Rationalising the effects of ionic liquids on a nucleophilic aromatic substitution reaction

Article abstract of DOI:10.1039/c7ob01476g

The nucleophilic aromatic substitution reaction between 1-fluoro-2,4-dinitrobenzene and ethanol was examined in a series of ionic liquids across a range of mole fractions. Temperature-dependent kinetic analyses were undertaken to determine the activation parameters for this reaction at the highest mole fraction. As the mole fraction of ionic liquid was increased, the rate constant of the reaction also increased, however the microscopic origin of the rate enhancement was shown to be different between different ionic liquids and also between different solvent compositions. These results indicate a balance between microscopic interactions that result in the observed solvent effects and a qualitative method for analysing such interactions is introduced.

Full text of DOI:10.1039/c7ob01476g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Rationalising the effects of ionic liquids on a nucleophilic aromatic
substitution reaction
a
a
a
a,
Rebecca R. Hawker, Michaela J. Wong, Ronald S. Haines and Jason B. Harper *
Received 00th January 20xx,
Accepted 00th January 20xx
The nucleophilic aromatic substitution reaction between 1-fluoro-2,4-dinitrobenzene and ethanol was
examined in a series of ionic liquids across a range of mole fractions. Temperature-dependent kinetics
analyses were undertaken to determine the activation parameters for this reaction at the highest mole
fraction. As the mole fraction of ionic liquid was increased, the rate constant of the reaction also increased,
however the microscopic origin of the rate enhancement was shown to be different between different ionic
liquids and also between different solvent compositions. These results indicate a balance between
microscopic interactions that result in the observed solvent effects and a qualitative method for analysing
such interactions is introduced.
DOI: 10.1039/x0xx00000x
www.rsc.org/
2
3, 24, 27, 29
nitrogen-based nucleophiles. In some cases,
ionic
Introduction
liquids enhanced the rate of the reaction however in another
3
0
case, ionic liquids gave smaller rate constants than in a
molecular solvent.
An ionic liquid is defined as a salt which has a normal melting
1
point below 100 °C. Having a range of interesting properties;
2
including low vapour pressure and high thermal stability;
2
5
3
The work of Welton et al. used knowledge of the Gibbs
energy change and the hydrogen bond basicity to design ionic
liquids to give increased yields compared with molecular
4
ionic liquids are potential alternatives to molecular solvents.
As the properties of ionic liquids are tuneable through
variation of the ionic components, they are used in a range of
5
applications including as electrolytes, catalysts, and also as
2
4
solvents. Campodónico et al. proved that the effect of ionic
liquids on this kind of reaction could be correlated with either
the hydrogen bond basicity or the Gutmann’s donor number
6
3
, 7
solvents in a number of organic and inorganic processes. For
effective use as solvents, it is necessary to be able to predict
any effects that an ionic liquid solvent will have on reaction
outcome.
2
7
for the ionic liquids examined. The work of D’Anna et al. used
temperature dependent studies, to show that the ionic liquid
was stabilising and organising around the transition state,
resulting in a decrease in the enthalpy and entropy of
activation compared with the molecular solvent; this
Through examination of ionic liquids as solvents in a range
of reactions, identification of important interactions (with
2
8
8
-13
14-21
interpretation was supported by computational studies.
The examples above employed nitrogen-based
nucleophiles. Previously we have examined an S Ar reaction
with an oxygen nucleophile; the reaction of 1-fluoro-2,4-
starting materials
and/or transition states
) provides the
potential for control of reaction outcome using known ionic
1
2, 13
N
liquids
or the design of novel ionic liquids to beneficially
2
2
affect a given process. An example of a type of reaction
considered to some extent previously is the nucleophilic
dinitrobenzene
1
and ethanol to form 2,4-dinitrophenetole 2
(Scheme 1).
aromatic substitution (S Ar) reaction. This reaction type has
N
been studied in ionic liquid solvents through examining the
reactions of different electrophiles (including activated
F
OEt
F
OHEt
23-26
27-30
NO
2
NO2
NO2
benzenes
and nitrothiophenes
) with a variety of
i)
NO
2
NO2
NO2
1
2
Scheme 1. The nucleophilic aromatic substitution (S
N
Ar) reaction between 1-fluoro-2,4-
dinitrobenzene 1 and ethanol to gain the 2,4-dinitrophenetole 2. i) EtOH, NEt
3
.
This reaction has been examined in a series of ionic liquids
with rate constant enhancements observed compared with the
9
, 15, 22
9
Initially, the increase in rate
molecular solvent, ethanol.
constant was proposed to be due to the interaction between
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the ionic liquid anion and the
π
1. An entropic benefit (a increase in the molecular solvent; previously the molecular solvent contained
-system of the
The reaction was re-examined with ethanol as the
9
fluorodinitrobenzene
‡
activation entropy) is consistent with organisation of the
3
d -acetonitrile (χCD3CN ca. 0.2). It had been considered that any
solvent around the starting materials (considered more likely differences in the nature of the two solvents would be small
than less organisation about the charge development in the relative to any effect of the ionic liquid; such similarity in
transition state) and was supported by molecular dynamics solvent effects has been seen previously for a different process
simulations. When the components of the ionic liquid were with the same dependence of rate constant on mole fraction
1
5, 22
16
varied
a general ionic liquid effect was observed (i.e. the of salt in different molecular solvents. The reaction shown in
9
same outcome was observed for all ionic liquids examined), Scheme 1 was monitored as previously
, 15, 22
19
using F NMR
with rate constant enhancement relative to ethanol again spectroscopy over a range of temperatures and the activation
noted. Generally the same basis for rate enhancement (in parameters determined here and previously for the molecular
terms of activation parameters) was seen.
solvent mixtures are shown in Table 1.
Importantly, in these earlier studies only one composition
of the reaction mixture was considered for each ionic liquid.
Previous work has shown that the solvent effect of an ionic
liquid can vary significantly with the proportion of the salt in
the reaction mixture and that this trend differs greatly
Table 1 The activation parameters for the reaction between the fluorobenzene 1 and
various mixtures of ethanol.
‡
-1 a
‡
-1
-1 a
Solvent
ethanol
χ
EtOH
ꢀH / kJ mol
ꢀS / J K mol
0.98
0.77
49.0 ± 0.5
-259.0 ± 1.6
7
, 11, 16, 17, 20, 21
b
between different reaction types.
As such, it is
ethanol/acetonitrile
48.7 ± 2.1
-249 ± 7
clearly relevant to consider the mixture composition for this
system.
a
b
Uncertainties quoted are from the fit of the linear regression. Data reproduced
9
from Jones et al.
In this study we markedly extend our understanding of the
solvent effects of ionic liquids on this reaction through
The activation parameters for the ethanol case (in the
-acetonitrile) are similar to the system containing
mixture. As well as demonstrating a dependence of reaction ethanol and d -acetonitrile, however, the slight differences
considering a range of proportions of salts in the reaction absence of d
3
3
outcome on the amount of ionic liquid present not seen for warrant discussion. The enthalpy of activation for both
previous systems, by extending the range of mixtures molecular solvent mixtures are the same within uncertainty,
considered, this work elucidates the different microscopic suggesting that there is no difference in the relative
origins for the observed solvent effects, further developing the stabilisation of the starting material and transition state
predictive framework for the effects of ionic liquid solvents on between the two systems. The entropy of activation differs
reaction outcome.
between the two cases, though the change is not large given
the error bounds; the ethanol case has a lower (more
negative) entropy of activation when compared with the
Results and Discussion
ethanol and d -acetonitrile case. This can be considered in two
3
different ways; either a) with a lower (more negative) entropy
of activation, there is greater ordering of the solvent around
the transition state, or b) there could be less ordering of the
solvent around the starting materials. Given that ethanol is
The ionic liquids 3-7 considered in this study are shown in
Figure 1. These salts are consistent with those used
1
5
previously and represent a series containing ionic liquids with
cations with varying charge localisation and accessibility.
3
1
more polar than acetonitrile and can readily interact with
both positive and negative charges, the former seems more
likely, though the difference in entropies of activation are
small and the interaction is not reflected in the activation
enthalpies.
Irrespective, these differences in the activation parameters
for the different molecular solvent compositions make little
difference to the previous arguments for the microscopic
9
, 15, 22
origins of the rate constant enhancements.
In fact, the
differences (including the smaller uncertainties) make the
entropic origins of the solvent effects more prominent!
Subsequent comparisons will be to the molecular solvent case
Figure 1. The ionic liquids examined in this study: 1-butyl-1-methylpyrrolidinium containing only ethanol.
bis(trifluoromethanesulfonyl)imide
([bmpyr][N(SO
2
CF
3
)
2
],
3),
1-butyl-3-
CF ], 4),
As introduced above, it was of interest to examine the
solvent effects of ionic liquids across a wider range of solvent
mixtures than previously measured. The ionic liquid
methylimidazolium bis(trifluoromethanesulfonyl)imide ([bmim][N(SO
2
3 2
)
1
-butyl-2,3-dimethylimidazolium
[bm im][N(SO CF ],
bis(trifluoromethanesulfonyl)imide ([bm
bis(trifluoromethanesulfonyl)imide ([TOA][N(SO
bis(trifluoromethanesulfonyl)imide
(
2
2
3
)
2
5),
1-butyl-2,3,4,5-tetramethylimidazolium
[
bmim][N(SO CF ) ]
3 2
4
was initially considered given the
im][N(SO CF
2
3
)
2
], 6), and tetraoctylammonium
2
4
2
CF ) ], 7).
3 2
extensive work on the solvent effects of mixtures containing
8
, 9, 11, 13, 19
this salt;
the kinetic analyses of the reaction shown
9
, 15, 22
in Scheme 1 were performed as per previous studies,
and
2
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the results can be seen in the mole fraction dependence plot
below (Figure 2).
1
9
8
7
6
5
4
3
2
1
.0E-03
.0E-04
.0E-04
.0E-04
.0E-04
.0E-04
.0E-04
.0E-04
.0E-04
.0E-04
5.0E-04
4.0E-04
3.0E-04
2.0E-04
1.0E-04
0.0E+00
0
.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Mole fraction of ionic liquid
Figure 3. The bimolecular rate constants for the reaction between
fluorodinitrobenzene and ethanol in different mole fractions of the salts
Li[N(SO CF (ꢀ), [bmpyr][N(SO CF (ꢀ), [bmim][N(SO CF (ꢀ),
bm im][N(SO CF ] 5 (ꢀ), [bm im][N(SO ] 6 (ꢀ), [TOA][N(SO CF ] 7 (ꢀ) in
0.0E+00
1
0
.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
] 4
0.8
0.9
2
3
)
2
]
2
3
)
2
]
3
2
3
)
2
]
4
Mole fraction of ionic liquid [bmim][N(SO
2
CF
3
)
2
[
2
2
3
)
2
4
2
CF
3
)
2
2
3 2
)
Figure 2. The bimolecular rate constants for the reaction between
fluorodinitrobenzene 1 and ethanol in different mole fractions of [bmim][N(SO CF ] 4
ethanol at 324 K. Uncertainties are reported as the standard deviation of three
replicates; some fall within the size of the markers used.
2
3 2
)
in ethanol at 324 K. Uncertainties are reported as the standard deviation of three
replicates; some fall within the size of the markers used.
2 3 2 2 3 2
[bmim][N(SO CF ) ] 4 ≈ [bmpyr][N(SO CF ) ] 3. It is difficult
to ascertain a trend simply from these rate data; this contrasts
11, 20
As the amount of the ionic liquid [bmim][N(SO CF ) ]
2 3 2
4
was
16, 18
2@P
13
with studies of S
N
2,
S
N
and condensation
increased in the reaction mixture, the rate constant of the
reaction shown in Scheme 1 also increased, up to a factor of
processes where the effectiveness of the ionic liquid varied
directly with the accessibility and localisation of the positive
charge on the cation. Whilst in this case the ionic liquid with
least coordinating cation gives the greatest rate constant
change and that with the most coordinating cation gives the
smallest change in the rate constant, the origin of the order of
effects of the remaining salts is less clear.In the case of the
6
0 at the highest proportion of the salt used (χ ca. 0.8). This is
IL
a large increase in rate constant on addition of an ionic liquid,
compared to (for example) the 2-4-fold increase seen for
8
,
11
bimolecular substitution reactions
and the 8-fold
1
3
enhancement observed in the case of an imine formation.
Interestingly, the extent to which the rate constant
changed with solvent composition becomes greater at higher
lithium salt, the trend is the same as for the ionic liquids 3-7
the rate constant increases with increasing proportions of salt.
The rate constant for Li[N(SO CF ]) at its highest mole
;
proportions of the salt
4 in the reaction mixture. That is, the
2
3 2
)
plot curves upward so for this S Ar process a greater
N
fraction (χIL ca. 0.15) is significantly faster than any of the ionic
liquids 3-7 at similar mole fraction (over 3 times as fast as
proportion of ionic liquid gives a greater rate enhancement
(
i.e. ‘more is better’). This dependence on the proportion of
the salt in the reaction is different to what has been seen
previously for other systems. For SN1
processes the rate constant decreases on moving to high χ in
[
TOA][N(SO
2
CF
3
)
2
]
7). This effect is consistent with
4
14,
32
observations for substitution
and cycloaddition
A principle advantage of ionic liquids over
traditional' salts remains; the proportion of salt that can be
1
9, 21
16, 18
and S 2@P
32, 33
N
processes.
IL
'
1
1, 20
the reaction mixture while for S 2
N
and bimolecular
achieved in the reaction mixture is larger.
13
condensation
processes the majority of the rate
Given the above, it is clearly of interest to determine the
microscopic origins of the rate constant enhancement at these
higher mole fractions (χIL ca. 0.8§) and compare them with
enhancement happens at χIL < 0.3, with little effect as the
amount of ionic liquid increases further.
The effect of changing the proportion of the ionic liquid in
the reaction mixture on the rate constant of the reaction was
9
those obtained previously as previously (χIL ca. 0.5 ). To this
end, temperature dependent kinetic analyses were carried out
and the activation parameters determined (Table 2).
then considered using the ionic liquids
3 and 5-7, to see if
changing the nature of the ionic liquid cation (charge
localisation and accessibility) affected the solvent effects
observed. The results are summarised in Figure 3, noting that
Immediately apparent from these new data is that there is
a change in the activation parameters on moving from the
lower proportions of ionic liquid in the reaction mixture to the
higher proportions considered here. Further, while previously
the differences in activation parameters between the cases
involving different ionic liquids at the lower mole fraction were
small (if even measurable, given uncertainties), with the
a
'traditional' salt with
a coordinating cation (lithium
bis(trifluoromethanesulfonyl)imide), Li[N(SO CF ) ]) is included
2 3 2
for a comparison.
All of the ionic liquids
3,
5-7 follow the same general trend
as [bmim][N(SO CF ) ]
2 3 2
4; the rate constant increases with
exception of the TOA salt 7, at the higher proportions of ionic
increasing proportion of the ionic liquid solvent. The relative
rate constants for each of the ionic liquids at the highest mole
liquids the differences between their effects are more marked.
These different effects can be best isolated by considering the
fractions used§ are in the order [TOA][N(SO CF ) ]
3 2
7 >
2
changes in activation parameters in three categories;§ χIL
.5, χIL 0.8 and χIL 0.5 0.8.
0 ꢁ
[
bm im][N(SO CF ) ] 5 ≈ [bm im][N(SO CF ) ] 6 >
2 2 3 2 4 2 3 2
0
0
ꢁ
ꢁ
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Table 2. The activation parameters for the reaction between the fluorobenzene 1 and interaction with the starting materials, given the charged
ethanol in either ethanol, Li[N(SO
2
CF
3
)
2
] or one of the ionic liquids 3-7, at the specified nature of both the solvent and the transition state. The
mole fractions.
difference between this case and the parent imidazolium
‡
-1 a
‡
-1
-1 a
system 4 is likely the extent of charge localisation on, and
Solvent
χ
salt
ꢀH / kJ mol
ꢀS / J K mol
hence interaction with, the cation; this will be discussed
further below. As above, the increase in the entropy of
activation is likely due to organisation about the starting
material. It is interesting to note that both enthalpic and
entropic effects contribute to rate enhancement in this case.
ethanol
Li[N(SO
0
49.0 ± 0.5
54.7 ± 3.5
45.7 ± 1.9
49.6 ± 0.5
49.0 ± 3.9
50.5 ± 1.7
41.0 ± 2.6
43.0 ± 2.3
44.6 ± 1.8
38.4 ± 1.9
41.0 ± 1.5
32.4 ± 1.0
-259.0 ± 1.6
-208 ± 11
-240 ± 6
-229 ± 2
-223 ± 12
-221 ± 5
-252 ± 8
-242 ± 7
-238 ± 6
-253 ± 6
-245 ± 5
-270 ± 3
2
CF
bmpyr][N(SO
bmim][N(SO
3
)
2
]
0.16
0.51
0.54
0.52
0.51
0.32
0.78
0.79
0.80
0.79
0.66
b
b
[
[
[
[
[
[
[
[
[
[
2
CF
3 2
) ] 3
c
2
CF
3
2
) ] 4
bm
2
4
im][N(SO
im][N(SO
2
2
CF
CF
3
3
)
2
] 5
b
bm
)
2
] 6
2 3 2
For the ionic liquid [TOA][N(SO CF ) ] 7, containing a very
b
TOA][N(SO
2
CF
)
3 2
] 7
] 3
] 4
sterically hindered cation, the activation parameters are
markedly different to the other cases. There is a large decrease
bmpyr][N(SO
bmim][N(SO
2
CF
3
)
2
2
CF
3
)
2
2 3 2
in the enthalpy of activation in the [TOA][N(SO CF ) ] 7 (χIL ca.
bm
2
4
im][N(SO
im][N(SO
2
CF
CF
3
3
)
2
] 5
] 6
0.3) case relative to the molecular solvent. This might be due
bm
2
)
2
to either less interaction with the starting materials, or greater
interaction with the transition state, compared with the
ethanol case. Given the extremely hindered nature of the
cation, there is the potential for either or both of these effects
to contribute, depending on the whether the cation or the
anion is more involved in the interactions; this will be
discussed further later. The entropy of activation compared to
the ethanol case is the same within uncertainty.€ This
similarity indicates a similar change in ordering on moving to
the transition state in each of these solvent systems, in
contrast to the other cases.
TOA][N(SO
2 3 2
CF ) ] 7
a
b
Uncertainties quoted are from the fit of the linear regression, Data reproduced
1
2
c
9
from Tanner et al. Data reproduced from Jones et al.
Comparison of activation parameters from χIL
Some of these data have been interpreted previously
are summarised here to highlight changes due to using ethanol
rather than ethanol containing -acetonitrile) as the
0 ꢁ 0.5
9
, 15
but
(
d
3
molecular solvent. Further, these arguments form the basis
for understanding changes in rate constant seen at higher
proportions of the salts 3-7 in the reaction mixture.
At this point it is worth discussing the lithium salt
2 3 2
Considering the ethanol and the [bmim][N(SO CF ) ] 4
2 3 2
Li[N(SO CF ) ] (χsalt ca. 0.15). The activation parameters are
cases, the enthalpies of activation are the same, which is
consistent with similar interactions between the solvent and
the transition state in each solvent system. The entropy of
different to those in mixtures containing one of the ionic
liquids 3-7; there is an increase in both the enthalpy and
entropy of activation compared with the ethanol case. The
increase in the enthalpy of activation suggests that there is
greater interaction with the starting materials and the increase
in the entropy of activation suggests a greater degree of
ordering around the starting materials; both of these are
considered more likely than the alternative involving
decreased interaction with the charge separated transition
state in a system containing the salt. As the lithium cation
activation for the ionic liquid
4 (χIL ca. 0.5) is higher (less
negative) than the ethanol case (χIL = 0); suggesting that there
is either less order around (more degrees of freedom about)
the transition state, or more order around the starting
materials compared to when ethanol was the solvent. The
latter was considered more likely due to the charged nature of
the components of the ionic liquid (which would be expected
to order more around the charge-separated transition state)
3
4
coordinates to oxygen readily it is likely the cation is
interacting with, and ordering around, the ethanol
contributing markedly to the activation parameters observed.
9
and was supported by molecular dynamics simulations
showing organisation of the solvent about the benzene
dominant interaction involves ordering of the ionic liquid
about the starting material
observed increase in the rate constant.
The ionic liquids [bm im][N(SO
bm im][N(SO
bmim][N(SO
1. The
4
1
; this is responsible for the
Comparison of activation parameters from χIL
0 ꢁ 0.8
It is worthwhile comparing the activation parameters in each
of the ionic liquids 3-7 at the highest mole fraction used to the
ethanol case; this comparison will lead into a discussion as to
the effects of changing from a 'dilute' to a 'more concentrated'
ionic liquid solution.
2
2
CF
3
)
2
]
5
and
[
4
2
CF
3
)
2
]
6
(χIL ca. 0.5) behave similarly to
[
2
CF
3
)
2
]
4
as solvents for the reaction shown in
Scheme 1; relative to the case in ethanol, the enthalpy of
activation is the same and the entropy of activation increases.
The same arguments presented above suggest that
For the cases of the ionic liquids 3, 4 and
6 very similar
trends in the activation parameters are observed. The
enthalpy of activation is lower at χIL ca. 0.8 than the ethanol
case, suggesting greater interaction with the transition state
for these ionic liquids when compared with ethanol. The
organisation of the solvent about the fluorodinitrobenzene
responsible for the greater rate constants seen.
1 is
2 3 2
For the [bmpyr][N(SO CF ) ] 3 case at χIL ca. 0.5, both the
activation parameters are different from those in ethanol.
There is a decrease in the enthalpy of activation consistent
with more interaction with the transition state relative to the
starting material, when compared with the ethanol case; this
argument is considered more likely than a decrease in
entropy of activation increases on moving from χIL = 0
ꢁ 0.8,
likely due to ordering around the fluorodinitrobenzene
1
.
Whilst theses entropic effects are smaller than between χIL = 0
4
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and 0.5, it is interesting to note that both enthalpic and activation; this is the opposite to what was observed on
entropic effects contribute to rate enhancement. moving from χIL = 0 0.5! Importantly, this indicates a change
For the ionic liquid there is a decrease in the enthalpy of in the balance of the interactions responsible for the solvent
activation at χIL ca. 0.8 compared to the χIL = 0 case, while the effects of the ionic liquid.
entropy of activation is the same. These data suggest Such a comparison for ionic liquid
ꢁ
5
7, is different as initial
increased interactions of the solvent with the transition state addition of salt results in a decrease in the enthalpy of
compared to the ethanol case, with similar organisational activation and no change in the entropy of activation. This
changes on moving between the starting material
transition state in each solvent system. This is different to either greater ordering in the transition state or decreased
what was observed between χIL = 0 and 0.5 for the same salt. ordering about the starting materials – is only significant at
For the [TOA][N(SO CF system, the enthalpy of high proportions of the ionic liquid. Notably, a difference in
1 and the suggests that the microscopic origin of this entropic cost - be it
2
3 2
) ] 7
activation is lower in the high mole fraction case than in the the relative importance of microscopic interactions is noted
ethanol case (χIL = 0). This change is the same direction though and a reduction in activation enthalpy is responsible for the
of greater magnitude to that observed on moving from changes in rate constants between the two systems.
ethanol to the case with the lower proportion of ionic liquid
present, likely with similar origins. The entropy of activation is Towards predicting solvent effects - Can a trend be identified?
lower in the high mole fraction case than in the ethanol case
The above comparisons highlight that the dominant
(χIL = 0). This entropic cost differs from the lower mole fraction
interactions resulting in the rate constant changes observed
vary not only with the ionic liquid but also with the mole
fraction change being considered; this is shown in Table 3. For
numerical and graphical comparisons of changes in activation
parameters, see ESI Table S14 and Figures S2-7.
case, although in both examples it is an enthalpic effect that is
responsible for rate enhancement.
It is important to compare these results with the effects of
ionic liquids on other S
N
Ar reactions. The results presented
here are consistent with the outcomes of reaction of
2
7, 28
thiophene electrophiles and nitrogen nucleophiles.
In Table 3. The activation parameters responsible for the rate constant enhancement for
the reaction between the fluorobenzene 1 and ethanol in each of the ionic liquids 3-7,
for the given change in mole fractions.
those cases activation parameter data indicate that at the
highest mole fraction the dominant interaction is between the
ionic liquid and the transition state.¥
χ
IL
0
ꢁ
0.5
χ
IL 0.5
-
ꢁ
0.8
IL
χ 0 ꢁ 0.8
‡
‡

‡
‡
‡
[
bmpyr][N(SO CF ) ] 3
2
3
2
ꢀH and ꢀS
ꢀH and ꢀS
‡
‡
‡
Comparison of activation parameters from χIL 0.5
ꢁ
0.8
[bmim][N(SO
2
CF
)
3 2
] 4
ꢀS
ꢀS
ꢀS
ꢀH
ꢀH
ꢀH
ꢀH
ꢀH
ꢀH and ꢀS
‡
‡
‡
ꢀH
[
[
[
bm
2
im][N(SO
im][N(SO
2
CF
CF
3
3
)
)
2
] 5
] 6
In the above comparisons, for some ionic liquids, their effects
do not change significantly based on the amount of ionic liquid
present. In other cases, the origins of the rate enhancements
are different at the two different mole fractions – this suggests
that the effects of adding more ionic liquid are different
depending on how much salt is already present! This is best
‡
‡
‡
‡b
bm
4
2
2
ꢀH and ꢀS
‡
‡
‡
TOA][N(SO
2
CF
3
2
) ] 7
§
ꢀH
a
There are no differences in the activation parameters from χIL 0.5
ꢁ 0.8.
b
See footnote ¢
It is important to note that the magnitudes of the
illustrated by considering the changes in activation parameters differences in activation parameters are not discussed here; a
on moving from mixtures containing χIL ca. 0.5 to those difference simply indicates whether a parameter is responsible
containing χIL ca. 0.8.
for a rate constant enhancement. Clearly the size of these
In the case of [bmpyr][N(SO
2
CF
3
)
2
]
3; both the enthalpy and differences (and hence contributions to rate enhancements)
entropy of activation are the same in each of the solvent vary; uncertainties in the activation parameter data make
mixtures considered. While there is a difference in observed detailed discussion problematic.¢ However, the key point is
rate constants, the origin of such is not discernable given that this analysis highlights some key trends that have the
uncertainties in the activation parameters derived. potential to be used predictively.
Importantly however, these data show that there is little
change in the behaviour of ionic liquid from χIL 0.5 0.8, and organisation and interactions involving (i) components of the
the rate constant increase is due to both enthalpic and ionic liquid and the starting materials, and (ii) components of
entropic considerations in each case.
the ionic liquid and the transition state.£ Where the change in
When interpreting Table 3 it is important to consider any
3
ꢁ
The ionic liquids 4-7 all follow the same trend in activation the enthalpy of activation is responsible for the rate constant
parameters; both the enthalpy and entropy of activation enhancement, the key interactions involve the components of
decrease when moving from χIL ca. 0.5 to χIL ca. 0.8. These data the ionic liquid and the transition state. In cases where the
suggest that when a greater proportion of ionic liquid is change in the entropy of activation causes the rate constant
present there are more interactions with, and greater enhancement, the principal organisation is of solvent about
organisation about the transition state; this is considered most the starting materials.$ In cases where both activation
likely given the charged species involved. Of particular interest parameters are listed, solvation of the transition state and the
is that the change in the rate constant between χIL 0.5
ꢁ
0.8 starting materials contribute to the observed rate constant
for each of the salts 4-6 is due to a decrease in the enthalpy of changes.¢
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ARTICLE
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For ionic liquids 3-6, from χIL
lead to the rate constant enhancement; the ionic liquids order the transition state dominate. The slight deviations from the
around the starting materials. For salt , there is also an more general trends are not anomalies, rather they inform
enthalpic component leading to the rate change, suggesting (and support!) the argument.
the ionic liquid is also interacting with the transition state. Organisation around the starting materials is favoured by
0
ꢁ
0.5, entropic contributions enthalpic contributions from the ionic liquid interacting with
3
3
The differences between these salts suggest that interaction ionic liquids with comparatively accessible and localised
with the transition state is cation-dependent with a more charges. Interactions with the transition state are both cation
accessible, localised charge (such as present on the cation of and anion dependent. That means that a more charge-
ionic liquid
3) more able to interact with the transition state.
localised and accessible cation will interact with the transition
In contrast to the other cases, for ionic liquid
7
it is the state more than one that is sterically hindered. However at the
enthalpy of activation that is results in the rate constant same time, the more accessible an anion is, the greater extent
enhancement. This suggests that ionic liquid has a greater to which it will interact with the transition state. This again
7
interaction with the transition state than ionic liquids 3-6. This results in a delicate balance; the more sterically hindered a
indicates that transition state interactions cannot only involve cation of the ionic liquid is, the less the cation will interact with
+
the cation of the added salt; the sterically hindered [TOA]
the transition state but the more the anion will interact with
cation would not be expected to interact with the transition the transition state and vice versa.
state well but would also not be able to interact strongly with
-
] anion, leaving it more available to interact
the [N(SO
2
CF
3
)
2
Experimental
with the transition state. As such, the interaction of the ionic
liquid with the transition state must involve both the cation
and the anion; there is clearly a balance between all of the
interactions in solution.
1
-Fluoro-2,4-dinitrobenzene 1 was commercially available and
was used without further purification. Ethanol and
triethylamine were purified according to literature
35
As a greater proportion of ionic liquid is added to the
solutions (column 3, Table 3), the enthalpy of activation is
shown to be responsible for the change in rate constant for
procedures and stored over activated molecular sieves until
use. The ionic liquids 3-6 were prepared with reference to
3
6, 37
literature methods,
imidazole or pyrrolidine formed the intermediate halide salt,
then anion metathesis with lithium
bis(trifluoromethanesulfonyl)imide formed the required ionic
liquids. The ionic liquid was prepared from the
alkylation of the corresponding
ionic liquids 4-6
.
This origin is in contrast to the χIL
0
ꢁ
0.5
cases, and suggests that interaction with the transition state
becomes more dominant for the imidazolium-based 4-6 at
higher mole fractions; this change is likely due simply to the
greater concentration of the ions in solution. Such interactions
7
3
8
corresponding commercially available bromide. All ionic
liquids were dried under reduced pressure (<0.1 mbar) for at
least 3 hours and were found to have <100 ppm water using
Karl Fischer titration methodology and contained <0.4 mol%
residual halide by ion chromatography. For full details of the
preparation, see ESI.
dominate at lower concentrations of ionic liquid
3 given the
relative charge localisation and accessibility for the cation.
+
7 with the sterically hindered [TOA] cation has
Ionic liquid
greater interaction with the transition state at higher mole
fractions due to an increased concentration of the
comparatively available anions present in solution.
1
9
F NMR kinetic experiments were carried out on either a
For the ionic liquids 3-6, the overall effects on moving from
Bruker Avance III 400, or Bruker Avance 600 spectrometer with
a BBFO probe using ca. 0.5 mL of reaction mixture in a 5 mm
NMR tube. Results were shown to be reproducible between
the spectrometers.
χ
IL
0
ꢁ
0.8, are due to a balance between enthalpic and
entropic contributions. This suggests that, although there are
significant interactions with the transition state at higher mole
fractions of these salts, any ordering about the transition state
is no more than that about the starting materials. The balance
between these interactions is delicate and care should be
taken in interpretation given the small differences between,
and the uncertainties in, the activation parameters.¢. In the
Kinetic analyses for the reaction were carried out in two
different ways. For studies investigating the mole fraction
dependence of the ionic liquids 3-7 on reaction outcome, the
reaction was carried out in solutions containing
-
1
fluorodinitrobenzene
1 (ca. 0.03 mol L ), triethylamine (ca.
-1
-1
.35 mol L ) and ethanol (0.5 to 16 mol L depending on the
2 3 2
case of the ionic liquid [TOA][N(SO CF ) ] 7 on moving to the
0
highest proportion used, only enthalpic effects are significant.
It is interesting to note that this ionic liquid never shows
significant entropic contributions to changes in rate constant.
reaction mixture) at 324 K; see ESI (Tables S1-6) for more
details. For the temperature dependence studies the reaction
was carried out in solutions containing fluorodinitrobenzene 1
+
-1
-1
This is likely due to the sterically hindered nature of the [TOA]
(
(
ca. 0.03 mol L ), triethylamine (ca. 0.35 mol L ) and ethanol
-1
cation; salt
materials.
7 is unlikely to organise well around the starting
0.5 mol L ); the temperature range used was 304-334 K; see
ESI (Tables S7-13) for more details. In all cases the reaction
was monitored in situ with the spectrometer set to the desired
temperature for the duration of the reaction.
From the presentation of Table 3 and the discussion above,
general trends in the solvent effects of ionic liquids for this
reaction are clear; at low mole fractions of salt, entropic
contributions from the ionic liquid organising around the
starting materials dominate and at higher mole fractions
All reactions were followed until more than 95% of the
starting material
1 was consumed, and all kinetic analyses
were performed in triplicate. NMR spectra were processed
6
| J. Name., 2012, 00, 1-3
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Orga Pn l iec a s&e Bd oi o nmo to al ed cj uu sl ta mr Ca rhg ei nms istry
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DOI: 10.1039/C7OB01476G
Journal Name
ARTICLE
using either MestReNova 10.0.2 or Bruker Topspin 3.5pl5
software. The pseudo-first order rate constants for the
reactions were calculated using the integration of the signal
Acknowledgements
RRH acknowledges the support of the Australian government
through the receipt of an Australian Postgraduate Award. JBH
acknowledges financial support from the Australian Research
Council Discovery Project Funding Scheme (Project
DP130102331). The authors would also like to acknowledge
the NMR facility within the Mark Wainwright Analytical Centre
at the University of New South Wales for NMR support.
due to the starting material
1 at δ ca. -110, by linear fitting of
the natural logarithm of the integrations using the Microsoft
Excel 14.4.3 LINEST function. Bimolecular rate constants were
obtained from the pseudo-first order constants by dividing by
the initial nucleophile concentration in the reaction mixture.
The activation parameters were then determined through
fitting the obtained data using the Microsoft Excel 14.7.0
8
, 39
LINEST function to the bimolecular Eyring equation.
Tables
Notes and references
containing the kinetic data for all of the systems described can
be found in the ESI, as can the plot from which the activation
parameters were obtained.
‡
A small amount of deuterated solvent was added to facilitate
acquisition of NMR spectra.
§
The largest proportion of the salt 7 used was less than for the
others; this TOA derivative has a large molecular weight and
solutions containing χIL > 0.65 could not be prepared. Similarly, in
the case of the lithium bis(trifluoromethanesulfonyl)imide, the
highest proportion of salt that could be reached was
Conclusions
The effect of a series of ionic liquids on a nucleophilic aromatic
substitution reaction was investigated and the microscopic χsalt = 0.20. All comparisons with the other systems (where greater
origins of these effects were deduced. The dependence of the proportions of the ionic liquids can be put in the reaction mixture)
are made with this in mind. Given the trend in all mole fraction
dependencies of rate constant, this is considered reasonable.
rate constant on the proportion of ionic liquid in the mixture
was determined and a novel motif was discovered; the more
ionic liquid present in the reaction mixture, the larger the rate
€
Whilst the large uncertainty in the entropy for the TOA derivative
constant. At the highest mole fraction for all ionic liquids the 7 contributes to this, even taking this into account, the activation
rate constant enhancement for this reaction was at least 60 entropy is markedly different to the ionic liquid cases 4-6.
times that in the molecular solvent, the largest enhancement
¥
Only the thiophene cases are commented upon here as activation
23-26
observed for reactions with a similar mechanism. This mole
fraction dependence is important as it demonstrates the first
parameter data is not reported in the other cases.
case where addition of the maximum amount of ionic liquid is ¢ Given the uncertainties in the observed activation parameters,
‡
‡
advantageous for reaction outcome.
generally the contributions to the activation energy (TꢀS and ꢀH )
were the same. The exception was the salt 6 from χIL
0 ꢁ 0.8,
The microscopic origins for the rate enhancement were
determined for this reaction at the highest mole fraction of
each of the ionic liquids used and these data were compared
where the enthalpic contribution dominated.
$
In these discussions, it is the dominant interaction/organisation
to previous results at a lower mole fraction. At higher mole that is being mentioned. The ionic liquid will interact with and order
fractions there is a change in the microscopic origins of the around all the species along the reaction coordinate, however the
rate enhancements come from the dominant interactions.
rate constant enhancements; at lower proportions of salt
present entropic contributions dominate whilst at higher
£
Also necessary to note are the interactions between components
proportions the rate enhancement is the result of enthalpic
effects. It is the balance between these two effects that
of the ionic liquids.
determines how effective an ionic liquid will be as a solvent for 1. S. Z. E. Abedin and F. Endres, Acc. Chem. Res., 2007, 40, 1106-
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A method of analysis for the activation parameters was
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