Rational selection of the cation of an ionic liquid to control the reaction outcome of a substitution reaction

Article abstract of DOI:10.1039/c8cc00241j

A range of ionic liquids was examined as solvents for a substitution reaction. They were chosen through rationally varying the ionic liquid cation in order to enhance the rate constant. Access to charge and electron-withdrawing substituents benefitted rat

Full text of DOI:10.1039/c8cc00241j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Rational selection of the cation of an ionic liquid to control the
reaction outcome of a substitution reaction†
Rebecca R. Hawker,a Ronald S. Hainesa and Jason B. Harpera
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
range of ionic liquids was examined as solvents for
a
have been interpreted at the level of molecular interactions.
substitution reaction. They were chosen through rationally varying There is a rate constant enhancement observed for this
the ionic liquid cation in order to enhance the rate constant. reaction when the ionic liquid solvent 1-butyl-3-
Access to charge and electron-withdrawing substituents methylimidazolium
benefitted rate enhancement, allowing ionic liquids to be ([bmim][N(SO2CF3)2],
rationally selected to control reaction outcome.
bis(trifluoromethanesulfonyl)imide
) is used, compared to acetonitrile.6, 7
9
When used as solvents, ionic liquids have the ability to affect
the reaction outcome of a range of organic and inorganic
processes.1-4 This feature, alongside their many useful
properties such as negligible vapour pressure5 and thermal
stability4 means that ionic liquids are desirable alternatives to
the volatile organic solvents4 currently used in synthesis.
Through systematic studies on well-known reactions, a
predictive framework of the effects that ionic liquids have as
Scheme 1. The Menschutkin reaction between benzyl bromide and pyridine to give
N-benzylpyridinium bromide, which has been previously examined in ionic liquids.6, 8, 9
The ionic liquids previously examined for this reaction have
contained imidazolium and ammonium cations (Figure 1). An
increase in the rate constant for the reaction was observed in
all of the ionic liquids that had sufficient access to the charged
centre on the cation (i.e. were not sterically hindered).8 For the
chlorinated imidazolium ionic liquids, the electron-
withdrawing nature of the chlorine substituents offset the
negative steric effects.10 With knowledge of what is required
for a rate constant enhancement, new ionic liquids can be
considered to exploit this pyridine-cation interaction, leading
to even larger rate constants for the reaction.
solvents can be developed. Such
a framework can be
established through kinetic analysis and by developing an
understanding of how the components of the ionic liquid
interact with species along the reaction coordinate. Knowledge
of how an ionic liquid will behave as a solvent will allow for
rational selection of ionic liquid components as well as the
ability to design novel ionic liquids to enhance the rate and/or
selectivity for a particular reaction.
The reaction between benzyl bromide and pyridine (a
Menschutkin reaction, Scheme 1) proceeds through an SN2
mechanism and the effects of ionic liquids on this reaction
Figure 1. General representations of the imidazolium and ammonium ionic liquids
previously considered as solvents for the Menschutkin reaction shown in Scheme 1 (R =
= =
H, Me or Cl; R1 = R2 = R3 = R4 nC8H17 or R1 = Me, R2 nC4H9, R3, R4 = -(C4H8)-7-10
This manuscript describes the use of a range of ionic liquids
(Figure 2) as solvents for the reaction in Scheme 1. The ionic
liquids selected vary both in the steric requirements of, and
the charge distribution in, the cation, in an effort to maximise
the solvent effects observed. The salts considered include both
known ionic liquids that are under-utilised as solvents in
organic reactions and previously unreported ionic liquids.
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Figure 2. The ionic liquids discussed here; they have been grouped into sets that can be usefully compared. N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide
([bmpyr][N(SO2CF3)2], 1), S-butylthiolanium bis(trifluoromethanesulfonyl)imide ([btl][N(SO2CF3)2], 2), N-butyl-N-methylpiperidinium bis(trifluoromethanesulfonyl)imide
([bmpi][N(SO2CF3)2], 3), N-butyl-N-methylmorpholinium bis(trifluoromethanesulfonyl)imide ([bmmo][N(SO2CF3)2], 4), N-butylpyridinium bis(trifluoromethanesulfonyl)imide
([bpy][N(SO2CF3)2],
5),
N-hexylpyridinium
bis(trifluoromethanesulfonyl)imide
([hpy][N(SO2CF3)2],
6),
N-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)pyridinium
bis(trifluoromethanesulfonyl)imide
([Fhpy][N(SO2CF3)2], 7), 1-butyl-3-methyl-1,2,3-triazolium bis(trifluoromethanesulfonyl)imide ([bmtr][N(SO2CF3)2], 8), 1-butyl-3-
methylimidazolium bis(trifluoromethanesulfonyl)imide ([bmim][N(SO2CF3)2], 9) and 3,3’-(1,5-pentane-diyl)bis(1-methylimidazolium) bis(trifluoromethanesulfonyl)imide
([pe(mim)2][N(SO2CF3)2]2, 10). Ionic liquids 1 and 9 shown in blue have been examined previously6-8 and are only discussed here.
All of the ionic liquids 2-8 and 10 were synthesised; in addition
Table 1. The activation parameters for the reaction shown in Scheme 1 in either
the novel compound
7 was fully characterised (for details
acetonitrile or one of the ionic liquids 1-10, at the specified mole fractions.
including physical properties, see ESI). The rationale for
selecting these solvents is based on our developing predictive
framework.8, 10 It was anticipated that ionic liquids containing
cations with greater access to the charged centre would result
in a larger rate constant than those without, and that those
with cations with electron-withdrawing substituents would
result in an increase in the rate constant compared to those
with the corresponding cations without those substituents.
The effectiveness of each of the ionic liquids 2-8 and 10 as
solvent for the chosen reaction was determined using kinetic
analyses. Temperature dependent kinetic analyses to
determine activation parameters of the ionic liquids 2-8 and 10
as solvents for the SN2 reaction were carried out using NMR
spectroscopy in a manner analogous to previous studies7-10
(see ESI for more details). This allowed for the construction of
Eyring plots (Figure S3-S7) and the determination of the
activation parameters (Table 1) for each of the ionic liquids 2-8
and 10. The reaction was analysed in mixtures containing one
of each of the ionic liquids examined at χ ca. 0.85;§ as well as
being a solvent system where the ionic liquid is the major
species, this allows comparison to previous studies.
Solvent
χIL ∆H‡ / kJ mol-1 a ∆S‡ / J K-1 mol-1 a
acetonitrile
0
44.7 ± 0.8
47.7 ± 1.3
49.9 ± 3.5
50.9 ± 1.2
47.6 ± 2.8
51.1 ± 1.7
47.1 ± 2.2
50.5 ± 4.1
-220 ± 3
-201 ± 4
-187 ± 13
-191 ± 4
-196 ± 10
-189 ± 6
-205 ± 8
-188 ± 15
[bmpyr][N(SO2CF3)2] 1b
0.86
0.85
0.84
0.70
0.84
0.36
0.36
[btl][N(SO2CF3)2] 2
[bmpi][N(SO2CF3)2] 3
[bmmo][N(SO2CF3)2] 4
[bpy][N(SO2CF3)2] 5
[hpy][N(SO2CF3)2] 6
[Fhpy][N(SO2CF3)2] 7
[bmtr][N(SO2CF3)2] 8
[bmim][N(SO2CF3)2] 9c
[pe(mim)2][N(SO2CF3)2]2 10
0.85
0.86
0.78
49.8 ± 2.0
49.9 ± 0.8
50.2 ± 0.8
-193 ± 7
-195 ± 3
-191 ± 7
a Uncertainties quoted are from the fit of the linear regression. b Data reproduced
from Tanner et al.8 c Data reproduced from Yau et al.7
allows evaluation of these solvent-solute interactions is to
consider the rate constants for the reaction in each of the ionic
liquids 1-10 at a given temperature (292.2 K, Table 2).¶
Considered first are the effects of ionic liquids
ca. 0.85), as this series allows for comparison of the extent of
charge localisation on the cation. In the ionic liquids and 8,
3, 5 and 8, (χ
3,
5
In an effort to differentiate the interactions between
different ionic liquids and pyridine, the activation parameters
were considered. All of the ionic liquids have the same effects
similar rate constants were observed; these rate constants
were also similar to those in the previously examined ionic
liquids
1 and 9. This indicates that there are similar
as [bmim][N(SO2CF3)2] 9, compared to the molecular solvent
interactions between the ionic liquid cation and the pyridine in
each case, suggesting that there isn’t a significant difference in
the extent of access to the charged centre(s) and the extent of
(de)localisation of the charge does not affect the interactions.
acetonitrile: an increase in both the enthalpy and entropy of
activation, suggesting stabilisation of, and organisation
around, the starting materials (predominantly the pyridine).6-8
While, this suggests that the microscopic origins of any solvent
effects are similar for all of the ionic liquids, the extent of
these interactions in each ionic liquid is not readily
differentiated given the uncertainties. A simple approach that
By comparing salts
9 and 10, the effect of the number of
charges on the cation can be examined. Access to the cationic
centre has shown to be important for this reaction;8 if there is
more than one cation, the effect might be greater. The rate
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By comparing solvent effects of the salts
electron-withdrawing substituents on the alkyl chain of the
cation can be examined. The ionic liquid containing fluorine
6 and 7, effects of
Table 2. The rate constant for the reaction shown in Scheme 1 at 292.2 K in either
acetonitrile or one of the ionic liquids 1-10, at the specified mole fractions.
7
a,c
Solvent
χIL
k2 / 10-4 L mol-1 s-1 a,b kIL / kCH3CN
atoms on the cation results in a higher rate constant for the
acetonitrile
0
6.08 ± 0.07
17 ± 1
1.0
reaction than the corresponding non-fluorinated salt 6. As for
[bmpyr][N(SO2CF3)2] 1d
0.86
0.85
0.84
0.70
0.84
2.7 ± 0.2
7 ± 1
the morpholinium salt
4, this suggests that the electron-
[btl][N(SO2CF3)2] 2
38 ± 10
15.1 ± 0.2
33 ± 3
withdrawing nature of the fluorine substituents increases the
cation-pyridine interaction, thus increasing the rate constant.
The importance of the nature of the azolium salt can also
be compared through the rate constants of the reaction in the
[bmpi][N(SO2CF3)2] 3
[bmmo][N(SO2CF3)2] 4
2.48 ± 0.04
5.4 ± 0.5
3.0 ± 0.2
18 ± 1
[bpy][N(SO2CF3)2] 5
[hpy][N(SO2CF3)2] 6
0.36
0.36
0.85
0.86
0.78
13.4 ± 0.3
26.3 ± 0.7
17 ± 2
2.19 ± 0.06
4.3 ± 0.1
[Fhpy][N(SO2CF3)2] 7
[bmtr][N(SO2CF3)2] 8
[bmim][N(SO2CF3)2] 9e
[pe(mim)2]2[N(SO2CF3)2] 10
imidazolium-based 9 and the triazolium-based 8. Changing the
2.9 ± 0.3
extent of the delocalisation of charge around the aromatic ring
might change the nature of the cation-pyridine interaction.
14.5 ± 0.5
22 ± 1
2.39 ± 0.09
3.6 ± 0.2
The rate constant in the triazolium-based
the corresponding imidazolium-based
8
9
is higher than in
however the
a Uncertainties are reported to one significant figure with values rounded to the
,
b
same level of accuracy. Uncertainties quoted are the standard deviation of
magnitude of the change in rate constant is much smaller than
the other effects seen here, so further analysis is unwarranted.
Of the ionic liquids examined, four stand out as resulting in
triplicate results. c Uncertainties are compounded from the rate constants. d Data
reproduced from Tanner et al.8 e Data reproduced from Yau et al.7
the greatest rate enhancements; salts
2, 4, 7 and 10. The
constant for ionic liquid 10 is higher than that for salt
9
sulfonium-based ionic liquid 2 has the greatest rate
suggesting that the salt containing a doubly charged cation has
greater interaction with pyridine.
enhancement (ca. seven times that of acetonitrile). However,
as mentioned in the presence of nucleophiles (including
Comparison of the rate constants in each of the ionic
pyridine), the ionic liquid
2 slowly reacts. The ionic liquid 7
liquids
1 and 2 allows the effects of increasing the access to
containing the fluorine substituents on the alkyl chain also
results in a notable increase in the rate constant (even though
it is present at only χ ca. 0.4§). However, the reduced solubility
of this salt in molecular solvents and the issues associated with
its synthesis (perfluoroalkyl halides are expensive reagents and
they react very slowly) make it less practical for common use.
the charged centre of the cation to be considered. The charge
on the pyrrolidinium cation (salt
on the thiolanium cation (salt
1
) is less accessible than that
2), based on the number of
subsꢀtuents aꢁached to the charged atom.‡ The ionic liquid
2
resulted in a higher rate constant than the ionic liquid 1; it was
the highest rate constant observed in any of the ionic liquids
examined. This effect is attributed to the lack of steric
hindrance around the sulfonium charge, increasing the
potential for cation-pyridine interactions.
The salts
4 and 10 containing the morpholinium cation and
multiple imidazolium centres, respectively, are not
encumbered by these issues.¶¶ As such, it is suggested that
the ionic liquids 4 and 10 are the best choice of ionic liquid
solvent for this type of substitution reaction (for a full analysis,
see Table S14). Following this observation, the effect of varying
the proportion of each of the ionic liquids in the reaction
mixture was examined allowing comparison with data for the
It was noted that the salt
2 slowly reacted with pyridine
under the conditions used (for details see ESI). Because of this,
and the steric effects on rate enhancement, the corresponding
selenolanium salt S12 was synthesised. This salt also reacted
with pyridine (faster than the ionic liquid
2). Given this
imidazolium ionic liquid 9 11
as reported previously11 with the results shown in Figure 3.
The ionic liquid containing the morpholinium cation
follows the same trend as [bmim][N(SO2CF3)2] with
increasing proportion of ionic liquid in the reaction mixture the
rate constant increases. Whereas for ionic liquid there is a
plateau at χ ca. 0.2, for ionic liquid the plateau doesn’t start
.
Kinetic analyses were carried out
reactivity, and the toxicity associated with organoselenium
compounds, this ionic liquid was not considered for further
kinetic analyses (for full details on the synthesis of salt S12 and
its decomposition in the presence of pyridine, see ESI).
4
9
;
By comparing salts that are sterically similar, but
electronically different, the effect of electron-withdrawing
substituents on the ionic liquid cation can be examined. The
effect of chlorination of imidazolium-based ionic liquids on any
solvent effects has previously been examined,10 however it is
also worth considering the effect of electron-withdrawing
substituents at other positions on the cation. By comparing the
9
4
until χ ca. 0.4. Irrespective of this detail, the trend is the same
with an increase in rate constant with ionic liquid and an effect
that diminishes with increasing proportion of the salt.‡‡
In the case of ionic liquid 10 containing the doubly charged
cation, the trend in the mole fraction dependence is again
ionic liquids
3
and
4
,
containing piperidinium and
similar to the other two ionic liquids
reached at χ ca. 0.2; similar to ionic liquid
liquid 10 gives a higher rate constant than salt
4
and
. The fact that ionic
across all the
9. The plateau is
morpholinium cations, respectively, the effect of an inductively
electron-withdrawing substituent in the cationic ring could be
examined. The rate constant of the reaction in Scheme 1 in salt
9
9
mole fractions examined suggests some degree of
cooperativity between each of the charged centres (for more
details and the corresponding normalised graphs see ESI). The
important thing to note here is the consistent trend in the
mole fraction dependence for each of the ionic liquids.
4
is approximately double that in the ionic liquid 3.†† This
difference suggests that the electron-withdrawing nature of
the oxygen in the morpholinium ring increases the cation-
pyridine interaction, which increases the rate constant.§§
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Conflicts of interest
There are no conflicts to declare.
Notes and references
§ The salts 3 and 7 could not be examined at χ 0.85; they are
solids at the temperatures used and insufficiently soluble in the
small amounts of other species present.
¶
In this case, 292.2 K. The ionic liquids 1 and 9 not examined at
8
this temperature7, had rate constants interpolated from the
Eyring plots.
‡ Whilst hyperconjugation would result in some charge on the
adjacent carbon centres, and this would differ between the two
cations, this difference would be markedly less significant than
the difference in steric constraints.
Figure 3. The bimolecular rate constants for the reaction shown in Scheme 1 in
different proportions of either [bmmo][N(SO2CF3)2] 4, (ꢀ), [pe(mim)2][N(SO2CF3)2]2 10,
(ꢀ) or [bmim][N(SO2CF3)2] 9 (ꢀ)a in acetonitrile at 295.2 K. Uncertainties are reported
as the standard deviation of three replicates; some values fall within the size of the
markers used. a Data reproduced from Schaffarczyk McHale et al.11
†† Although the effects of the ionic liquids
examined at different mole fractions (0.85 and 0.70
respectively), the rate constant in salt is significantly higher
than that in salt ; given the mole fraction dependence of this
2 and 3 were
3
2
reaction, demonstrated here and elsewhere,11 increasing the
mole fraction would not be expected to change this argument.
§§ Whilst there is the potential for direct oxygen-cation
interactions, these have been shown to be markedly less than
with nitrogen13 and previous studies involving oxygen centred
nucleophiles show no significant interactions.14, 15 As such, the
inductive effect is considered much more likely.
In summary, the effects of a range of ionic liquids on a
bimolecular nucleophilic substitution reaction were
investigated. The ionic liquids were specifically chosen to
increase the rate constant for the reaction, based on
knowledge of what is required for rate enhancement: no steric
hindrance around cation and introduction of electron-
withdrawing substituents. The ionic liquid with the most
accessible charge led to the greatest rate constant
enhancement (ca. seven times that of the molecular solvent)
and ionic liquids that contained electron-withdrawing
substituents at various positions on the cation also saw
significant rate constant increases. Importantly, the activation
parameters confirm the microscopic origins of the effects and
the validity of the rationale for choosing these systems. These
results are significant, as they confirm that ionic liquids can be
designed to get the desired reaction outcome for this process.
Of the most effective ionic liquids, the ‘overall best’
solvents were chosen by considering stability of the salt, cost
and ease of synthesis. These salts demonstrated the same
trend in mole fraction dependence as the previously examined
case; this is significant as it further demonstrates the
effectiveness of the predictive principles being developed.
Overall, these results have show that the components of
ionic liquids can be rationally chosen to control the rate
constant for this reaction. These salts might be applied to
other processes where the same interactions were responsible
for reaction outcome, such as condensation reactions that
might be important for heterocycle synthesis.12 However, the
process is more general as when what is required for rate
enhancement is known, interactions can be exploited such
that ionic liquids can be designed for the reaction at hand,
allowing for solvent-controlled reactivity.
¶¶ This ionic liquid
3 can reach χ ca. 0.7 in acetonitrile; given the
mole fraction dependence of this reaction type (see literature11
and herein) this was not considered a limitation.
‡‡ This is unlikely due to mass transfer; see ESI for discussion.
1. J. P. Hallett and T. Welton, Chem. Rev., 2011, 111, 3508-3576.
2. R. R. Hawker, R. S. Haines and J. B. Harper, in Targets in
Heterocyclic Systems, eds. O. A. Attanasi, R. Noto and D. Spinelli,
Società Chimica Italiana, 2014, pp. 141-213.
3. S. T. Keaveney, R. S. Haines and J. B. Harper, in Encyclopedia of
Physical Organic Chemistry, ed. U. Wille, Wiley, 2017.
4. C. Chiappe and D. Pieraccini, J. Phys. Org. Chem., 2005, 18, 275-
297.
5. C. Hussey L, Pure Appl. Chem., 1988, 60, 1763-1772.
6. H. M. Yau, A. K. Croft and J. B. Harper, Faraday Discuss., 2012,
154, 365-371.
7. H. M. Yau, A. G. Howe, J. M. Hook, A. K. Croft and J. B. Harper,
Org. Biomol. Chem., 2009, 7, 3572-3575.
8. E. E. L. Tanner, H. M. Yau, R. R. Hawker, A. K. Croft and J. B.
Harper, Org. Biomol. Chem., 2013, 11, 6170-6175.
9. H. M. Yau, S. J. Chan, S. R. D. George, J. M. Hook, A. K. Croft and
J. B. Harper, Molecules, 2009, 14, 2521-2534.
10. R. R. Hawker, J. Panchompoo, L. Aldous and J. B. Harper,
ChemPlusChem, 2016, 81, 574-583.
11. K. S. Schaffarczyk McHale, R. R. Hawker and J. B. Harper, New J.
Chem., 2016, 40, 7437-7444.
12. S. T. Keaveney, K. S. Schaffarczyk McHale, R. S. Haines and J. B.
Harper, Org. Biomol. Chem., 2014, 12, 7092-7099.
13. S. T. Keaveney, K. S. Schaffarczyk McHale, J. W. Stranger, B.
Ganbold, W. S. Price and J. B. Harper, ChemPhysChem, 2016, 17,
3853-3862.
14. S. G. Jones, H. M. Yau, E. Davies, J. M. Hook, T. G. A. Youngs, J.
B. Harper and A. K. Croft, Phys. Chem. Chem. Phys., 2010, 12,
1873-1878.
RRH acknowledges the Australian Government (Research
Training Program Scholarship). JBH acknowledges the
Australian Research Council (DP130102331, DP10103682) and
UNSW (Faculty Research Grant). The support of the NMR and
BMSF facilities (UNSW) and Dr Hank De Bruyn and Dr Natasha
Sciortino (Sydney, DSC and TGA) are gratefully acknowledged.
15. B. J. Butler and J. B. Harper, New J. Chem., 2015, 39, 213-219.
4 | J. Name., 2012, 00, 1-3
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