The Dependence of Ionic Liquid Solvent Effects on the Nucleophilic Heteroatom in SNAr Reactions. Highlighting the Potential for Control of Selectivity

Article abstract of DOI:10.1002/cplu.201900173

Nucleophilic aromatic substitution (S_NAr) reactions of 1-fluoro-4-nitrobenzene using similar nitrogen and sulfur nucleophiles were studied through extensive kinetic analysis in mixtures containing ionic liquids. The interactions of the ionic li

Full text of DOI:10.1002/cplu.201900173

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DOI: 10.1002/cplu.201900173
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The Dependence of Ionic Liquid Solvent Effects on the
Nucleophilic Heteroatom in SNAr Reactions. Highlighting
the Potential for Control of Selectivity
Karin S. Schaffarczyk McHale, Ronald S. Haines, and Jason B. Harper*[a]
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Nucleophilic aromatic substitution (SNAr) reactions of 1-fluoro-4-
nitrobenzene using similar nitrogen and sulfur nucleophiles
were studied through extensive kinetic analysis in mixtures
containing ionic liquids. The interactions of the ionic liquid
components with the starting materials and transition state for
each process were investigated in an attempt to construct a
broad predictive framework for how ionic liquids affect reaction
outcome. It was found that, based on the activation parameters,
the microscopic interactions and thus the ionic liquid solvent
effect were different for each of the nucleophiles considered.
The results from this study suggest that it may be possible to
rationally select a given ionic liquid mixture to selectively
control reaction outcome of an SNAr reaction where multiple
nucleophiles are present.
Introduction
substitution reactions has been considered.[6,9] In both cases, it
was noted that the balance of interactions in solution changed,
significantly affecting reaction outcome.
Ionic liquids are salts with low melting points (conventionally
[1]
°
defined as being below 100 C) due to the bulky charge
This study focuses on understanding how varying the
nature of the nucleophile affects the ionic liquid solvent effects
observed for nucleophilic aromatic substitution (SNAr) reactions.
Previous studies have investigated the SNAr reaction between
ethanol and 1-fluoro-2,4-dinitrobenzene 1 (Scheme 1) in mix-
tures containing one of a range of different ionic liquids.[10] In
those studies, the key interactions responsible for rate constant
enhancement were shown to vary with the proportion of the
ionic liquid added,[10c,d] although at all solvent compositions
containing an ionic liquid an increase in the rate constant was
observed compared to the ethanol case.
Changing the nucleophilic heteroatom will likely change the
interactions between the nucleophile and the components of
any ionic liquid in the reaction mixture, and hence the reaction
outcome. For a nitrogen nucleophile, interactions between the
nitrogen lone pair and the ionic liquid cation are likely; these
interactions have previously been shown to be key in determin-
ing ionic liquid solvent effects in both condensation and SN2
processes.[6,11] The effect of moving to a sulphur nucleophile is
less clear (as equivalent studies with sulphur species have not
been carried out), however, the interactions would be expected
to vary from the other cases considered. Additionally, on
varying the heteroatom, the nature of the transition state of the
diffuse nature of their constituent ions that results in irregular,
disrupted packing. The physicochemical properties (i.e. melting
point, viscosity, density, etc.) of ionic liquids can be easily varied
by changing the cation and anion combination, leading to ionic
liquids being deemed as ‘designer solvents’.[2] Ionic liquids have
been used in a range of applications including but not limited
to: bioprocessing,[3] electrolytes for batteries,[4] applications
involving carbon dioxide[5] and as solvents for synthetic
processes.[1c,6]
Given the versatile nature of ionic liquids and the ability to
selectively tune their physical properties for a given purpose,
ideally it should be possible to select a specific ionic liquid as a
solvent for a given reaction. In order to do so, the effects of
ionic liquids on the outcome of the reaction in question need
to be understood. Much work has been undertaken investigat-
ing the effects ionic liquids have when used as solvents for a
range of reactions,[7] particularly on understanding specific
interactions between the ionic liquid solvent and species along
the reaction coordinate across
a
range of solvent
compositions.[6,8]
A focus of some of these studies has been to investigate
how varying the substrates affects the interactions of the
components of the ionic liquid with species along the reaction
coordinate and thus the outcome of the observed ionic liquid
solvent effect. Particularly, the effect of varying the nature of
the electrophile in condensation and bimolecular nucleophilic
[a] K. S. Schaffarczyk McHale, Dr. R. S. Haines, Assoc. Prof. J. B. Harper
School of Chemistry
University of New South Wales,
UNSW Sydney, NSW 2052 (Australia)
E-mail: j.harper@unsw.edu.au
Scheme 1. The nucleophilic aromatic substitution reaction between 1-fluoro-
2,4-dinitrobenzene 1 and ethanol to give the benzene 2 which has been
previously studied in mixtures of an ionic liquid and ethanol.[10]
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cplu.201900173
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practical solution-phase kinetics. The electrophile 3, was chosen
instead of the 1-fluoro-2,4-dinitrobenzene 1 used in the
previous studies[10] as removal of the ortho nitro group allowed
measurement of the rate constant over a practical time interval.
However removal of the ortho group can affect the SNAr
mechanism and associated solvent effects;[13] this will be taken
into consideration in the discussion to follow. Acetonitrile was
used in these studies as the molecular solvent (cf. ethanol
previously). It was not expected that this change would affect
the observation of ionic liquid solvent effects, based on the
minimal differences seen in related substitution processes with
significant charge build-up in the transition state.[14]
The bimolecular rate constants of the reaction of 1-butyl-
amine 4a with the benzene 3 were determined across a range
of solvent compositions of 1-butyl-3-methylimidazolium bis
(trifluoromethanesulfonyl)imide ([Bmim][N(SO2CF3)2], 6) in
acetonitrile (Figure 1). [Bmim][N(SO2CF3)2] 6 was selected as it is
the ionic liquid that has been examined in the relevant studies
on the previous SNAr reaction[10] as well as the aforementioned
bimolecular processes,[6] allowing the most direct comparisons
to be made.
There was a two-fold increase in the rate constant on
changing the proportion of the ionic liquid 6 in the reaction
mixture from χ6 =0 to χ6 �0.2. On increasing the amount of
ionic liquid 6 from χ6 �0.2 upwards, the rate constant decreases
with increasing proportions of the salt 6 in the reaction mixture.
However, for all solvent compositions containing the salt 6 the
observed rated constant is greater than in acetonitrile.
This trend in the mole fraction dependence of the rate
constant is markedly different from the case for the reaction
shown in Scheme 1 where an oxygen rather than nitrogen
nucleophile was used, where the bimolecular rate constant
continued to increase as the amount of ionic liquid in the
reaction mixture increased.[10b–d] Instead, the observed trend is
more akin to what has been reported for bimolecular processes
involving nitrogen nucleophiles, suggesting that the dominant
interaction(s) driving the ionic liquid solvent effects in these
systems may be the same.
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Scheme 2. The nucleophilic aromatic substitution reaction between 1-fluoro-
4-nitrobenzene 3 and one of the nucleophiles 4a and 4b to give the
corresponding adducts 5.
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Figure 1. The bimolecular rate constants for the reaction between 1-butyl-
amine 4a and the benzene 3 in different proportions of the ionic liquid
°
[Bmim][N(SO2CF3)2] 6 in acetonitrile at 51.0 C. Uncertainties are reported as
the standard deviation of triplicate results with some uncertainties falling
within the size of the markers used.[15]
initial addition step will vary (in, for example, the extent of
charge development), which will affect interactions involving
that species.
With the above in mind, it is clearly of interest to evaluate
which of the aforementioned microscopic interactions is
dominant (or if multiple interactions are responsible for the
overall solvent effect) when different nucleophiles are consid-
ered. It is also of interest to see if these interactions can be
rationally varied (through changing the nature of the ionic
liquid and the proportion of the salt in the reaction mixture)
and exploited to control reaction outcome. To this end, the
reaction between 1-fluoro-4-nitrobenzene 3[12] and either 1-
butylamine 4a or 1-propanethiol 4b in mixtures containing an
ionic liquid have been examined (Scheme 2).
To investigate the interactions responsible for the observed
solvent effects, temperature dependent kinetic studies were
undertaken by measuring the rate constant across a range of
temperatures and analysing the data using a bimolecular Eyring
plot[16] (see Figure S6 in the Supporting Information). The
solvent compositions chosen for this study were: acetonitrile
(χ6 =0), an intermediate solvent composition by which the
majority of the rate enhancement observed has occurred (χ6
�0.2) and the case where the ionic liquid 6 is diluted by
reagents only (χ6 �0.8).
Results and Discussion
From the activation parameters presented in Table 1 there
is an increase in both the enthalpy and entropy of activation on
changing the solvent composition from χ6 =0 to χ6 �0.2,
though the changes are small compared to those seen in other
cases.[6,9b] At the temperatures considered, the variation of the
entropy change dominates, accounting for the rate constant
enhancement observed.
Effects of Ionic Liquids on an SNAr Reaction Involving a
Nitrogen Nucleophile
Initially this study focused on how changing from an oxygen
nucleophile to a nitrogen nucleophile would affect ionic liquid
solvent effects on an SNAr process. 1-Butylamine 4a was chosen
as it is similar in chemical structure to the oxygen nucleophile
studied previously,[10] with a boiling point that allows for
These activation parameters suggest that the dominant
interaction causing the rate constant enhancement at χ6 �0.2
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ionic liquid, interactions with the transition state dominate.[10c,d]
As such, the interactions implicit from the activation parameters
(and the resulting rate constants) for an SNAr process involving
a nitrogen nucleophile are consistent with a combination of the
previously observed ionic liquid effects.
In an attempt to further understand the ionic liquid-starting
material interactions observed in the SNAr reaction discussed
above, the mole fraction dependence of the rate constant and
temperature dependent kinetic studies conducted above were
carried out with an ionic liquid containing a different cation;
Table 1. Activation parameters for the reaction between 1-butylamine 4a
and the benzene 3 in mixtures of [Bmim][N(SO2CF3)2] 6 in acetonitrile.
Uncertainties reported are propagated from the linear regression.
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7
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9
χ6
ΔH�/kJmolÀ 1
ΔS�/JKÀ 1 molÀ 1
0
0.19
0.80
40.6�1.0
47.0�1.8
42.9�1.1
À 267�3
À 243�6
À 260�3
(relative to χ6 =0) is between the components of the ionic
liquid 6 and the starting materials; there is a greater interaction
of the solvent, with, and organisation of the solvent about, the
starting materials. (It is considered that destabilisation of, and a
lesser degree of ordering about, the transition state is unlikely
given the charged nature of both the ionic liquid 6 and the
transition state.) This trend in the activation parameters is
consistent with previous observations of the ionic liquid solvent
effect where addition of a nitrogen nucleophile is involved in
the rate determining step.[6,9b,17]
For the previously studied SNAr reaction involving ethanol
as the nucleophile (Scheme 1) the same trend in the activation
parameters (an increase) was observed on addition of small
amounts of ionic liquid in the reaction mixture (χ6 <0.5).[10b–d]
Those changes in activation parameters were also attributed to
ionic liquid-starting material interactions, particularly the anion
of the ionic liquid interacting with the electrophile 3.[10d] With
the data presented thus far it is difficult to isolate the particular
starting material(s) involved in this case where there is a
nitrogen nucleophile.
The trend in the activation parameters shown in Table 1
between χ6 �0.2 and χ6 �0.8 is the opposite to that observed
at lower proportions of salt 6 in the reaction mixture; both
parameters decrease. Overall, on moving from acetonitrile (χ6 =
0) to ionic liquid diluted only by reagents (χ6 �0.8), there are
marginal increases in both parameters.
A decrease in activation parameters is characteristic of
either a reduction in the interactions between the ionic liquid 6
and the starting materials (which seems unlikely) or an increase
in the stabilising interaction between the ionic liquid 6 and the
transition state (which seems more reasonable, particularly
given the charged nature of all species involved). This analysis
suggests that in this reaction at high proportions of the salt 6 in
the reaction mixture, the interaction of the components of the
ionic liquid with the transition state become more significant
relative to the interactions with the starting material (which
dominate at low mole fractions of the salt 6) such that, at the
highest concentration of salt 6 used, there is almost a balance
of these interactions.
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tetraoctylammonium
bis(trifluoromethanesulfonyl)imide
ð½TOA�½NðSO2CF3Þ2�; 7). The [TOA]+ cation has a particularly
hindered charge centre and this ionic liquid has been used
previously to observe the effects of minimising potential
interactions with the cation of an ionic liquid.[6,10b–d,18] The
hindered nature of the charged centre of [TOA]+ also means
that the anion of the ionic liquid would be expected to
associate less with the cation and thus be more available to
interact with species along the reaction coordinate. (The anionic
component of the salt has been seen previously to dominate
the effects of ionic liquids on this type of reaction.[8]) Both of
these considerations shall be taken into account in the
discussion below.
The dependence of the bimolecular rate constant for the
reaction between 1-butylamine 4a and the benzene 3 on the
proportion of the ionic liquid [TOA][N(SO2CF3)2] 7 in acetonitrile
is depicted in Figure 2. The trend observed is broadly similar to
the trend in the [Bmim][N(SO2CF3)2] 6 case but several key
differences must be noted. First of all, the maximum rate
constant enhancement observed is smaller (ca. 25% cf. 70%
above). Secondly, the downward trend in rate constant at
higher proportions of the salt 7 in the reaction mixture results
in rate constants the same as in acetonitrile. Immediately clear
is that changing the cation of the ionic liquid changes the
reaction outcome, likely as a result of changing the microscopic
interactions involving the cation of the ionic liquid.
To better understand the interactions of the ionic liquid
[TOA][N(SO2CF3)2] 7 in the SNAr reaction shown in Scheme 2, the
activation parameters at specific solvent compositions were
It is worth contrasting these interactions with observations
in the literature. For bimolecular processes involving a nitrogen
nucleophile,[6] the key interaction between the ionic liquid
cation and the nitrogen nucleophile does not change signifi-
cantly above a low proportion of salt in the reaction mixture.
Such an effect is consistent with the changes observed here.
For the SNAr reaction shown in Scheme 1 involving an oxygen
nucleophile, at low proportions of added salt, starting material-
ionic liquid interactions dominate, while at high proportions of
Figure 2. The bimolecular rate constants for the reaction between 1-butyl-
amine 4a and the benzene 3 in different proportions of the ionic liquid
°
[TOA][N(SO2CF3)2] 7 in acetonitrile at 51.0 C. Uncertainties are reported as
the standard deviation of triplicate results with some uncertainties falling
within the size of the markers used.
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�0.1 to χ7 �0.6 is ca. 2 kJmolÀ 1 greater suggesting more
starting material-ionic liquid interactions are occurring at the
highest mole fraction of the salt 7 considered.
Overall, the work in this section shows that for SNAr
reactions containing a nitrogen nucleophile, ionic liquid-starting
material interactions are responsible for the changes in reaction
outcome across all proportions of the salt 7 considered (cf. ionic
liquid-transition state interactions at high salt concentrations in
the case of oxygen nucleophiles).[10c,d] Whilst specific sites of
interactions are difficult to isolate, those involving both the
cation and anion are implied.
Table 2. Activation parameters for the reaction between 1-butylamine 4a
and the benzene 3 in mixtures of [TOA][N(SO2CF3)2] 7 in acetonitrile.
Uncertainties reported are propagated from the linear regression.
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3
4
5
6
7
8
9
χ7
ΔH�/kJmolÀ 1
ΔS�/JKÀ 1 molÀ 1
0[a]
0.11
0.62
40.6�1.0
45.7�1.1
47.6�0.9
À 267�3
À 249�3
À 245�3
[a] Reproduced from Table 1 above for ease of comparison.
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determined using the same methodology as described above
(Eyring plots can be found in the Supporting Information,
Figure S7). The solvent compositions chosen were: χ7 =0
(acetonitrile, reproduced from above), χ7 �0.1 (where the great-
est rate enhancement was observed) and χ7 �0.6 (where the
ionic liquid 7 is diluted by reagents only). The data are
presented in Table 2.
Effects of Ionic Liquids on an SNAr Reaction Involving a
Sulphur Nucleophile
To further expand upon our understanding of ionic liquid
solvent effects on SNAr reactions it was thought that examina-
tion of a sulphur nucleophile would be of interest, particularly
given their prevalence. As such, the reaction between the
electrophile 3 and 1-propanethiol 4b (Scheme 2) was consid-
ered. The benzene 3 was chosen as the electrophile for this
system to allow direct comparison with the amine 4a SNAr
reaction discussed in the previous section. The differences
between the electrophile used in this work and the previous
ethanol system have been discussed above and the same
considerations shall be made for the thiol 4b system as was
done for the amine 4a system. 1-Propanethiol 4b was chosen
as the nucleophile for similar reasons as the amine 4a; the
boiling point of the thiol 4b made solution-phase kinetics
practical and was closest to that of the amine 4a. Moreover, the
molecular weight of amine 4a and thiol 4b are the similar thus
ensuring that the diffusion of these species are comparable.
Also, variation of carbon chain length by one unit (i.e. from
propyl to butyl) has been shown to not significantly impact
nucleophilicity.[6,20] It was necessary to add triethylamine, a non-
nucleophilic base, to the thiol 4b system for the reaction to
proceed whilst this was not necessary for the amine 4a system.
Given the difference in pKa values of the thiol 4b and
triethylamine the addition of base to this system is not
expected to significantly alter the nucleophilicity of the thiol
4b.[21]
In initial studies on this system, it was immediately apparent
that, even in an excess of the nucleophile 4b, the reaction did
not follow pseudo first order kinetics. This is not unusual,
having been observed previously for other SNAr
reactions[8c,d,13c,d,18,22] and simply means that the initial bimolecu-
lar addition step of the SNAr mechanism is not rate determining.
Modelling of the observed data included many possible
mechanisms for the sulphur-containing SNAr reaction in ques-
tion, with each model systematically increasing in complexity (a
discussion of this process is included in the Supporting
Information). The model that was eventually used fits the
observed data to multiple steps, but importantly allows
determination of the bimolecular rate constant for the first step
of the reaction, nucleophilic addition of species 4b to the
On changing the solvent composition from χ7 =0 to χ7 �0.1
there is an increase in both the enthalpy and entropy of
activation. As discussed above, this trend in the activation
parameters is likely due to increased interaction of the ionic
liquid 7 with, and ordering of the ionic liquid 7 about, the
starting materials. Given the sterically hindered charged centre
on the cation of [TOA][N(SO2CF3)2] 7 (compared to [Bmim][N
(SO2CF3)2] 6), in this case the dominant interaction resulting in
the change in the rate constant is likely the anion of the salt 7
interacting with, and organising about, the electrophile 3.
Importantly, these data do not suggest a lack of interaction
between the cation of [Bmim][N(SO2CF3)2] 6 and the starting
materials of the process. Whilst interactions between the cation
and the nucleophile are not implicit from the activation
parameter data (which in any case are based on small rate
constant changes), understanding gained from previous
examples,[6,10b,c] along with the reduced rate constant
enhancement observed relative to the imidazolium salt 6 case,
does suggest interactions between the nucleophile and the
cation of the salt occur.
No change in the activation parameters was observed on
changing the solvent composition from χ7 �0.1 to χ7 �0.6
suggesting that there is little change in the balance of
interactions within the [TOA][N(SO2CF3)2] 7 system on changing
the concentration of the salt. Whether or not the magnitude of
each of the possible interactions has changed is unclear based
on these data alone.[19] When the same salt was used in the
related aromatic substitution involving an oxygen nucleophile
(Scheme 1),[10b,c] there was
a decrease in both activation
parameters relative to the molecular solvent case indicating
that the dominant interaction was of the ionic liquid 7 with the
transition state of the process; changing the nature of the anion
of the salt also implied that it was involved in these
interactions.[10d] The difference in this case may be due to the
nature of the transition state, though this seems less likely than
potential additional anion-starting material interactions possible
between the amine 4a and the anion. This idea is supported
further by considering that the magnitude of the change in the
enthalpy of activation from χ7 =0 to χ7 �0.6 compared to χ7
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Table 3. Activation parameters for the initial nucleophilic addition step of
the reaction between 1-propanethiol 4b and the benzene 3 in mixtures of
[Bmim][N(SO2CF3)2] 6 in acetonitrile. Uncertainties reported are propagated
from the linear regression.
1
2
3
ΔH�/kJmolÀ 1
ΔS�/JKÀ 1 molÀ 1
4
χ6
5
6
7
8
0
40.0�1.6
22.3�2.4
39.7�2.6
62.1�2.8
À 285�5
À 317�7
À 258�8
À 186�8
0.20
0.50
0.79
9
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key solvent compositions in a similar manner to that for the
amine 4a system discussed earlier. The mole fractions chosen
were: the molecular solvent acetonitrile (χ6 =0), a case to allow
direct comparison with the amine 4a system studied above (χ6
�0.2), an intermediate proportion of ionic liquid 6 to allow
direct comparison with the previously studied ethanol system
(χ6 �0.5) and the case where the ionic liquid 6 is diluted by
reagents only (χ6 �0.8). The data are presented in Table 3. It
should be noted that activation discussion as to their
implications can be found in the Supporting Information
(Figures S16–S23 and Tables S21, S23, S25, S27, S29, S31 and
S33).
On changing from χ6 =0 to χ6 �0.2 in the reaction mixture
there is a decrease in both activation parameters that, as
discussed above, suggests ionic liquid-transition state interac-
tions are principally responsible for the rate constant
enhancement observed. As the solvent composition changes
from χ6 �0.2 to χ6 �0.5 and from χ6 �0.5 to χ6 �0.8 there is an
increase in both the enthalpy and entropy of activation,
suggesting interaction of the ionic liquid 6 with the starting
materials is the dominant interaction in determining the rate
constant increases as the amount of ionic liquid in the reaction
mixture increases beyond χ6 �0.2.
Scheme 3. The initial, reversible nucleophilic attack step for the aromatic
substitution reaction between 1-propanethiol 4b and 1-fluoro-4-nitroben-
zene 3 to obtain the Meisenheimer complex 8.
electrophile 3 (Scheme 3), allowing direct comparison with
previous work.
With this model in hand, the dependence of the rate
constant for the reaction of the nucleophile 4b to the electro-
phile 3 on the proportion of [Bmim][N(SO2CF3)2] 6 (again chosen
to allow comparison with previously) present in the reaction
mixture was, investigated. These data are presented in Figure 3.
Equivalent plots for the other rate constants determined are
available in the Supporting Information (Figures S8-S15).
The trend in rate constant is markedly different to that seen
for the nitrogen nucleophile 4a cases. There is a monotonic,
though not linear, increase in the rate constant as the amount
of [Bmim][N(SO2CF3)2] 6 in the reaction mixture increases. The
rate constant observed at χ6 �0.8 is nearly 40 times greater
than that observed for the acetonitrile (χ6 =0) case. These
trends in the mole fraction dependence of the rate constant are
perhaps more similar to those seen previously for the SNAr
reaction of ethanol shown in Scheme 1, in that case an
approximately exponential increase in rate constant by up to
ca. 120 times was observed.[10b–d]
This trend in the activation parameters, and therefore
microscopic interactions, for the thiol 4b system is the opposite
to what is observed for both the amine 4a case above and the
previously studied ethanol SNAr reactions.[10b,c,23] In both the
amine 4a and ethanol studies there was an increase in the
enthalpy and entropy of activation at low-intermediate propor-
tions of [Bmim][N(SO2CF3)2] 6 in the reaction mixture (χ6 �0.2
and χ6 �0.5, respectively) due to ionic liquid-starting material
interactions. At the higher mole fractions of [Bmim][N(SO2CF3)2]
6 ionic liquid-transition state interactions were observed and
were the dominant interaction in the ethanol system.[10b,c,23] The
magnitude of the changes in the activation parameters are also
significantly greater than those for the aforementioned SNAr
reactions suggesting that the changes in interactions in the
thiol 4b system are more significant than the other systems.
The potential interactions for the thiol 4b system are similar to
those discussed for the amine 4a system; the ionic liquid could
interact with the electrophile 3, the nucleophile 4b, and/or the
transition state.
To further understand the interactions causing the ionic
liquid solvent effects observed for the thiol 4b system in
[Bmim][N(SO2CF3)2] 6, activation parameters were determined at
Figure 3. The bimolecular rate constants for the reaction between 1-
propanethiol 4b and the benzene 3 in different proportions of the ionic
A benefit of the more complex kinetic model for the thiol
4b reaction is that, as mentioned above, activation parameters
were obtainable for all steps of the reaction and therefore
enthalpy and entropy profiles for the reaction are obtainable
°
liquid [Bmim][N(SO2CF3)2] 6 in acetonitrile at 51.0 C. Uncertainties are
reported as the standard deviation of triplicate results with some
uncertainties falling within the size of the markers used.
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across a range of solvent compositions by considering the
differences in the activation parameters determined for each
step. This can provide additional information about the
interactions present in the thiol 4b system, an advantage over
the previously studied SNAr systems. The full enthalpy and
entropy profiles at each solvent composition can be found in
the Supporting Information (Figures S25–S28). Only the initial
nucleophilic addition step shall be discussed here as it is the
only direct comparison that can be made with both the amine
4a system discussed above and the previously studied ethanol
system.[10,23] The enthalpy profiles for this step are presented in
Figure 4 below.
The following discussion will focus on comparing how the
nature of the transition state changes in an effort to understand
the microscopic interactions in solution as the proportion of the
ionic liquid 6 in the reaction mixture is varied. From the
enthalpy profiles, the transition state changes from a very ‘early’
(or reactant-like) transition state at χ6 �0.2 (relative to χ6 =0) to
an increasingly ‘late’ (or product-like) transition state at χ6 �0.5
and then a truly ‘late’ transition state at χ6 �0.8. That is, the
transition state goes from resembling the starting materials to
more closely emulating the charged Meisenheimer complex. At
a low proportion of the salt 6 in the reaction mixture (χ6 �0.2)
the activation parameters suggest that ionic liquid-transition
state interactions dominate; the ionic liquid is stabilising the
transition state resulting in it being more ‘reactant-like’. As the
amount of ionic liquid in the reaction mixture increases, a
greater degree of charge development in the transition state
would be better stabilised, explaining why the transition state
becomes ’later’ at higher proportions of the salt 6. However, if
the ionic liquid 6 interacts more favourably with the starting
materials in this system, as suggested by the activation
parameters, the magnitude of ionic liquid-starting material
interactions would increase relative to ionic liquid-transition
state interactions when the transition state is comparatively
‘late’ as it would no longer resemble the starting materials at
higher proportions of the salt 6 in the reaction mixture.
In an effort to further understand the ionic liquid inter-
actions in solution, the reaction between the thiol 4b and the
1
2
3
4
5
6
7
8
9
benzene
3
was also examined in the ionic liquid
½TOA�½NðSO2CF3Þ2� 7, for the same reasons as outlined above in
the amine case. The dependence of the bimolecular rate
constant for the nucleophilic addition of the thiol 4b onto the
benzene 3 on the proportion of the ionic liquid [TOA][N
(SO2CF3)2] 7 in the reaction mixture was initially investigated
(Figure 5).
It should be noted immediately that the complex kinetics
observed in acetonitrile and mixtures containing the salt 6 for
this reaction were not seen in mixtures containing the salt 7,
rather first order kinetics were observed in the presence of an
excess of the thiol 4b. Whilst the origin of this change is not
clear, it both greatly simplified analysis and suggests that there
is a distinct difference in solvent interactions when using
½TOA�½NðSO2CF3Þ2� 7 compared to [Bmim][N(SO2CF3)2] 6. Such
observations are not unusual for SNAr reactions; it has been well
documented that changing the nature of the solvent can affect
the observed reaction outcome by changing, for example, the
rate determining step.[13d,24]
The first thing to note from the data shown in Figure 5 is
that there is a decrease in the rate constant as the proportion
of [TOA][N(SO2CF3)2] 7 in the reaction mixture increases with
the rate constant at χ7 �0.6 being ca. 20% of that observed in
acetonitrile (χ7 =0). This trend is opposite to that observed for
the other SNAr systems discussed in this work and also the
previously studied ethanol reaction.[10b–d,23] This difference in the
trend of the rate constant with the amount of ionic liquid 7 in
the reaction mixture is another indication that the balance of
the interactions of the salt 7 with species along the reaction
coordinate are likely different from those observed in the other
SNAr reactions considered.
Once again, temperature dependent kinetic studies were
undertaken in an analogous manner to those discussed earlier
in this work. The solvent compositions chosen were: χ7 =0
(acetonitrile, reproduced from above), χ7 �0.2 (to allow direct
comparison with the amine 4a and the [Bmim][(N(SO2CF3)2] 6
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Figure 4. The enthalpy profile for the first step of the reaction between 1-
propanethiol 4b and the benzene 3 in different proportions of the ionic
liquid [Bmim][N(SO2CF3)2] 6 in acetonitrile. The mole fractions of the ionic
liquid 6 are: χ6 =0 (black, top left), χ6 �0.2 (red, top right), χ6 �0.5 (green,
bottom left) and χ6 �0.8 (purple, bottom right). Uncertainties are propa-
gated from the uncertainties in the enthalpy of activation reported in Table 3
and S21.
Figure 5. The bimolecular rate constants for the reaction between 1-
propanethiol 4b and the benzene 3 in different proportions of the ionic
°
liquid [TOA][N(SO2CF3)2] 7 in acetonitrile at 51.0 C. Uncertainties are reported
as the standard deviation of triplicate results with some uncertainties falling
within the size of the markers used.
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thiol 4b case above) and χ7 �0.6 (the case where the ionic
liquid 7 is diluted by reagents only). The activation parameters
determined can be found in Table 4 below and the correspond-
ing Eyring plots in the Supporting Information (Figure S24).
From the data presented in Table 4 when changing the
solvent from χ7 =0 to χ7 �0.2 there is no measurable difference
liquid is important for ionic liquid-transition state interaction
whereas the key ionic liquid-starting material interaction is
between the anion of the ionic liquid and the starting materials,
presumably, the electrophile 3.
1
2
3
4
5
6
7
in the activation parameters. Given that there is a correspond- Conclusion
8
9
From this study it is clear that the solvent effects of an ionic
Table 4. Activation parameters for the reaction between 1-propanethiol
4b and the benzene 3 in mixtures of [TOA][N(SO2CF3)2] 7 in acetonitrile.
Uncertainties reported are propagated from the linear regression.
liquid on an SNAr reaction will change depending on the nature
of the nucleophile and the amount and nature of the ionic
liquid used.
10
11
12
13
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23
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χ7
ΔH�/kJmolÀ 1
ΔS�/JKÀ 1 molÀ 1
For nitrogen nucleophiles, rate constant enhancement is
small and little change is seen after initial addition of a small
amount of ionic liquid. This outcome is similar to those
observed previously in ionic liquids for bimolecular processes
involving a nitrogen nucleophile.[6] The cation of the ionic liquid
appears important for nucleophile interactions, as has been
previously noted, and this opens up the possibility to rationally
choose ionic liquids to favour this reaction in a method akin to
previously for related systems.[6,25]
0[a]
0.20
0.59
40.0�1.6
39.9�2.1
62.6�4.2
À 285�5
À 282�7
À 228�13
[a] Reproduced from Table 3 above for ease of comparison.
ing change in the rate constant (albeit small in absolute terms),
this suggests any changes in the interactions as the solvent
system changes are too small to measure using this method-
ology. There is then an increase in both activation parameters
upon going from χ7 =0 to χ7 �0.6 and χ7 �0.2 to χ7 �0.6. As
discussed early, an increase in both the enthalpy and entropy of
activation in these systems are likely due to increased
interaction and organisation of the ionic liquid 7 about the
starting materials.
The key difference in terms of interactions observed on
addition of each of the salts 6 and 7 is that no ionic liquid-
transition state interactions are observed when using [TOA][N
(SO2CF3)2] 7 as the solvent. This observation suggests that the
cation of the ionic liquid is important in the ionic liquid-
transition state interactions observed in SNAr reactions involving
a thiol nucleophile. This lack of ionic liquid-transition state
interaction could also explain the solvent effect on the
complexity of the kinetics; no interactions with the transition
state suggest similar limited interactions with the Meisenheimer
Where a sulphur nucleophile was used in an SNAr reaction,
the rate determining step was shown to be highly solvent
dependent. Importantly, in terms of the ionic liquid used,
interactions with the cation of the ionic liquid are key in
influencing this dependence. Once more, changing the cation
dramatically changed the solvent effect and rational selection
of an ionic liquid to control reaction outcome is a possibility.
Significantly, the observed solvent effects of addition of
ionic liquids to reactions involving each of these nucleophile
types differ based on the amount of ionic liquid added (and the
type of ionic liquid). Thus, there is the potential to use this
knowledge to control reaction outcome when multiple nucleo-
philes are present in a synthetic setting. For instance, in an SNAr
reaction where oxygen, nitrogen and sulphur nucleophiles are
competing for the same electrophile, the order of reactivity
might be controlled through rational selection of an ionic liquid
allowing predictable and selective control of reaction outcome.
Preliminary studies suggest that selectivity for either the nitro-
gen 5a and sulphur 5b products of the reaction depicted in
Scheme 2 can be controlled through choice of either
acetonitrile or the ionic liquid 6 as solvents, respectively (see
the Supporting Information for further details, Figures S31 &
S32).
complex that would result in
a (relatively) high energy
intermediate such that all subsequent reactions proceed quickly
and the first step is rate determining. This outcome contrasts
with the significant stabilisation of the intermediate in
acetonitrile and the ionic liquid 6 (Figure 4), resulting in a much
more complicated mechanism.
In the [TOA][N(SO2CF3)2] 7 solvent system there was a
decrease of the rate constant at all solvent compositions. This
change can be attributed to strong interaction of the ionic Experimental Section
liquid 7 with the starting materials suggested by the activation
1-Fluoro-4-nitrobenzene 3 was commercially available and was
parameter data. In this case, the data highlight the importance
of interactions involving the anion of the ionic liquid, likely with
the electrophile as has been previously observed where ethanol
was the nucleophile.[10,23]
It has been shown that for an SNAr reaction involving a thiol
nucleophile, the complexity of the mechanism is very solvent
dependent and this dependence is due to differing degrees of
stabilisation of (particularly) the Meisenheimer complex. The
accessibility of the charged centre of the cation of an ionic
used without further purification. The following reagents were
purified according to literature methods.[26] Triethylamine and 1-
butylamine 4a were distilled and stored over activated molecular
°
sieves at À 20 C. 1-Propanethiol 4b was distilled and stored over
activated molecular sieves at room temperature. Acetonitrile was
dried by stirring over potassium carbonate for 24 h before
distillation. The ionic liquid [Bmim][N(SO2CF3)2] 6 was prepared
according to literature methodology;[27] 1-bromobutane was added
to 1-methylimidazole, both distilled prior to use, to yield the
bromide precursor salt. The bromide salt then underwent a salt
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methathesis reaction with lithium bis(trifluoromethanesulfonyl)
imide to afford the desired ionic liquid. [TOA][N(SO2CF3)2] 7 was
also prepared through the same salt metathesis reaction of the
appropriate bromide precursor salt. Both ionic liquids 6 and 7 were
dried under reduced pressure (<0.1 mbar) at room temperature
until a constant pressure reading was obtained and <200 ppm
water was detected using Karl-Fischer titrimetry. Ion chromatog-
raphy determined <1% bromide content in the ionic liquids 6 and
7 confirming the absence of the bromide salt precursor. Full
experimental detail for these preparations can be found in the
Supporting Information.
Keywords: aromatic substitution · ionic liquids · kinetics ·
nucleophilic substitution · solvent effects
1
2
3
4
5
6
7
8
9
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1
All reactions were monitored via H NMR spectroscopy using either
a Bruker Avance III 400, 500 or 600 NMR spectrometer equipped
with either a BBO, BBFO or TBI probe with results proving to be
reproducible regardless of the spectrometer or probe used.
Reaction progress was monitored following signals corresponding
to depletion of the electrophile 3 at ca. 7.4 and 8.4 ppm and signals
corresponding to formation of the aromatic product 5a at ca. 6.8
and 8.0 ppm for the amine 4a reaction and signals corresponding
to formation of the aromatic product 5b at ca. 7.8 and 8.2 ppm for
the thiol 4b reaction. For the determination of the dependence of
the rate constant on the proportion of ionic liquid in the reaction
mixture, stock solutions were prepared containing the benzene 3
and the nucleophile (amine 4a or thiol 4b in a 12-fold excess,
relative to the benzene 3) in differing amounts of the ionic liquid 6
and 7 in acetonitrile. For the thiol 4b reaction it was necessary to
add a base, triethylamine (ca. 2 times equivalents, relative to the
benzene 3) to the reaction mixture Kinetic samples were stored at
°
À 20 C prior to use with ca. 0.5 mL of the reaction mixture in a
5 mm NMR tube. These reactions were monitored either in situ or
were placed in a water bath at the selected temperature with
spectra recorded periodically until >90% conversion of the starting
material
3 was observed. For the thiol 4b reaction in
½TOA�½NðSO2CF3Þ2� 7 initial rate methodology was employed (i.e.
reaction progress monitored until 8–10% completion).[28] The
temperature dependence of the rate constants were determined in
an analogous manner to that described above at four temperatures
°
across a range of 30 C. By fitting these data to the appropriate
Eyring equation[16] using the LINEST function in Microsoft Excel the
activation parameters were determined.
Additional details for the kinetic analyses including temperatures,
rate constants, equations used to determine the rate constants and
composition of stock solutions (masses, concentrations of reagents
and mole fraction of ionic liquid), rate equations and derivations
can be found in the Supporting Information.[29]
Acknowledgements
JBH acknowledges financial support from the Australian Research
Council Discovery Project Funding Scheme (Projects DP130102331,
DP180103682). KSSM acknowledges the support of the Australian
government through the receipt of a Research Training Pro-
gramme Stipend. The authors would like to acknowledge the NMR
Facility within the Mark Wainwright Analytical Centre at the
University of New South Wales for NMR support.
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[11] Diffusion studies have also shown that the ionic liquid 6 interacts with
nitrogen nucleophiles to a greater extent than oxygen nucleophiles.[29]
[12] The electrophile 3 was chosen due to its lower reactivity cf. species 2.
Conflict of Interest
The authors declare no conflict of interest.
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½TOA�½NðSO2CF3Þ2� 7 was monitored to completion at select mole
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followed pseudo-first order conditions such that initial rates method-
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[19] The rate constant data suggest that there is a change in the interactions
at higher mole fractions of the salt 7 in the reaction mixture. The
methodology employed here may not be sufficient to detect such
changes in the activation parameters with such a small change in the
magnitude of the rate constant.
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Manuscript received: March 17, 2019
Revised manuscript received: April 9, 2019
Accepted manuscript online: April 10, 2019
[21] Upon addition of triethylamine to thiol 4b there is no significant
change in the 1H NMR spectra (cf. thiol 4b, see Figures S29–30 in the
Supporting Information). Also. the mole fraction of triethylamine added
to the reaction mixture is sufficiently small that it would not have a
significant impact on the overall solvent effect allowing for direct
analysis and comparison of how varying the amount of ionic liquid in
the reaction mixture affects the observed solvent effects.
Please note: Minor changes have been made to this manuscript
since its publication in ChemPlusChem. The Editor.
ChemPlusChem 2019, 84, 465–473
www.chempluschem.org
473
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