The effects of ionic liquids on azide-alkyne cycloaddition reactions

Article abstract of DOI:10.1039/c0ob00306a

The effect of a series of ionic liquids on the regioselectivity of the azide-alkyne cycloaddition process was investigated, demonstrating an increased selectivity for the least hindered triazole. The effects of an ionic liquid on the activation parameters for the process were determined and found to be intermediate between coordinating and non-coordinating salts. The importance of knowing the water content of the system is demonstrated by marked changes in the activation parameters in the presence of small concentrations of water.

Full text of DOI:10.1039/c0ob00306a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The effects of ionic liquids on azide-alkyne cycloaddition reactions†
Stephen R. D. George, Gavin L. Edwards and Jason B. Harper*
Received 23rd June 2010, Accepted 23rd August 2010
DOI: 10.1039/c0ob00306a
The effect of a series of ionic liquids on the regioselectivity of the azide-alkyne cycloaddition process
was investigated, demonstrating an increased selectivity for the least hindered triazole. The effects of an
ionic liquid on the activation parameters for the process were determined and found to be intermediate
between coordinating and non-coordinating salts. The importance of knowing the water content of the
system is demonstrated by marked changes in the activation parameters in the presence of small
concentrations of water.
selectivity changes14 observed have been attributed to various
Introduction
solvent parameters,15,16 particularly hydrogen bonding to the Lewis
acidic cation.15 In contrast, the rate enhancements observed for
the nitrile oxide case12 cannot be explained by interaction with the
cation of the ionic liquid (which would, in fact, decrease the rate17),
nor can the increase in preference for the more sterically hindered
dihydroisoxazole product.12 Rather, the results were rationalised
in terms of the electrostatic interactions between the ions resulting
in compression of, and hence increased steric demand in, the
transition state.
Ionic liquids are arbitrarily defined as salts which are liquid below
◦
100 C.1 The typically bulky and charge diffuse ions2–4 on which
they are based frustrate crystallisation, while the electrostatic
forces present result in very low vapour pressures.5 This, along with
the ability to ‘tune’ the properties of the solvent through variation
of the constituent ions,3,4,6 has seen these systems proposed as
alternatives to environmentally damaging organic solvents.7,‡
A current limitation to the application of ionic liquids is that the
outcomes of reactions in terms of rates and selectivities often differ
between ionic liquids and molecular solvents and there has been
limited investigation of the origin of these changes.8,§ To increase
their application, an understanding of their effects on reactions
similar to that available for molecular solvents is required.9
Our group has focussed on considering the key difference
between molecular and ionic solvents, that being the electrostatic
interactions between the components of the latter. This has
involved kinetic studies of a range of substitution mechanisms,10,11
which have demonstrated the importance of considering both the
interactions of the ions with incipient charges in the transition state
and with the starting materials. Particularly, the entropic change
due to differences in solvent ordering has been shown to be crucial
in determining the effect of ionic liquids on reaction outcome.
Of particular interest are recent results investigating the effect
of a range of ionic liquids on the outcome of nitrile oxide
cycloadditions.12 Related Diels–Alder cycloadditions have been
extensively studied in ionic liquids13 and rate enhancements and
The work described herein considers the effects of an ionic liquid
on cycloaddition reactions between an alkyne and an azide.18
Whilst a previous report19 has considered such effects of ionic
liquids on an azide-alkyne cycloaddition, the ionic liquid was
significantly diluted by reagents (c < 0.5), only one example of
effect on regioselectivity is reported and rate changes are reported
qualitatively in terms of isolated yields after a given time. This
report seeks to test the generality of the effects of ionic liquids
on heterocycle-forming cycloaddition processes by considering at
high dilution changes in regioselectivity and rates compared to
molecular solvents. The origin of such effects has been probed
through determination of activation parameters for the process.
This overcomes a limitation present in our previous work,12 where
such kinetic interpretation was impossible due to dimerisation of
the nitrile oxide starting material.
Experimental
The alkynes 1a,b were commercially available and used with-
out further preparation. The azides 2a–d were prepared using
literature methods, from the corresponding bromides in the
case of azides 2a,b,20 the corresponding amine using a diazo
transfer reagent21 for compound 2c22 and the corresponding
alcohol for the t-butyl case 2d.23 1-Butyl-3-methylimidazolium
bis(trifluoromethanesulfonyl)imide was prepared from the corre-
sponding chloride4 and dried to constant weight over phosphorus
School of Chemistry, University of New South Wales, Sydney, NSW, 2052,
Australia. E-mail: j.harper@unsw.edu.au; Fax: +61 2 9385 6141; Tel: +61
2 9385 4692
† Electronic supplementary information (ESI) available: Spectral data for
mixtures of the regioisomers 3 and 4. Regioselectivity data for reaction
of compounds 1a and 2c in various molecular solvents. Comparison of
observed activation parameters to those for individual processes in parallel
reactions. Activation parameters for the formation of each of the isomers
3i and 4i in reaction of compounds 1c and 2a. Rate data, activation
parameters and Eyring plots for the reaction of compounds 1c and 2a
in various solvent systems. See DOI: 10.1039/c0ob00306a
1
pentoxide. H NMR spectra were recorded either on a Bruker
Avance 500 spectrometer (500 MHz), a Bruker Avance 400
spectrometer (400 MHz) or on a Bruker DPX 300 spectrometer
(300 MHz).
Mixtures of the regioisomeric pairs 3 and 4 were prepared by
taking the appropriate azide 2 (ca. 5 mmol) in the appropriately
substituted alkyne 1 (ca. 20 mmol) and heating at reflux for either
‡ It is worth highlighting that these species are not entirely innocuous
(for some toxicology studies see the work of Scammells,33 and others34).
However, the ability to retain the solvent remains a significant advantage.
§ There are specific cases where the reactivity of the components of an ionic
liquid,35 particularly through the use of protic cations36 and basic anions37
alters the reaction outcome. These cases do not rely on fundamental
properties of the ionic liquid and will not be referred to further here.
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Table 1 The ratios of the triazoles 3 and 4 formed in the reaction between
one of the azides 2a–d in an excess of one of the alkynes 1a,b at reflux. The
results are the averages of triplicate experiments
48 h (reactions of azides 2a–c) or 7 days (reaction of azide 2d).
The reaction mixture was concentrated in vacuo to remove excess
alkyne and the residue was purified using column chromatography
(pentane followed by ethyl acetate) to give a mixture of the
desired triazoles 3 and 4. The connectivity of the systems was
determined through comparison with literature24 examples which
either allowed for direct determination of signals due to the 4-
substituted isomers 3 (and by elimination, the 5-substituted isomer
4) or for similar core structures to be compared and the connected
signals determined using COSY 2D NMR spectroscopy. This
assignment allowed determination of regioselectivity by analysis
Azide 3 : 4 on reaction with alkyne 1aa 3 : 4 on reaction with alkyne 1ba
2a
2b
2c
2d
1.2 0.1 : 1
1.20 0.07 : 1
3.1 0.2 : 1
>10 : 1b
1.00 0.05 : 1
1.00 0.05 : 1
1.2 0.1 : 1
3.6 0.4 : 1
a Uncertainties quoted are 95% confidence intervals.
b Only one isomer was observed.
1
of the crude reaction mixtures using H NMR spectroscopy in
these and subsequent cases.
To examine the solvent effects on regioselectivity, the appropri-
ately substituted azide 2 (ca. 20 mg) and alkyne 1 (ca. 3 equiv.) were
dissolved in the desired solvent (600 mL). The mixtures were then
heated to 60 ◦C for two weeks. Where molecular solvents were
used, the solvent was removed in vacuo and the crude product
1
mixture analysed using H NMR spectroscopy. In the case of
the ionic liquids, a small sample of the reaction mixture was
dissolved in deuteriochloroform and then analysed using 1H NMR
spectroscopy.
Kinetic analyses in solvents containing molecular solvents were
carried out by preparing solutions containing the azide 2a (ca.
2.5 mg) in the appropriate molecular solvent (600 mL). The molec-
ular solvent was either d3-acetonitrile, d3-acetonitrile containing
lithium bis(trifluoromethanesulfonyl)imide (5.0 g in 2.0 mL) or
d3-acetonitrile containing tetrabutylammonium tetrafluoroborate
(4.0 g in 2.0 mL). The azide solution was then added to the
alkyne 1c (ca. 25 mg) in an NMR tube, the vessel sealed and
the reaction followed at either 325, 335 or 345 K to >50%
completion by considering the integration of the signal due
to methyl group on the alkyne 1c in the 1H NMR spectrum.
Kinetic analyses for the ionic liquid cases were carried out
similarly, except that samples of the alkyne 1c (ca. 2.5 mg)
dissolved in the 1-butyl-3-methylimidazolium bis(trifluoro-
methanesulfonyl)imide/d3-acetonitrile mixture (600 mL, 7% d3-
acetonitrile v/v) were added to the azide 2a (ca. 25 mg). From
this information, the pseudo first-order rate constants for the re-
actions under these conditions were calculated and, consequently,
the second-order rate constants at each temperature were also
calculated. The activation parameters were then determined using
the bimolecular form of the Eyring equation.25
Scheme 1 The Huisgen reaction between each of the alkynes 1a,b and
each of the azides 2a–d, carried out to determine the steric requirements
of the cycloaddition process.
studies demonstrated insignificant differences between the signals
being compared, indicating this method as reliable for determining
the regioisomeric composition of these mixture. The results for
reactions carried out in an excess of alkyne 1 as solvent are
summarised in Table 1.
Reaction of each of the azides 2a,b with each of the alkynes 1a,b
gave mixtures of the corresponding isomers 3 and 4 in approxi-
mately equal amounts indicating that there are no significant steric
interactions in these cases favouring one isomer over the other. The
slight decrease in regioselectivity upon using phenylacetylene 1b
highlighted a possible secondary effect when such a substituent is
present (which will be discussed further below) though the effect
is small when compared to subsequent changes.
Formation of the triazoles 3c and 4c occurred with notable re-
gioselectivity, indicating the the neopentyl substituent introduces
significant steric interactions. Whilst reaction of the alkyne 1a with
the azide 2d did not proceed readily, only the isomer 3d could be
detected in the reaction mixture.
Perhaps surprisingly, the selectivities observed on reaction of
each of the azides 2c,d with phenylacetylene 1b were not as marked
as in the hexyne 1a case. This was shown to not be a function of
temperature¶ and replacing the phenyl group with a cyclohexene
substituent did not have a significant effect.ꢀ This suggests that
Results and Discussion
The cycloaddition reactions between each of the alkynes 1a,b and
each of the azides 2a–d (Scheme 1) were examined to determine the
steric effects of substituents on the stereoselectivity of the reaction,
without significantly altering any electronic contributions. The
azides 2a–d were chosen as, along with being readily prepared, the
substituents cover a large range of steric bulk as measured using
Taft–Hancock constants.26 Similarly, the commercially available
alkynes 1a,b present contrasting extremes.
After initial preparation and characterisation of the regioi-
someric mixtures 3 and 4, the regioselectivity of the process
was determined through comparison of the integrations of the
signals unique to each isomer due to either the 4-substiuent, the
5-substiuent or the resulting aromatic system. Relaxation time
¶ Reactions between compounds 1b and 2c carried out at 50 ◦C rather
than 90 ◦C result in a measured ratio of 1.02 0.06 : 1 from triplicate
experiments.
ꢀ Reactions between the azide 2c and cyclohexenyl acetylene gave the
triazoles 3 and 4 in a ratio of 1.1 : 1 from a single experiment.
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Table 2 The ratios of the triazoles 3h and 4h formed in the reaction
between reagents 1b and 2d in the solvent specified. The results are the
averages of triplicate experiments
transition state resulting from the increased internal pressure of
the solvent.
In the one previously reported case19 where an ionic liquid
was found to affect the regioselectivity of an azide-alkyne cy-
cloaddition, the effect was in the opposite direction. That is, an
increase in preference for the more sterically hindered isomer was
observed. However, given the smaller nature of the substituents
on the resultant triazole in this case and the requirement for
significant steric bulk in order for regioselectivity to be observed it
is unlikely that steric factors dominate in this case; interaction of
the components of solution with the frontier molecular orbitals of
the reagents may account for the outcome. Whilst such interactions
cannot be ruled out in the examples reported here, the argument
presented remains the simplest one to account for the effects of
the ionic liquids and is consistent with previous findings.12
In order to further examine the effects of the ionic liquid on
the outcome of azide/alkyne cycloaddition processes, temperature
dependent kinetic studies were undertaken to garner enthalpic
and entropic information. Rather than use the systems described
above, which proceeded impractically slowly for kinetic studies, the
reaction between the azide 2a and methyl propiolate 1c to give the
regioisomers 3i and 4i was examined (Scheme 2). The polarisation
of the alkyne 1c not only increases the rate of reaction by ca. fifty
times, but also increases the selectivity of the process to ca. 8 : 1
in favour of the less hindered regioisomer 3i. The reaction was
followed by observing consumption of the alkyne 1c. As such,
the activation parameters calculated clearly have contributions
from each of the triazole formation pathways, however the high
regioselectivity of the process means that the contribution from
the major product dominates (see ESI†). Further, due to the small
proportion of the minor product and the resulting uncertainties,
calculated values in the acetonitrile case for each isomer were the
same and so such analysis was not considered for the other systems
(see Table S2, ESI†).
Solvent system
3h : 4ha
heptane
acetonitrile
ethanol
[Bmim][N(SO2CF3)2] (c = 0.68)
[Bmim][PF6] (c = 0.74)
[Bmim][N(CN)2] (c = 0.76)
3.2 0.2 : 1
5.3 0.4 : 1
3.8 0.2 : 1
7.3 0.9 : 1
6.3 0.4 : 1
6.7 0.6 : 1
a Uncertainties quoted are 95% confidence intervals.
the conformationally restrained nature of the substituent reduces
steric effects in the transition state in these cases.
Based on the above, the reactions between the alkyne 1a
and the azide 2c and between the alkyne 1b and the azide 2c
were considered to examine the effects of ionic liquids on the
regioselectivity of azide-alkyne cycloadditions. However, carrying
out the former set of reactions in molecular solvents showed
the selectivity of the process to be markedly dependent on the
molecular solvent chosen (see Table S1, ESI†). The observed
greater selectivity in polar solvents may be due to coiling of the
butyl group on the alkyne 1a, as has been observed for squalene,27
increasing the steric bulk of the substituent. Irrespective, given
the non-homogeneous nature of ionic liquids28 (which contributes
to the reason that use of dipole and dielectric descriptors to
describe ionic liquids remains fraught29) the reaction site and
its nature would be poorly defined in these systems. Therefore,
it was considered unsuitable to examine the reaction between
compounds 1a and 2c in ionic liquids as it would be difficult
to deconvolute any data garnered, with any generic effects of the
ionic liquid being impossible to separate from polarity induced
effects.
The reactions producing the regioisomers 3h and 4h were
analysed in a range of molecular solvents and ionic liquids
(Table 2). The molecular solvents were chosen as they represent
a range of polarity and hydrogen-bonding ability. The ionic
liquids chosen are based on the 1-butyl-3-methylimidazolium
([Bmim]+) cation with the charge balanced by one of three
anions bis(trifluoromethanesulfonyl)imide ([N(SO2CF3)2]-), hex-
afluorophosphate ([PF6]-) and dicyanimide ([N(CN)2]-). Along
with being representative ionic liquids from literature, being
readily prepared and purified, representing a range of observed
miscibility behaviour,30 they were also considered in the nitrile
oxide case previously.12
Scheme 2 The Huisgen reaction between the alkyne 1c and the azide 2a
to produce the triazoles 3i and 4i, used for kinetic studies.
The effect of changing the nature of the molecular solvent on the
reaction outcome in this case is not as significant as in the previous
case. On changing the solvent from molecular to ionic, there was an
increase in the observed regioselectivity with more of the sterically
less hindered isomer 3h formed in each of the ionic liquids. Based
on the observations in molecular solvents, this change cannot
be accounted for in terms of apparent solvent polarity. The
observations indicate that steric interactions in the transition state
are more significant in the ionic liquid cases than for molecular
solvents; this is consisent with what has been observed previously
for nitrile oxide cycloadditions in ionic liquids.12 The results may,
once again, be rationalised by considering a compression of the
It is worth noting that in the ionic liquid case, decomposition
of the alkyne 1c was observed in concentrated solutions. Hence,
an excess of the azide 2a was used in this case and, under the
conditions of the experiment (which included d3-acetonitrile to
facilitate NMR spectroscopy), the alkyne 1c was found to be stable.
The kinetic data (see Table S3, ESI†) gathered allowed gen-
eration of an Eyring plot (see ESI†), which in turn allowed
generation of the activation parameters for each system (Table 3).
The activation parameters for the reaction in acetonitrile indicate
two major energetic costs on going to the transition state; both
entropic and enthalpic. Considering the extent of bond breakage
and formation required to form the transition state, the significant
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Table 3 Activation parameters for the reaction between the alkyne 1c and the azide 2a in the solvent system specified
Solvent system
DH‡/kJ mol-1a
DS‡/J K-1 mol-1a
acetonitrile
69.8 2.2
79.0 3.3
-178
6
acetonitrile containing lithium
bis(trifluoromethanesulfonyl)imide (c = 0.31)
acetonitrile containing tetrabutylammonium
tetrafluoroborate (c = 0.24)
-138 10
63.1 2.3
71.8 3.8
-194
7
[Bmim][N(SO2CF3)2] (c = 0.50)
-166 11
a Uncertainties quoted are 95% confidence intervals.
enthalpy of activation is expected for the system. The negative
entropy change is consistent with the two starting materials
coming together in the transition state; that is, an increase in the
ordering of the system occurs upon transition state formation and
thus an entropic cost is incurred.
Upon the addition of lithium bis(trifluoromethanesulfonyl)
imide to acetonitrile both the enthalpy and entropy of activation
are seen to increase. The rate increases observed on moving to this
system can therefore be put down to an entropic benefit offsetting
an enthalpic cost. In the case of the addition of this lithium salt,
the key point observed previously from regioselectivity studies
of nitrile oxide cycloadditions and kinetic studies of Menschutkin
reactions31 was coordination of the starting material by the lithium
cation. In the reaction being examined here, coordination of
the starting materials might be expected to be greater than the
transition state. This is borne out in the observed increase in both
the activation parameters.
It is worth noting that some caution is required in the use of
the ionic liquid [Bmim][N(SO2CF3)2] in studying these reactions.
Unless the ionic liquid is rigorously dried (reaction mixture cH2
<
O
0.01, corresponding to to < 0.03% v/v), the reproducibility of the
rate data is typically very poor with very large changes in observed
rates with small changes in the amount of water present. Further,
the results for activation parameters are markedly different. For
example, at cH2O ca. 0.05 in the reaction mixture, corresponding to
0.15% v/v, the activation parameters are (43.2 3.5) kJ mol-1 and
(-256 10) J K-1 mol-1. Whilst it is of interest that both are much
less than in acetonitrile, it is difficult (and likely not particularly
useful) to discuss the origin of the change except to say that the
addition of water to the ionic liquid clearly introduces greater
stabilisation of, and organisation about, the starting materials.
Further, it serves as a warning to highlight the importance of
knowing the makeup of any ionic liquids used and confirms
that the physical changes observed for small concentrations of
impurities in ionic liquids32 also translate to kinetic studies.
In contrast, addition of the non-coordinating salt tetrabuty-
lammonium tetrafluoroborate to acetonitrile results in a decrease
in both the activation parameters; in this case, the observed rate
increases can be put down to an enthalpic benefit. The origin
of this enthalpic benefit is not immediately apparent but can
be considered as due to properties of the system other than
coordination. The results imply either both a destabilisation and
an increase in degrees of freedom of the starting materials, or
a stabilisation and a decrease in the degrees of freedom of the
transition state as compared to when the solvent is acetonitrile.
As any interaction of the starting materials with the salt solution
would likely stabilise and order the system, the above results are
most likely due to a decrease in the enthalpy and entropy of the
transition state. This effect may be caused by either an increase
of ordering around the transition state, a compression of the
transition state (likely, lowering the energy required to react and
lowering the degrees of freedom) or both factors simultaneously.
The addition of >90% v/v ionic liquid [Bmim][N(SO2CF3)2]
does give a rate increase when compared to the acetonitrile case,
however the differences in activation parameters between the
two cases are alone insufficient to determine the origin of the
effect. Consideration of the differences between the two other
salts used and the ionic liquid allows some information to be
garnered, as does the earlier regioselectivity studies. The latter
suggest a compression of the transition state but any decrease
in the activation parameters associated with such is offset by
coordination of the cation to the starting materials. The former
demonstrate that the ionic liquid might be considered to lie
intermediate in terms of coordinating ability in this system,
between the two extremes of the other salts used.
Conclusions
The effects of a series of ionic liquids based on the [Bmim]+ cation
on the addition of an azide to an alkyne showed an increase
in the proportion of the less sterically hindered triazole. This is
consistent, though the change not as dramatic, as that observed
with nitrile oxide cycloaddition processes.12 The rate of an azide-
alkyne cycloaddition was shown to be faster in an ionic liquid than
acetonitrile, though the effect was smaller than might have been
expected based on the nitrile oxide case. The origin of this effect
could not be attributed to either an entropic or enthalpic origin,
however the effects on the activation parameters were intermediate
between those of a coordinating and those of a non-coordinating
salt.
Finally, this work demonstrates the importance of knowing
the composition of the reaction medium. While we have shown
previously the marked effects of changing the mole fraction of
ionic liquid on reaction rates,10 the small changes in composition
here result in significant changes in activation parameters and rate
of reaction. This needs to be borne in mind by anyone using ionic
liquid reaction media.
Acknowledgements
JBH acknowledges financial support from the University of New
South Wales Faculty Research Grants Programme. All authors
would like to thank the support of the members of the NMR
Facility in the UNSW Analytical Centre.
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