A highly efficient synthetic procedure for deuteriating imidazoles and imidazolium salts

Article abstract of DOI:10.1039/b009097m

Both substituted imidazoles and 1,3-dialkylimidazolium salts can be fully deuteriated on the heterocyclic ring using D₂O over heterogeneous Pd catalysts: deuteriated 1-alkyl-3-methylimidazolium chloride and hexafluorophosphate ionic liquids can also be prepared in good yields utilising readily available and relatively low cost sources of deuterium.

Full text of DOI:10.1039/b009097m

A highly efficient synthetic procedure for deuteriating
imidazoles and imidazolium salts
Christopher Hardacre,*ab John D. Holbrey and S. E. Jane McMath
b
a
a
School of Chemistry, The Queen’s University of Belfast, Belfast BT9 5AG, Northern Ireland
The QUILL centre, The Queen’s University of Belfast, Belfast BT9 5AG, Northern Ireland.
E-mail: c.hardacre@qub.ac.uk; Fax: +44 28 9038 2117; Tel: +44 28 9027 4592
b
Received (in Cambridge, UK) 13th November 2000, Accepted 17th January 2001
First published as an Advance Article on the web 8th February 2001
Both substituted imidazoles and 1,3-dialkylimidazolium
salts can be fully deuteriated on the heterocyclic ring using
Table 1 Percentage deuterium incorporation at the ring H(4/5) positions in
i) 1,3-dimethylimidazolium chloride and (ii) 1-methylimidazole using
various catalysts
(
D
2
O over heterogeneous Pd catalysts: deuteriated 1-alkyl-
3
-methylimidazolium chloride and hexafluorophosphate
%
Of ring H(4/5) deuteriated
ionic liquids can also be prepared in good yields utilising
readily available and relatively low cost sources of deute-
rium.
Catalysta
(i)
(ii)
1
—
0% Pd/C
90
99
95
33
45
91
b
Imidazole and imidazolium salts are key systems in nature (in,
—
87
0
for example, histidine and vitamin B12, and as components in
10% Pd/Al
5% Pt/C
2
O
3
DNA base-pair structure, biotin, etc).1 As such they have a
5
% Pt/Al
2
O
3
5
tremendous range of applications in pharmaceutical, veterinary
and agrochemical products. Other important applications in-
clude formulation of high temperature polymers and corrosion
a
Little difference was found varying the catalyst loading between 5 and
0%. b Second deuteriation cycle.
1
2
inhibitors, for the formation of carbenes (as replacements for
3
phosphine ligands in transition metal catalysis), and as the
basis for ionic liquids - clean solvents for catalysis, extraction
freeze-pump thaw cycles, after which the temperature was
raised to 100 °C and left for 1 h. This technique has been used
extensively for the deuteriation of other heterocycles, com-
technology and electrochemical applications.4
For our ongoing investigations of the liquid structure of ionic
liquids by neutron diffraction, access to deuteriated materials in
order to provide neutron-scattering contrast was required. For
these studies, it was necessary to prepare significant quantities
9
monly pyridines and related molecules. Using this method,
1
,3-dimethylimidazolium chloride was deuteriated at the ring
H(2) (99%) and H(4/5) (90%) positions using a 10% Pd/C
catalyst. The general applicability of this system was demon-
strated by deuteriation of imidazole, 1-methylimidazole and
(
3–5 g) of both fully deuteriated and selectively deuteriated
(exchange on the ring positions only) samples of 1,3-dimethyl-
imidazolium chloride or hexafluorophosphate and 1-ethyl-
-methylimidazolium chloride or hexafluorophosphate. Only
1
,3-dimethyl-, 1-ethyl-3-methyl- and 1,3-dibutylimidazolium
chlorides with 90–96% deuterium incorporation at the ring H(4/
) positions after one cycle. Exhaustive deuteriation of
3
one of these materials, 1-ethyl-3-methylimidazolium-d11 chlo-
ride, is currently commercially available and is supplied in
small quantities and at prohibitively high cost for this
experiment. This paper describes a versatile low cost method-
ology to prepare these deuteriated materials. Although ionic
liquids research provided the driving force behind this in-
vestigation, these molecules are also of significant interest as
mechanistic probes, particularly in biochemical studies, espe-
5
alkylimidazolium salts was tested at elevated temperatures, and
showed that, although exchange of the alkyl group hydrogens is
possible, it is inefficient. For example, the maximum deuterium
incorporation in methyl side chains on 1,3-dimethyl-
imidazolium chloride at 250 °C over any catalyst was 43% after
1
2 h.
In general, palladium catalysts are much more active for the
1
2
5
cially where H and D NMR spectroscopies are utilised.
Ring deuteriation of imidazolium cations has been performed
exchange reaction than platinum catalysts in both imidazole and
imidazolium-based systems. The lack of H/D exchange at the
H(4/5) positions using platinum is not well understood at
present. Explanations include a change in molecular adsorption
geometry between the two metals or site blocking by strongly
6
2 2
using D O by Dieter et al. In this study, shaking with D O was
sufficient to exchange the most acidic ring-hydrogen, H(2);
however, exchange of the ring-hydrogens, H(4/5), was found to
require more forcing conditions, i.e. heating in D
Using this method, the ring-deuteriated salt, 1-ethyl-3-methyl-
imidazolium-d chloride could be prepared. In contrast, imida-
2 2 3
O–K CO .
adsorbed molecules (originating via a surface reaction of the
10,11
imidazole).
Experiments are currently underway to under-
3
stand this process more fully.
6
8
zoles are much less susceptible to H/D exchange (10 –10 times
slower) than the corresponding imidazolium salts.7 Full ring
deuteriation of imidazole is also possible under forcing acidic
Using the methodology described above to deuteriate the ring
positions, a general procedure was devised in which the
synthesis and deuteriation of the 1,3-dialkylimidazolium salts is
divided into three discrete steps which can be manipulated in a
modular fashion (Scheme 1). This involved a sequence in which
imidazole is alkylated to 1-alkylimidazole, then ring-deuter-
,8
conditions. Lui et al. incorporated 90% deuterium using D
D SO
2 4
2
O–
at 200 °C for 4 h after two passes. Here we show that
by using D O and a heterogeneous catalyst, both imidazolium
5
2
salts and substituted imidazoles can be ring deuteriated easily
under mild, neutral conditions.
The
deuteriation
of
1-methylimidazole
and
1
,3-dimethylimidazolium chloride was screened using palla-
dium and platinum catalysts on a variety of supports† (Table 1).
The deuteriations were performed following a pre-reduction of
the catalyst in flowing dihydrogen at rt. The substrate dissolved
Scheme 1 (a) CD OD, RuCl /(n-BuO) P; (b) D O, 10% Pd/C; (c) RX
(CD Cl, C D I).
3 2 5
3
3
3
2
in D
2
O was added to the catalyst and underwent a number of
DOI: 10.1039/b009097m
Chem. Commun., 2001, 367–368
This journal is © The Royal Society of Chemistry 2001
367

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iated with subsequent quaternisation with a second alkylating
agent to yield the desired deuteriated 1,3-dialkylimidazolium
salt. The order of the sequence depends on the relative
efficiency of each step and the nature of the anions in the final
the ring H(2) in aqueous solution, it is also possible to
selectively control the H/D substitution of the ring H(2) and
H(4/5) by H/D exchange.
Financial support from the Department of Education in
Northern Ireland (S. E. J. M.) and the Queen’s University Ionic
Liquids Laboratory (S. E. J. M., J. D. H) is gratefully
acknowledged. Johnson Matthey and Degussa are thanked for
the generous donation of the carbon catalysts and aluminium
oxide respectively.
1
,3-dialkylimidazolium salt. It is also important to consider
whether deuteriation of the ring should be performed before or
after the quaternisation. This is dependant on the relative
stability of the H/D exchanged hydrogens with respect to
scrambling in the subsequent reactions, e.g. quaternisation.
Here, the initial alkylation of the imidazole could not be
performed cleanly using conventional procedures,12 since a
number of by-products were also formed. For example,
methylation of imidazole with iodomethane under neutral
conditions led to the formation of a mixture of 1H-imidazolium
iodide, 1-methylimidazole and 1,3-dimethylimidazolium iod-
ide. Under these reaction conditions, the imidazole acts as a
base for the alkylation. However, since 1-methylimidazole is
more reactive towards methyl iodide than imidazole itself, this
leads to a final product mixture, which cannot easily be
separated. Due to this problem, this method can only be applied
to symmetrically substituted 1,3-dialkylimidazolium salts. In
the field of room temperature ionic liquids, cation asymmetry is
an important feature in order to provide the variation in
properties such as melting point, viscosity and density, which
allows their use as tuneable solvents.13
Notes and references
†
Oxide supported catalysts were synthesised by wet impregnation from
PdCl and H PtCl precursors on Degussa Alumina grade C, the catalysts
2
2
6
were then calcined and reduced under hydrogen. ICP analysis of metal
content was used to confirm catalyst loading. Pd/C and Pt/C catalysts were
supplied by Johnson Matthey.
‡
Methanol-d
obtained from Aldrich and used as supplied.
1-Methyl-d -imidazole. Ruthenium chloride hydrate (0.63 g, 2.41 mmol),
4
(99.8%) from Apollo Scientific Ltd. All other reagents were
3
tri(n-butyl)phosphite (2.30 g, 9.19 mmol) and imidazole (10.78 g, 0.158
3
mol) were sequentially dissolved in 1,4-dioxane (300 cm ) in a stirred 1 L
4
autoclave. After addition of methanol-d (20 g, 0.554 mol), the mixture was
heated at 200 °C under 40 bar pressure of nitrogen for 18 h. Following
reaction, the liquid was decanted from the spent catalyst and solvent/excess
methanol were removed. The resulting pale yellow oil was vacuum distilled
3
at 100 °C to give 1-methyl-d -imidazole as a colourless oil (6.5 g, 49%) and
Alkylimidazoles may be synthesised via a number of other
analysed by GC-MS. m/z (EI) 85, accurate mass 85.072 (Calc for
C H N D , 85.072), NMR d /ppm (CDCl ) 7.49 (1H, s), 7.01 (1H, s), 7.86
routes. Arduengo et al.14 prepared 1,4,5-trimethyl-d
-imidazole
9
4
3
2
3
H
3
as a precursor to perdeuteriated carbenes via a cyclisation route
using perdeuteriated methylamine, prepared by deuteriation of
deuteriated nitromethane. Alkylation of imidazole has also been
performed catalytically with methanol over a homogeneous
ruthenium–tributylphosphite catalyst; Tanaka et al.15 claimed
(1H, s); d
(-CD ); d
recovered from the distillation flask. Overall yield, based on imidazole was
5%, unreacted deuteriated methanol was recovered from the solvents by
distillation and could be reused.
-Methylimidazole-d . Palladium on activated carbon (2 g, 10% Pd) was
reduced under dihydrogen (1 atm), for 1 h at rt. 1-Methylimidazole (10 g,
.117 mol) was dissolved in pure D O (50 g, 0.28 mol), and added to the
C 3
/ppm (CDCl ) 135.26 (C2), 126.93 (C4), 118.05 (C5), 30.59
3
D
/ppm (CDCl
3
) 29.64 (-CD ). Unreacted imidazole (34%) was
3
7
1
6
9
9.5% conversion and greater than 98% selectivity for the
production of methylimidazole. This presents a potentially
0
2
more effective route than that of Arduengo et al.14 for the
reduced catalyst. The reaction mixture was degassed by three freeze pump
thaw cycles, then heated with stirring at 100 °C for 1 h. The reaction mixture
was filtered to remove the catalyst, and the aqueous solvent was removed
under reduced pressure, and then in vacuo to give the ring-deuteriated
3
formation of 1-methyl-d -imidazole using deuteriated methanol
as a low-cost methylating agent and also gives the opportunity
to utilise longer-chain alcohols (for instance, deuteriated
ethanol).
1
-methylimidazole (9.4 g, 91%). Extent of deuteriation was analysed by loss
1
13
in H and changes in C NMR.
,3-Dimethylimidazolium-d chloride. Chloromethane-d
mmol) was condensed onto 1-methylimidazole-d (1.0 g, 11.4 mmol) in a
9
Here, 1,3-dimethylimidazolium-d chloride was prepared
1
9
3
(1.0 g, 18.7
from imidazole in three steps, introducing deuteriatated func-
tionality at one nitrogen (via an alkyl group), to the ring and
finally in a quaternisation step adding a deuteriated methyl
group to the second nitrogen.‡ In the first step, imidazole was N-
6
carius tube cooled to 2180 °C with liquid nitrogen. The tube was then
sealed and brought to rt, then heated at 80 °C for 15 h to give the
1
9
,3-dimethylimidazolium-d chloride as a colourless crystalline solid (1.6 g,
methylated with deuteriated methanol to 1-methyl-d
3
-imidazole
99%).
over a homogeneous ruthenium–tributylphosphite catalyst in
15
1 R. J. Sundberg and R. B. Martin, Chem. Rev., 1974, 74, 471.
1
,4-dioxane at 200 °C/40 bar pressure with overall 75% yield
based on recovered imidazole) and was isolated by vacuum
distillation. The resulting 1-methyl-d -imidazole was then
deuteriated on the ring with D O over a Pd/C catalyst to give the
fully perdeuteriated 1-methylimidazole. This was then alkylated
with chloromethane-d to give the 1,3-dimethylimidazolium-d
chloride, and with iodoethane-d to 1-ethyl-3-methyl-
2
3
F. Eng and H. Ishida, J. Mater. Sci., 1986, 21, 1561.
W. A. Herrmann, L. J. Goossen, C. Kocher and G. R. J. Artus, Angew.
Chem., Int. Ed. Engl., 1996, 35, 2805.
(
3
2
4
5
T. Welton, Chem. Rev., 1999, 99, 2071.
K. Lui, J. Williams, H. R. Lee, M. M. Fitzgerald, G. M. Jensen, D. B.
Goodin and A. E. McDermott, J. Am Chem. Soc., 1998, 120, 10 199.
K. M. Dieter Jr., C. J. Dymek, N. E. Heimer, J. W. Rovang and J. S.
Wilkes, J. Am. Chem. Soc., 1988, 110, 2722.
3
9
5
6
imidazolium-d11 iodide in good overall yields. This approach
allows the greatest flexibility in the chemistry and permits the
selective introduction of deuterium to any of the functional
areas of the imidazolium cation using relatively inexpensive and
readily available deuteriated starting materials. The hexa-
fluorophosphate salts were obtained by metathesis from the
7 O. Clement, A. W. Roszak and E. Buncel, J. Am. Chem. Soc., 1996, 118,
612; E. Buncel, O. Clement and I. Onyido, J. Am. Chem. Soc., 1994,
1
16, 2679; J. R. Jones and S. E. Taylor, Chem. Soc. Rev., 1981, 10,
3
29.
8
9
J. L. Wong and J. Keck Jr., J. Org. Chem., 1974, 39, 2398.
For example, J. A. Elvidge, J. R. Jones, R. B. Mane and J. M. A. Al-
Rawi, J. Chem. Soc., Perkin Transactions 2, 1979, 386; G. E. Calf, J. L.
Garnett and V. A. Pickles, Aust. J. Chem., 1968, 21, 961.
halide salt with Na[PF
11 chloride was then isolated from the corresponding hexa-
fluorophosphate salt by metathesis with LiCl in acetone-d . All
6 2
] in D O. 1-Ethyl-3-methylimidazolium-
d
6
1
0 K. Pekmez and A. Yildiz, Z. Phys. Chem., 1996, 96, 109.
1
13
the salts were collected as colourless crystals. H and C NMR
spectra were obtained to assess the levels of deuteriation in the
salts and in all cases the deuterium incorporation was greater
than 97%. It should be noted that, for the ring deuteriations, this
required two cycles in order to increase the deuterium level
from 90 to > 97%.
11 R. T. Carlin, T. H. Cho and J. Fuller, Proceedings of the 12th
International Symposium on Molten Salts, ed. P. C. Truelove, H. C. De
Long, G. Stafford and S. Deki, PV99-41, p. 90, The Electrochemical
Proceedings Series, Pennington NJ, 1999; K Anderson, P. Goodrich, C.
Hardacre, S. E. J. McMath, in preparation.
2 M. R. Grimmett, Imidazole and benzimidazole synthesis, 1997,
Academic Press, London.
3 A. S. Larsen, J. D. Holbrey, F. S. Tham and C. A. Reed, J. Am. Chem.
Soc., 2000, 122, 7264.
1
1
1
This procedure (Scheme 1) enables the preparation of ionic
liquids and other 1,3-dialkylimidazolium salts (i.e. as pre-
cursors to carbene ligands) in which deuteriation of the cation
can be selectively applied to any position; one or two N-alkyl
substituents and ring. Moreover, combined with the lability of
4 A. J. Arduengo III, H. V. R. Dias, D. A. Dixon, R. L. Harlow, W. T.
Klooster and T. F. Koetzle, J. Am. Chem. Soc., 1994, 116, 6812.
15 N. Tanaka, M. Hatanaka and Y. Watanabe, Chem. Lett., 1992, 575.
368
Chem. Commun., 2001, 367–368