letters 43 (2002) 387–389
Table 2. Catalytic Rosenmund–von Braun reaction of
Aryl Iodides and bromides with NaCN in ionic liquids
satisfactory results when 2 equiv. of CuCN were used
(entry 4–7), regardless of the halide-based ionic liquids
used. It should be pointed out that the isolated yields
were lower than the conversion. This is presumably
attributable to insufficient extraction using 1:2 of
EtOAc:hexanes. By employing
a higher ratio of
EtOAc:hexanes such as 1:1 or 2:1 it was possible to
remove essentially all the desired products from ionic
liquid media.6 On the other hand, it seemed that the
electronic character of the substituents (such as
methoxy and cyano group) did not have significant
effects on the reaction. Aryl bromides such as 2-
bromonaphthalene and 1-bromonaphthalene gave satis-
factory results only when the reaction temperature was
raised to 130°C for 24 h (entries 8 and 9). 1-
Chloronaphthalene presented much lowered reactivity
(entry 10).
Table 1. Rosenmund–von Braun reaction of iodobenzene
with CuCN in ionic liquids
The mechanism of the Rosenmund–von Braun reaction
most likely involves a copper-assisted nucleophilic aro-
matic substitution. That is, activation of the aromatic
ring by a cationic copper(I) species is achieved via the
formation of either a s-complex between copper metal
and the lone pairs of the halogen atom or a p-complex
between the metal species and the aromatic ring. This is
followed by nucleophilic attack of cyanide (CN−),
which leads to elimination of iodide. Radical mecha-
nisms may also operate. Nevertheless, copper(I) plays a
catalytic role.7 It is also known that a copper catalyst
together with a sufficient amount of NaCN or KCN
can bring about the same transformation.3c Hence we
examined the utility of halide-based ionic liquids in
catalytic Rosenmund–von Braun reaction employing
NaCN as the cyanide source. Table 2 shows the results.
Thus, using a catalytic amount (5 mol%) of CuCN and
2 equiv. of NaCN in halide-based ionic liquids (bmiX,
X=Cl, Br or I) at 120°C, 2-iodonaphthalene was con-
verted to 2-cyano-naphthalene in high yield. Switching
from bmiI/CuI (entries 1b and c) to bmiCl/CuCl low-
ered the conversion rate (entry 1d). Other aryl iodides
also underwent the catalytic Rosenmund–von Braun
reaction to give the nitrile compounds (entries 2–4).
The premixing of copper catalysts with ionic liquids
seemed to have no effect on the conversion rates
(entries 1c, 2b and 4b). It is reasoned that by premixing
there is formation of clathrate8 (CuI2 ) between CuI
−
and the iodide anion (I−) of bmiI ionic liquid. There-
fore, the catalysts should be expected to remain active
even when they were to be reused, although it is
arguably true that the immobilized catalysts should
have formed clathrates with the halide anions of ionic
liquids upon first use.

J. X. Wu et al. / Tetrahedron Letters 43 (2002) 387–389
389
2-Bromonaphthalene
underwent
transformation
zolium bromide in Heck reaction, see: Xu, L.; Chen, W.;
Xiao, J. Organometallics 2000, 19, 1123.
(ꢀ55% based on GC/MS) to nitrile product in bmiBr
using CuCN as catalyst and 2 equiv. of NaCN (entry
5). When only 1 equiv. of NaCN was used in conjunc-
tion with CuCN as catalyst, all of the above reactions
proceeded much more slowly. It is known that the
addition of cyanide to the activated aryl halides is a
reversible process, therefore it is not surprising that
higher concentration of cyanide is the key to render this
type of reaction toward completion.3c
3. (a) Rosenmund, K. W.; Struck, E. Ber. 1919, 52, 1749; (b)
von Braun, J.; Manz, G. Ann. 1931, 488, 111. For reviews,
see: (c) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev.
1987, 87, 779; (d) Ito, T.; Watanabe, K. Bull. Chem. Soc.
Jpn. 1968, 41, 419.
4. Drechsler, U.; Hanack, M. In Comprehensive Supramolec-
ular Chemistry; Atwood, J. L.; Davies, J. E. D.; MacNicol,
D. D.; Vogtle, F., Eds.; Pergamon, 1996; Vol. 9, p. 283.
5. bimCl (mp 41°C), bmiBr (mp below room temperature)
and bmiI (mp −72°C) were prepared by heating a mixture
of n-butyl halides (1.5 equiv.) with 1-methylimidazole fol-
lowed by removal of unreacted n-butyl halides, respec-
tively. Although bmiCl is solid at room temperature,
warming up or addition of co-solvents such as water can
render them liquid-like due to their hydrophilicity. For the
latest reference regarding the melting points of bmiCl and
bmiI, see: Huddleston, J. G.; Visser, A. E.; Reichert, W.
M.; Willauer, H. D.; Broker, G. A.; Rogers, R. D. Green
Chem. 2001, 3, 156.
It is noteworthy that the copper catalysts immobilized
in ionic liquids can indeed be reused for several times
without loss of activity. Thus, upon removal of prod-
ucts via similar extraction procedure using organic sol-
vents, another 1 equiv. of substrates and 1 equiv. of
NaCN were added to the ionic liquid reaction media
containing copper catalyst. We observed that these
reactions led to similar results. Studies on the possible
catalyst leaching from ionic liquids are in progress.
In summary, in this preliminary communication the
Rosenmund–von Braun-type reaction of aryl halides
and NaCN using copper(I) salts as catalysts in ionic
liquids based on 1-n-butyl-3-methylimidazolium halide
salts (bmiX) has been demonstrated. Isolation of the
desired products can be achieved via a simple extrac-
tion using organic solvent mixes. The ionic liquids
containing immobilized copper catalyst can be reused
continuously.9
6. When more polar solvent mix was used in extraction, trace
amount of ionic liquids were observed in NMR. Filtration
of the extractant through a thin pad of silica gel could get
rid of this impurity.
7. Lindley, J. Tetrahedron 1984, 40, 1433.
8. Sitze, M. S.; Schreiter, E. R.; Patterson, E. V.; Freeman,
R. G. Inorg. Chem. 2001, 40, 2298–2304 and references
cited therein.
9. (a) A general procedure for cyanation reaction in ionic
liquids using a catalytic amount of copper catalysts: In
capped 2-dram vials, mixtures of 1 mmol of aromatic
halides, 0.05 mmol of copper catalysts, 2 mmol of NaCN
and 0.5 mL of halide-based ionic liquids were heated at
120°C with stirring for 24 h. The reactions were monitored
using GC/MS or NMR, and products were extracted using
solvent mixes (2:1 or 1:1 hexanes:EtOAC) or straight
EtOAc (3×3 mL).
Acknowledgements
The authors thank Wesleyan University for a start-up
grant. A summer NSF-REU undergraduate research
fellowship (to B.B. of Tougaloo College, MS) is also
acknowledged.
(b) A general procedure for cyanation reaction catalyzed
by pre-mixed catalysts: In capped 2-dram vials, 0.05 mmol
of copper iodide and 0.5 mL of bmiI ionic liquid were
mixed at 100°C for 5 min until the mixtures became
homogeneous. 1 mmol of aryl halides and 2 mmol of
NaCN were then added. The mixtures were stirred at
120°C for 24 h. The reactions were monitored using GC/
MS or NMR, and products were extracted using solvent
mixes (2:1 or 1:1 hexanes:EtOAC) or straight EtOAc (3×3
mL).
References
1. For recent reviews on ionic liquids in organic chemistry,
see: (a) Carlin, R. T.; Wilkes, J. S. In Advances in Non-
aqueous Chemistry; Mamantov, G.; Popov, A., Eds.;
VCH: New York, 1994; (b) Chauvin, Y.; Olivier, H.
ChemTech 1995, 25, 26; (c) Seddon, K. R. J. Chem. Tech.
Biotech. 1997, 68, 351; (d) Olivier, H. J. Mol. Cat. A:
Chem. 1999, 146, 285; (e) Welton, T. Chem. Rev. 1999, 99,
2071; (f) Wasserscheid, P.; Keim, W. Angew. Chem., Int.
Ed. 2000, 39, 3772.
(c) 2-Cyanonaphthalene: 1H NMR (300 MHz, CDCl3) l 8.
26 (s, 1H), 7.92 (m, 3H), 7.64 (m, 3H).
(d) 1,4-Dicyanobenzene: 1H NMR (300 MHz, CDCl3) l
7.81 (s, 4H).
(e) p-Phenylbenzonitrile: 1H NMR (300 MHz, CDCl3) l
7.76 (d, 8 Hz, 2H), 7.70 (d, 8 Hz, 2H), 7.60 (d, 8 Hz, 2H),
7.52–7.46 (m, 3H).
2. (a) Sarasin, J. Helv. Chim. Acta 1923, 6, 370; (b) von
Auwers, K.; Mauss, W. Ber. 1928, 61, 2411; (c) For a
recent reference on the use of 1-n-butyl-3-methyl-imida-