Probing the importance of ionic liquid structure: A general ionic liquid effect on an SNAr process

Article abstract of DOI:10.1039/c3ob41634h

The effect of a range of ionic liquids, with systematic variations in the cation and anion, on the rate constant of an aromatic substitution process was investigated. Temperature-dependent kinetic data allowed calculation of activation parameters for the process in each solvent. These data demonstrate a generalised ionic liquid effect, with an increase in rate constant observed in each ionic solvent, though the microscopic origins of the rate constant enhancement differ with the nature of the ionic liquid.

Full text of DOI:10.1039/c3ob41634h

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Probing the importance of ionic liquid structure:
a general ionic liquid effect on an SNAr process†
Cite this: DOI: 10.1039/c3ob41634h
Eden E. L. Tanner,a Rebecca R. Hawker,a Hon Man Yau,a Anna K. Croft‡b and
Jason B. Harper*a
The effect of a range of ionic liquids, with systematic variations in the cation and anion, on the rate con-
stant of an aromatic substitution process was investigated. Temperature-dependent kinetic data allowed
calculation of activation parameters for the process in each solvent. These data demonstrate a general-
ised ionic liquid effect, with an increase in rate constant observed in each ionic solvent, though the micro-
scopic origins of the rate constant enhancement differ with the nature of the ionic liquid.
Received 9th August 2013,
Accepted 25th September 2013
DOI: 10.1039/c3ob41634h
www.rsc.org/obc
to be those with reagents,38–40 identification of the primary site
of interaction on the starting material was carried out using
Introduction
Ionic liquids, which are salts consisting of bulky organic molecular dynamics simulations and/or experimentally by mod-
cations and charge-diffuse anions1 with melting points below ifying the reagents. Whilst the site of interaction on the starting
100 °C,2 have garnered a great deal of attention as potential material was determined, this work did not indicate the site of
replacements for traditional molecular solvents in well-studied interaction on the ionic liquid.
organic reactions.3 This attention can be attributed to favour-
We have recently considered experimentally what is required
able properties such as negligible vapour pressure,4 potential of the cation of an ionic liquid to enhance the rate of the reaction
recyclability,5 and, most importantly, the ability to modify the of the bromide 1 with pyridine 2 to give the salt 3 (Scheme 1).
charged components, which may result in drastic changes in Initial studies using the ionic liquid 1-butyl-3-methylimidazolium
the physicochemical properties of the solution.6,7 However, ([Bmim]+) bis(trifluoromethanesulfonyl)imide ([N(CF3SO2)2]−) 4
their widespread usage is currently limited by the lack of showed a rate enhancement due to an entropic effect,39 which
understanding related to the origin of the changes frequently was attributed to coordination of the cation of the species to the
observed in the outcome of organic processes when ionic nitrogen centre of the nucleophile 2. Through modification of
liquids replace molecular solvents.8,9
the cation of the ionic liquid, it was demonstrated that general
Several groups, including those of Welton,10–18 Chiappe19–27 electrostatic interactions between the nucleophile and the posi-
and D’Anna,28–35 have considered the microscopic origins of tively charged centres on the cation (rather than specific hydro-
changes in the reaction outcome of organic processes in ionic gen bonding) are particularly important and that access of the
liquids. We have previously examined substitution,36–42 cyclo- nucleophile to the charged centre was necessary to observe a rate
addition43,44 and catalysed processes,45,46 particularly focussing enhancement relative to a molecular solvent.42
on cases where activation parameter data could be determined.
In contrast to the Menschutkin reaction described above,
Such data indicate that interactions between the components of whilst there is also an entropy-driven increase in the rate constant
a given ionic liquid and either the starting materials or the inci- of the reaction outlined in Scheme 2 on moving from a molecular
pient charges in the transition state result in significant solvent to the ionic solvent 4, the principal interaction is an
changes to the entropy and enthalpy of activation for the anion-π interaction between the substrate 5 and the anion of
process. In cases where the key solvent interactions were shown the ionic liquid 4; this interaction was inferred, from
molecular dynamics simulations, to decrease on moving to the
aSchool 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
bDepartment of Chemical and Environmental Engineering, University of Nottingham,
University Park, Nottingham, NG7 2RD, UK
†Electronic supplementary information (ESI) available: Preparation of the ionic
liquids 8–15, general kinetic procedures, rate data for the Eyring plots shown in
Fig. 1 and 2. See DOI: 10.1039/c3ob41634h
‡Previous address: School of Chemistry, University of Wales Bangor, Bangor,
Scheme 1 The Menschutkin reaction between the bromide 1 and pyridine 2
to give the corresponding salt 3, which proceeds via an SN2 mechanism.
Gwynedd, LL57 2UW, United Kingdom.
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Scheme 2 Ethanolysis of the fluorinated nitrobenzene 5, through the Meisen-
heimer complex 6, to give the ether 7.
intermediate 6.39§¶ Once again, while the site of interaction on
the substrate 5 is understood, it was not clear what features of the
solvent anion are important in influencing reaction outcomes.
Further, since the initial organisation of the solvent around the
substrate also indicates close association of the cation with both
the anion and the substrate 5, it was unknown how changing that
component of the solvent might affect reaction outcome.
The work described herein seeks to clarify the above by sys-
tematically altering the nature of either the anion or the cation
of the ionic liquid and observing the effect on the activation
parameters of the reaction shown in Scheme 2. Initially a
series of ionic liquids (4, 8–11) containing anions with increas-
ing charge localisation was considered to determine whether
the degree of interaction of the anion with the substrate is a
factor in the observed rate enhancement and, therefore, if
charge localisation can be manipulated to optimise reaction
outcome.47 Subsequently, a series of ionic liquids (4, 12–15)
containing cations of different structure was investigated.
These structural alterations vary access to the positively
charged centres42 and it was of interest to see whether this
change affects reaction outcome, be it through direct inter-
action with the starting material 5 or by varying the cation–
anion interaction and hence the anion-substrate 5 interaction.
spectrometer (600 MHz) using ca. 0.6 mL of reaction mixture
in a 5 mm NMR tube. In the case of ionic liquids 8–9 and
12–16, kinetic analyses were carried out in solutions contain-
ing ethanol (ca. 2.1 mol), triethylamine (ca. 0.42 mol) and dini-
trofluorobenzene 5 (ca. 0.06 mol) over a range of temperatures
between 304 K and 344 K. In the case of ionic liquids 10 and
11, the ionic liquid component was diluted by ionic liquid 4
(mole fraction of ionic liquids 10 and 11 are 0.53 and 0.42,
respectively) to ensure miscibility with the reagents, then used
as described above. In each case, the reaction was followed
using 19F NMR spectroscopy until more than 95% of the start-
ing material 5 was consumed. Spectra were taken at regular
intervals during the reaction and at least twenty spectra were
obtained for each kinetic run. The extent of reaction was
deduced by integration of the signal corresponding to the
fluorine in the starting material (δ ca. −109). From this infor-
mation, the pseudo-first order rate constants for the reaction
of the benzene 5 under these conditions, and subsequently
the second-order rate constants, at each temperature were
calculated. The activation parameters were then determined
using the bimolecular Eyring equation.52
Experimental
Ethanol and triethylamine were both purified and dried
according to literature methods,48 whilst the fluorodinitro-
benzene 5 was used as received without further purification.
The ionic liquids 8–10 were prepared from the chloride 11
through anion metathesis.49 The ionic liquids 12–15 were pre-
pared from the corresponding chloride,49,50 whilst ionic liquid
9 was prepared from the corresponding bromide (see ESI†).51
All ionic liquids were dried to constant weight at 70 °C under
reduced pressure (1 mbar) before use.
19F NMR spectra were recorded either on a Bruker Avance
400 spectrometer (400 MHz) or
a Bruker Avance 600
Results and discussion
§The interactions are also different to the cases where a charged nucleophile is
used,35 as the principal interactions are between the nucleophile and the cation.
¶While some theoretical studies have shown that SNAr reactions proceed by a
concerted mechanism, the stepwise mechanism through the Meisenheimer
intermediate 6 would be expected for reaction of the fluoride 5.53
The reaction shown in Scheme 2 was initially carried out at a
single temperature (324 K) in ethanol and ionic liquids 8–16 to
establish the relative values of the rate constants in all of the
solvents and to allow comparison with literature data in ionic
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liquid 4.39 At this temperature, the second-order rate constant can be separated into two groups based on the activation para-
for the ethanolysis of the benzene derivative 5 is similar in all meters observed. The first group, consisting of ionic liquids 8
of the ionic solvents 4 and 8–16 and, at a minimum, ten times and 9, show significant increases in both activation enthalpy
greater than that in the molecular solvent under the same con- and entropy when compared with both the molecular
ditions. Given this general rate constant increase, temperature- solvent and the parent system 4. In these cases, the large
dependent kinetics were undertaken to better understand if increase in activation enthalpy, which can be attributed to
the origin of this increase varies across the ionic liquids increased interactions between the anion and the starting
studied, which may be indicative of changes in the solvent– material 5, is offset by the corresponding increase in activation
solute interactions. Kinetic experiments allowed the construc- entropy that facilitates the observed rate enhancement. The
tion of Eyring plots and from these activation parameters were changes relative to when the ethanolysis of the benzene deriva-
obtained, which provide information on the interactions tive 5 is carried out in the ionic liquid 4 suggest that a greater
occurring at a microscopic level in the solution.
degree of charge localisation in the anion, compared to the
Initially, ionic liquids containing different anionic com- bis(trifluoromethanesulfonyl)imide anion considered orig-
ponents (4, 8–11) were considered (Fig. 1, Table 1). Across the inally, facilitate stronger anion-π interactions.
range of temperatures studied the rate constant for the reac-
The second pairing consists of the ionic liquids 10 and 11.k
tion shown in Scheme 2 in the ionic liquids 4 and 8–11 was These are not practical as solvents alone for the process as the
greater than in the molecular solvent. Within the range of tetrafluoroborate 10 does not dissolve the reagent 5, whilst the
ionic liquids, whilst there are some general trends (for chloride 11 is a solid over the range of temperatures studies.
example, the chloride case 11 has a greater rate constant than As such, they were diluted with the ionic liquid 4 prior to use,
the other cases), the small differences relative to the uncertain- though they still constituted the majority of the ionic com-
ties in the rate constants limit further discussion.
ponent of solution (Table 1). When the reaction was carried
Of greater interest than the overall similar rates is the trend out in these solvent systems, the ethanolysis of the fluoride 5
in the activation parameters for the process. If the ionic liquid proceeded with activation parameters that matched those
4 is considered the ‘parent’, the solvents with different anions observed by the parent ionic liquid 4. The anions of the ionic
liquids 10 and 11 are considered more coordinating than all of
the other ionic solvents discussed previously, so it was antici-
pated that both the activation enthalpy and entropy would be
more positive as a result; this was not the case, suggesting that
the interactions between the anionic component of the solvent
and reagent 5 had not changed. This could be because the
tetrafluoroborate and chloride anions interact with the starting
material 5 to the same degree as the bis(trifluoromethane-
sulfonyl)imide anion. However, given the former are much
more coordinating, this seems unlikely. A more probable expla-
nation would be that the charge-dense anions interact with the
cations to a greater extent than in the simple ionic liquids (as
there is a larger cation-interacting anion ratio than in the binary
Fig. 1 Eyring plot for the second-order rate constants for the reaction outlined
kIt is worth noting that in molecular solvents chloride is more nucleophilic than
in Scheme 2 carried out in either ethanol ( ) or one of the ionic liquids 4 ( ),39 8
ethanol,54 so reaction with the ionic liquid 11 must be considered. Initial experi-
(
), 9 ( ), 10 in 4 ( ) or 11 in 4 ( ). In all cases, the ionic liquid was only
ments to follow reaction of the fluoride 5 showed that the signal due to the
starting material 5 in the 19F NMR spectrum decreased in size and a signal due
to the fluoride anion each appeared at a rate qualitatively similar to previous
cases. At ca. one half-life, both the starting material 5 and the product 7 were
observed using 1H NMR spectroscopy; the presence of the latter was confirmed
through addition of an authentic sample. There was no evidence of 1-chloro-2,4-
dinitrobenzene, the result of the chloride ion reacting with the starting material.
Given the reactivity of aryl chloride species with ethanol are known to be lower
than the reactivity of the corresponding fluoride species,55 if it were an inter-
mediate its conversion to the ether 7 would be the rate determining step of this
process (given the rate of fluoride ion formation has already been determined
and is comparable to reaction of ethanol with aromatic 5). In such a case, the
chloride intermediate would build up and be observable in the 1H NMR spec-
trum. As it is not, this indicates the chloride anion does not act as a nucleophile
in this reaction. While this is interesting in that the nucleophilicity of the two
competing species is inverted in ionic liquids relative to molecular solvents this
was not further considered here. Changes in the relative nucleophilicity of
halide anions have been shown previously,15,16 including in reference to nucleo-
philic aromatic substitution processes.23,24
diluted by reagents (benzene 5, ethanol and triethylamine; mole fractions out-
lined in Table 1), except ionic liquids 10 and 11, as outlined below.
Table 1 Activation parameters for the reaction described in Scheme 2 in the
solvent specified, with the mole fraction given for the ionic liquid cases
Solvent
χIL
ΔH‡/kJ mol−1 a
ΔS‡/J K−1 mol−1 a
Ethanol
—
0.54
0.63
48.1 1.7
49.6 0.5
58.0 3.1
57.4 1.9
47.2 2.7
45.6 3.7
−250
−229
5
2
4b
8
9
−201 10
0.62
−201
−238
−233 12
6
8
10 in 4
11 in 4
0.53 (0.59)c
0.43 (0.60)c
a Uncertainties quoted are standard deviations. b Data reproduced
from Jones et al.39 c Number in parentheses is the total mole fraction
of ionic liquid, including dilution by ionic liquid 4.
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systems considered previously). As a result, the bis(trifluoro-
methanesulfonyl)imide anion is free to interact with the start-
ing material 5, resulting in identical activation parameters to
those observed when ionic liquid 4 is used alone.**
In combination, the rate and activation parameter data for
the process outlined in Scheme 2 in the ionic liquids 4 and
8–11 suggest the increase in rate constant observed relative to
the molecular solvent39 is not dependent on the charge localis-
ation in the anion; however, the activation parameters indicate
differences at the microscopic level. That is, a change in one
activation parameter is balanced by a proportionate, but
inverse, change in the other. Irrespective of this, an increase in
the rate constant for the ethanolysis of the fluoride 5 is seen
for all ionic liquids considered. Further, the small differences
between reaction outcomes on using mixtures of ionic liquids
compared to the parent 4 indicate that the presence of small
amounts of halide impurities in the ionic solvent – a frequent
concern for ionic liquids synthesised through salt metathesis –
would not be expected to significantly affect reaction outcome
provided that the interactions between the halide and the
ionic liquid cation are much stronger than those between the
halide and the reagent 5.††
Fig. 2 Eyring plot for the second-order rate constants for the reaction outlined
in Scheme 2 carried out in either ethanol ( ) or one of the ionic liquids 4 ( ),39
12 ( ), 13 ( ), 14 ( ), 15 ( ) or 16 ( ). In all cases, the ionic liquid was only
diluted by reagents (benzene 5, ethanol and triethylamine; mole fractions out-
lined in Table 2).
Table 2 Activation parameters for the reaction described in Scheme 2 in the
solvent specified, with the mole fraction given for the ionic liquid cases
Solvent
χIL
ΔH‡/kJ mol−1 a
ΔS‡/J K−1 mol−1 a
Given the importance of the anion–cation interactions in
determining reaction outcome demonstrated above, it is of
interest to consider what impact structural alterations on the
cation of the ionic liquid have on the relationship with the
anion and the substrate 5 and, consequently, the rate constant.
As such, the rate constant of the reaction outlined in Scheme 2
was measured over a range of temperatures in the ionic liquids
4 and 12–16 and the activation parameters determined (Fig. 2,
Table 2). As was observed in the series of ionic liquids with
varying anions, across the range of temperatures studied the
rate constant of the reaction in the ionic liquids 4 and 12–16 is
Ethanol
4b
12
13
14
15
16
—
48.1 1.7
49.6 0.5
49.0 3.9
51.5 3.2
50.5 1.7
45.7 1.9
41.0 2.6
−250
−229
5
2
0.54
0.52
0.50
0.51
0.51
0.32c
−223 12
−211 10
−221
−240
−252
5
6
8
a Uncertainties quoted are standard deviations. b Data reproduced
from Yau et al.38 c Lower value due to the cation being larger than in
the other cases. Volume fraction remains the same.
greater than in the molecular solvents. The differences in impact the entropy-driven rate enhancement observed when
observed rate constants are smaller than those observed for using ionic solvent 4, or that any effects cancel each other out.
the series of ionic liquids with different anions and will not be
In the case of pyrrolidinium-based ionic liquid 15, the acti-
further discussed.
vation parameters determined are the same within uncertainty
Once again, of more interest are the activation parameters as in the molecular solvent, ethanol, and differ from the pre-
for the process in the various solvents. Initially it is useful to viously considered ionic liquids 4 and 12–14. While from these
consider the imidazolium series of ionic liquids used (4 and data the microscopic origin of the rate enhancement observed
12–14). Previously, methyl substitution at the C-2 position has in the salt 15 cannot be determined, two points are clear from
been shown to not affect the ability of the cation to interact the data presented; (i) that the origin of the enhancement in
with electron-rich reagents, whilst methyl substitution at the the rate constant is different from that of all of the previous
C-4 and C-5 positions does decrease the extent of interaction.42 ionic liquids considered (4, 8–14) and (ii) even dramatic struc-
As shown in Table 2, the activation parameters for the process tural changes do not affect the capacity for the ionic liquid to
outlined in Scheme 2 in the ionic liquids 4 and 12–14 are very facilitate rate enhancement in this class of reaction.
similar where no clear trend can be seen. This suggests that
The final ionic liquid considered, the tetraalkylammonium
substitution of the imidazolium framework does not affect the salt 16, represents a case where access to the charged centre of
cation–anion or cation-reagent 5 interactions substantially to the cation is extremely restricted. The use of an ionic liquid
with such a bulky cation also results in changes to the acti-
vation parameters for the process outlined in Scheme 2 when
compared with both the molecular solvent and the parent
ionic liquid 4. Rather than the entropic benefit observed in
the ionic solvent 4, the rate constant enhancement relative
**This argument is consistent with the decreased reactivity of chloride observed
in these systems and detailed in the footnote above. It should be noted that the
anion ([N(CF3SO2)2]−) is present in excess relative to the reagent 5.
††This is reasonable given the relative interaction energies shown previously
to ethanol observed in solvent 16 is due to a decrease in
the enthalpy of activation. This decrease suggests that the
between components of an ionic liquid and between each component and an
aromatic solute.56
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organisation of the components of the solvent about the start-
ing material 5 seen for solvent 4 is not present; given the
Acknowledgements
decreased access to the charged centre of the cation, this is HMY acknowledges the support of the Australian government
unlikely to be due to increased interactions between the cation through the receipt of an Australian Postgraduate Award. EELT
and anion. Rather, it is probably the result of the steric bulk of acknowledges the support of Cochlear through the receipt of
the cation preventing the organisation seen earlier.39 Irrespec- an Undergraduate Award in Chemistry. AKC is grateful to the
tive, the observed rate data indicate that, while large structural Royal Society for the award of a Travel Grant. JBH acknowl-
changes to the cation do affect microscopic interactions, the edges financial support from the University of New South
rate constant of the reaction remains effectively unchanged Wales Goldstar Grants Programme and the Australian
irrespective of the ionic liquid used.
Research Council Discovery Project Funding Scheme (Project
Finally, it is worth considering that, generally, an increase DP130102331).
in one activation parameter on moving to any of the ionic
liquids considered is paired with an increase in the other para-
meter. This enthalpy–entropy compensation is consistent
Notes and references
with what has been observed previously by us in this39 and
other systems.37,38,40–42,44 In the case shown here, it is rational-
ised by organisation of the components of the ionic solvent
about the electrophile 4 and the rate enhancement is the
result of the entropic benefit outweighing the enthalpic cost.
Whilst it may be of interest to consider what this indicates in
terms of the organisation of components of solution (how
bulk solvent ordering changes about species along the reaction
coordinate) further discussion is limited given that mole frac-
tion dependent data, reported for other examples,9,36,37,41 is
not available here.
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