The effect of ionic liquids on the outcome of nitrile oxide cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2008.12.045

Nitrile oxide cycloadditions between benzonitrile oxide and a series of alkenes were investigated in ionic liquids and molecular solvents. The regioselectivity of the process alters on changing solvent type, with the steric requirements of the reaction be

Full text of DOI:10.1016/j.tetlet.2008.12.045

Tetrahedron Letters 50 (2009) 992–994
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Tetrahedron Letters
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The effect of ionic liquids on the outcome of nitrile oxide cycloadditions
*
Camille E. Rosella, Jason B. Harper
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Nitrile oxide cycloadditions between benzonitrile oxide and a series of alkenes were investigated in ionic
liquids and molecular solvents. The regioselectivity of the process alters on changing solvent type, with
the steric requirements of the reaction being increased in ionic liquids. The rate of the cycloaddition pro-
cess was found to be faster in ionic liquid solvents, and a concomitant increase in the rate of dimerisation
of the nitrile oxide starting material was also observed.
Received 3 November 2008
Accepted 9 December 2008
Available online 16 December 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Synthetic chemistry relies heavily on the use of molecular sol-
vents. Many of these solvents have been found to be environmen-
tally unfriendly, so their use in industry is generating interest in
alternative reaction media.1,2 One potential answer to these prob-
lems lies with ionic liquids. Ionic liquids are versatile reaction
media; changing either ion may change the physical properties of
the liquid, allowing it to be altered to suit the required conditions
for a certain reaction.2 Furthermore, ionic liquids have the poten-
tial to be recycled and re-used many times,3,4 greatly reducing
waste and the impact on the environment.
These solvents may be considered to have great potential, and it
has already been shown that a range of organic and inorganic syn-
theses can be carried out in ionic liquids.5,6 However, the outcome
of a range of reactions has been shown to be dramatically altered,
both in terms of rates and product outcome, on changing from a
molecular solvent to an ionic liquid, and currently such changes
cannot be readily predicted.7 For example, Diels–Alder cycloaddi-
tions have been studied extensively in ionic liquids with an in-
crease in endo-selectivity and rate typically observed.5 While
these changes have been attributed to solvation parameters (such
as hydrogen bonding8,9) which apply more generally to molecular
solvents, there are concerns over the effect of the dilution of the
reaction media with reagents and the fact that similar results are
observed in ionic liquids based on either phosphonium10 or pyrid-
inium11 cations where hydrogen bonding is greatly reduced. As
such, explaining these outcomes in terms of a fundamental prop-
erty that differentiates ionic liquids from molecular solvents would
be useful.
of the reactants and the solvent.12 As such, this reaction is well sui-
ted to studying the changes that occur on moving from a molecular
solvent to an ionic liquid, and it is the investigation of these
changes which is the focus of the work presented here.
Initially, the effect of changing from molecular solvents to ionic
liquids on the regioselectivity of nitrile oxide cycloadditions was
investigated. Benzonitrile oxide 2, chosen as a representative ni-
trile oxide and generated in situ from the corresponding chloro-
aldoxime 1,14 was reacted with each of a series of alkenes 3–5 in
either a molecular solvent or an ionic liquid. The alkenes 3–5 were
chosen as they have differing steric and electronic effects on reac-
tion outcome (Scheme 1).
All the ionic liquids 9–11 chosen for investigation are based on
the well-described 1-butyl-3-methylimidazolium cation ([Bmim]+),15
and represent a range of properties from the hydrophobic bistrifli-
mide salt 9 through the water-soluble dicyanimide salt 11. The
molecular solvents chosen (acetonitrile, ethyl acetate and THF)
represent a collection of common solvents with empirical polarity
measurements in the same range as that for the ionic liquids
9–11.16
OH
N
O
N
NEt
3
Cl
1
2
3 R = Ph, R' = CO Et
R'
N
b
2
A related cycloaddition process is the 1,3-dipolar cycloaddition
between a nitrile oxide and an alkene to give a mixture of two
dihydroisoxazoles.12 Along with producing compounds that are
synthetically versatile,13 the ratio of the regioisomers produced is
dependent on factors such as the steric and electronic properties
4 R = Me, R' = CO Et
2
5 R = Et, R' = CH OH
R
2
N
Ph
Ph
6 R = Ph, R' = CO Et
O
2
O
7 R = Me, R' = CO Et
2
8 R = Et, R' = CH OH
R'
R
R
R'
2
a
* Corresponding author. Tel.: +61 2 9385 4692; fax: +61 2 9385 6141.
E-mail address: j.harper@unsw.edu.au (J.B. Harper).
Scheme 1. Preparation of the nitrile oxide 2, and subsequent reaction with each of
the alkenes 3–5 to give the corresponding dihydroisoxazoles 6–8a,b.
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.045

C. E. Rosella, J. B. Harper / Tetrahedron Letters 50 (2009) 992–994
993
regioisomeric ratios are given in Table 1, with each ratio being the
average of at least three replicate reactions in a given solvent.
Initially, ethyl trans-cinnamate (3) was considered as the elec-
tronic and steric effects on the regioselectivity of the nitrile oxide
cycloaddition favour the formation of the same regioisomer, dihyd-
roisoxazole 6b. As such, it is unsurprising that this isomer is fa-
voured over the other, 6a, in a ratio of ca. 5.5:1 in molecular
solvents. When the solvent is changed from a molecular solvent
to an ionic liquid, there is a dramatic change in the regioselectivity,
with the ratio of isomers 6a:6b being 1:>10. That is, any effects
that favour the formation of isomer 6b in molecular solvents are
magnified in the ionic liquids 9–11.
It is worth noting that the extent of reaction in the water-solu-
ble ionic liquid 11 was very small, even after optimisation, and
none of the minor isomer 6a could be detected. While the origin
of the decrease in extent of conversion is unknown, as a result, this
solvent was omitted from subsequent studies.
Ethyl crotonate (4) is similar to ethyl trans-cinnamate (3), but
the bulky phenyl group is replaced with a considerably smaller
methyl group. The formation of the isomer 7b is favoured by the
electronic character of the substrate 4, while steric interactions fa-
vour the other isomer 7a; this is in contrast to the previous case.
Here, the former effect dominates with the ratio of the isomers
7a:7b found to be ca. 1:2.9 in molecular solvents. This ratio de-
creases to ca. 1:1.9 on going from a molecular solvent to an ionic
liquid. That is, the isomer whose formation is favoured by steric ef-
fects and disfavoured by electronic effects is formed to a greater
extent in ionic liquids 9 and 10 than in molecular solvents.
trans-2-Penten-1-ol (5) has substituents on either side of the
double bond which are of very similar size,19 so the electronic ef-
fects arising from the presence of the hydroxy group might be ex-
pected to dominate in the formation of the dihydroisoxazoles 8a
and 8b. Through consideration of related systems,20 the hydroxy
group is anticipated to result in the C3 position of the alkene 5
being more susceptible to attack by the negatively charged oxygen
of the nitrile oxide 2. Thus, the isomer 8b is the electronically fa-
voured one, though it is worth noting that it is also slightly steri-
cally favoured.19 The sum of these effects is clearly relatively
small with the ratio of the isomers 8a and 8b being ca. 1:1.4 in
molecular solvents. The change in this ratio on going to the ionic
liquids 9 and 10 was small, with the ratio being ca. 1:1.2 in the io-
nic liquid 9 and the same, within uncertainty, as the molecular sol-
vents for the ionic liquid 10.
+
+
+
N
N
N
N
N
N
O O
N
F
P
F
F C
CF
3
N
N
3
F
F
F
F
S
S
N
O
O
9
11
10
In each case, triethylamine was added to the reaction mixture
slowly to reduce the extent to which the nitrile oxide 2 dimerises
to the corresponding furoxan,17,18 and this time of addition was
optimised to maximise the extent of conversion. For reactions per-
formed in molecular solvents, the chloroaldoxime 1 (ca. 50 mg)
and the appropriate alkene (ca. 2 equiv) were dissolved in the sol-
vent (6 mL), and triethylamine (440 lL) was added as a solution
(ca. 3 mL) over ca. 6 h. Reactions in ionic liquids were performed
similarly though it was found that greater extents of conversion
were achieved through addition of neat triethylamine over longer
time periods (12–24 h). Note that this is consistent with observed
effects of ionic liquids on the dimerisation process, which will be
discussed later.
The regioisomeric composition of the reaction mixtures was
analysed using 1H NMR spectroscopy. In the case of the reactions
in molecular solvents, the solvent was removed in vacuo and the
residue analysed while in the case of the reactions in ionic liquids,
a small sample of the reaction mixture was analysed directly. 1H
NMR spectroscopy is a convenient method for the analysis of the
product mixtures as each of the dihydroisoxazoles 6–8a,b gives
rise to signals in a region which is free from interferences such
as signals due to residual solvent and starting materials. Further,
initial studies indicated that attempted isolation of dihydroisoxaz-
oles from ionic liquids resulted in selective extraction of one regio-
isomer making analysis of such extracts inappropriate for
determining the regioselectivity of the process.
The ratio of the isomers produced by any one reaction was
determined by taking the ratio of the average integrations of visi-
ble signals due to the C4 and C5 protons on the dihydroisoxazole
products, and the extent of conversion was calculated through
comparison of these integrations with that for the signals due to
the residual alkene protons (Fig. 1). Separate T1 studies were con-
ducted to ensure appropriate choice of delay times between scans,
and hence reliability of the signal integration. The values for these
These results demonstrate the effects of using an ionic liquid
rather than a molecular solvent. In the cases of the cinnamate 3
and the crotonate 4, where both steric and electronic effects are
present, it is not necessarily straightforward to immediately
deconvolute the effect of changing solvent types. However, the
reactions involving trans-2-penten-1-ol (5) allow simplification of
the arguments. Given that difference in the size of the substituents
on the alkene 5 is very small and selectivity based on any differ-
Table 1
Ratios of the dihydroisoxazoles 6–8a:b produced in the cycloaddition of benzonitrile
oxide 2 and the appropriate alkenes 3–5 in the solvents are shown, with average
extent of conversion from the alkene given in parentheses. Each ratio is the average of
at least three replicates, and the uncertainty given is the standard deviation
Solvent
6a:6b
7a:7b
8a:8b
Acetonitrile
Ethyl acetate
THF
9
10
11
1:6.54 0.42 (44%)
1:4.84 0.63 (37%)
1:5.29 0.32 (38%)
1:15.17 0.67 (29%)
1:12.17 0.75 (84%)
1:>10a (<5%)
1:2.88 0.09 (13%)
1:2.95 0.07 (16%)
1:2.95 0.03 (17%)
1:1.91 0.02 (27%)
1:2.20 0.10 (34%)
—
1:1.40 0.04 (19%)
1:1.41 0.02 (35%)
1:1.39 0.06 (33%)
1:1.19 0.05 (14%)
1:1.56 0.15 (12%)
—
Figure 1. 1H NMR spectrum (300 MHz, CDCl3) of the reaction between the nitrile
oxide 2 and the alkene 3 showing the signals used to calculate the ratio of the
isomers 6a and 6b produced (d 4.95 and 5.05, 4.46 and 5.99) and extent of
conversion (above plus d 6.44).
a
The minor isomer was not observed and, as such, the ratio represents an esti-
mated minimum excess of the major isomer.

994
C. E. Rosella, J. B. Harper / Tetrahedron Letters 50 (2009) 992–994
The most striking feature of this plot is that when the reaction is
carried out in the ionic liquid 9, the extent of conversion of the cin-
namate 3 to the products 6a and 6b reaches ca. 50% prior to the
first NMR spectrum being obtained, and does not increase further
from this point. This indicates that at this time, since there is re-
agent 3 remaining, there must be none of the nitrile oxide 2 pres-
ent, having completely dimerised to the corresponding furoxan.
When the reaction is carried out in acetonitrile, the extent of reac-
tion continues to increase, indicating that nitrile oxide 2 remains
for the entirety of the experiment, thus demonstrating that the rate
of dimerisation is greater in the ionic liquid 9 than in acetonitrile.
This is consistent with the observation earlier that the slower addi-
tion of triethylamine (and hence generation of the nitrile oxide 2)
is necessary to maximise the extent of conversion in ionic liquids.
The reaction carried out in acetonitrile reaches a corresponding ex-
tent of conversion after ca. 15 min, indicating that the rate of the
nitrile oxide cycloaddition is also increased in ionic liquid 9 though
clearly to a lesser extent than the dimerisation process.
Figure 2. Extent of conversion of the cinnamate 3 to the regioisomers 6a and 6b
with time in a mixture containing initially the cinnamate 3 and a 20-fold excess of
the nitrile oxide 2 in either acetonitrile (d) or the ionic liquid 9 (N).
In conclusion, it has been demonstrated that the regioselectivity
of nitrile oxide cycloaddition reactions changes on going from a
molecular solvent to an ionic liquid with the latter solvent type
favouring the least sterically hindered product. This is consistent
with an increased cohesive pressure resulting in a smaller, more
sterically demanding transition state. The rate of the process is also
increased, though an increase in the rate of the dimerisation of the
nitrile oxide starting material is also observed. We are currently
investigating the effect of ionic liquids on the rates and regioselec-
tivities of other cycloaddition processes, where such reaction of the
starting material is not a consideration.
ence would be expected to be minimal, the regioselectivity (and
any changes in it on changing from a molecular solvent to an ionic
liquid) in this case can be attributed to the electronic nature of the
substrate. Hence, these results show that the selectivity based on
the electronic nature of the substituents around the double bond
is not largely affected by changing to an ionic solvent.
Using this as a starting point, it is suggested that the results for
ethyl crotonate (4), where moving to an ionic liquid favours the
sterically least hindered isomer 7a over the electronically favoured
isomer 7b, are consistent with an increase in the regioselectivity
based on steric interactions in conjunction with a small change
in that due to electronic effects. For the cycloaddition of the nitrile
oxide 2 with ethyl trans-cinnamate (3), where the isomer 6b is pro-
duced to a greater extent in ionic liquids as it is favoured by both
steric and electronic effects, an increase in selectivity due to steric
interactions outweighs any change due to the electronic nature of
the substrate on changing solvent to an ionic liquid.
The last two cases described demonstrate that changes in regi-
oselectivity on moving from a molecular solvent to an ionic liquid
are dominated by steric effects. This suggests that steric interac-
tions in the transition state leading to the isomers 6–8a,b are more
significant in ionic liquids than they are in molecular solvents. Io-
nic liquids, due to the electrostatic interactions between their con-
stituent ions, have higher cohesive pressures than molecular
solvents.21 Thus, the increase in regioselectivity based on steric
interactions on changing from a molecular solvent to an ionic li-
quid can be rationalised by an increased cohesive pressure of the
solvent compressing the transition state and increasing the steric
interactions present. The difference between the reaction out-
comes in the two ionic liquids is small when compared to the dif-
ferences between ionic and molecular solvents.
Acknowledgements
Financial support was provided by UNSW through the Faculty
Research Grants Programme. The expertise and able support of
the NMR Facility in the UNSW Analytical Centre, particularly Dr.
James Hook, is gratefully acknowledged as is that offered by Mr.
Hon Man Yau.
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