Ionic liquid effects on a multistep process. Increased product formation due to enhancement of all steps

Article abstract of DOI:10.1039/c5ob01214g

The reaction of a series of substituted benzaldehydes with hexylamine was examined in acetonitrile and an ionic liquid. In acetonitrile, as the electron withdrawing nature of the substituent increases, the overall addition-elimination process becomes fast

Full text of DOI:10.1039/c5ob01214g

Organic &
Biomolecular Chemistry
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Ionic liquid effects on a multistep process.
Increased product formation due to enhancement
of all steps†
Cite this: Org. Biomol. Chem., 2015,
13, 8925
Sinead T. Keaveney, Ronald S. Haines and Jason B. Harper*
The reaction of a series of substituted benzaldehydes with hexylamine was examined in acetonitrile and
an ionic liquid. In acetonitrile, as the electron withdrawing nature of the substituent increases, the overall
addition-elimination process becomes faster as does the build-up of the aminol intermediate. Under
equivalent conditions in an ionic liquid, less intermediate build up is observed, and the effect on the rate
on varying the substituent is different to that in acetonitrile. Extensive kinetic analysis shows that the ionic
liquid solvent increases the rate constant of all steps of the reaction, resulting in faster product formation
relative to acetonitrile; these effects increase with the proportion of ionic liquid in the reaction mixture.
Differences in the equilibrium position of the addition step in the ionic liquid were found to account for
both the decrease in intermediate build up relative to acetonitrile, as well as the differing trend in the
overall rate of product formation as the substituent was changed. The microscopic origins of these ionic
liquid effects were probed through temperature dependent analyses, highlighting the subtle balance of
interactions between the ionic liquid and species along the reaction coordinate, particularly the impor-
tance of charge development in the transition state.
Received 14th June 2015,
Accepted 17th July 2015
DOI: 10.1039/c5ob01214g
www.rsc.org/obc
perties obtained by simply varying the ion combination used;
this makes them promising candidates as designer solvents.10,11
Introduction
There is a continually growing library of synthetic procedures Further, it has been widely demonstrated that ionic liquids can
available to chemists allowing many chemical transformations affect reaction outcomes differently to organic solvents, with
to be performed, although many of these methods are not many reactions proceeding more readily and/or more selectively
without their drawbacks with a number of synthetic routes in ionic liquids.12–22 Despite this, the lack of understanding of
requiring elevated temperatures and prolonged periods of time these solvents is inhibiting their more widespread application,
to proceed. There are many different approaches to optimizing and hence a more thorough understanding of this reaction
a specific transformation, such as catalysis,1,2 and irradiation,3 medium is of interest to all chemists, so the full potential of
yet the use of solvents to control reaction outcome is an inter- ionic liquids can be realized.
esting alternative.4
There has been much experimental10,12 and computational
Ionic liquids, salts that are molten below 100 °C,5,6 have work23–27 that has sought to understand the microscopic
become of interest as solvents due to a number of attractive pro- origin of changes in the rate and the selectivity of organic pro-
perties, including low vapour pressure7–9 and low flammability,9 cesses in an ionic liquid, compared to molecular solvents. By
compared to traditional molecular solvents. The extensive range systematically examining a number of well-understood organic
of anions and cations available allows for tailor-made ionic processes, our group has been developing a set of principles
liquids to be prepared, with specific physical and chemical pro- that can be used to predict ionic liquid effects on organic reac-
tion outcomes;4,28–39 this work has mainly focused on the
effect of the solvent on reaction rate and product selectivity. In
much of this work, entropic effects have dominated the
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
changes in reaction outcome seen, with differences in
the extent to which the ionic liquid solvates the reagents and
the transition state driving the changes in reaction outcome
observed. The body of work that has emerged in this area over
recent years is beginning to shape our understanding of ionic
liquid solvent effects, and will allow ionic liquids to be chosen
E-mail: j.harper@unsw.edu.au; Fax: +61 2 9385 6141; Tel: +61 2 9385 4692
†Electronic supplementary information (ESI) available: Rate constant data on
which all the Hammett plots are based; additional Hammett plots, as referenced
in the text; mole fraction dependent rate constant data and plots for all systems
discussed, including the data on which the plots in Fig. 4 and 7 are based; temp-
erature dependent kinetic data from which the activation parameters shown in
Tables 2, 3, 5 and 8 are derived. See DOI: 10.1039/c5ob01214g
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and utilized more rationally in organic synthesis, although Another interesting approach is to investigate how Ka values of
there is still much more work that needs to be done.
species vary between molecular and ionic solvents.45–47 Pio-
One aspect that has yet to be thoroughly examined is the neering work in this area has appeared in recent years where
effect that changing a substituent on a reactant has on the the relationship between Ka values and the substituents elec-
ionic liquid solvent effects; that is, how the rate of a reaction tronic perturbing ability was investigated;47,48 the linear
changes as the electronic perturbing ability of the substituent relationship between pKa values and σp for a range of substi-
is varied, including whether a mechanism or rate-determining tuted benzoic acids in [Bmim][N(CF3SO2)2] 1 (and other ionic
step change occurs. In molecular solvents, since the pioneer- solvents)47 suggests that the existing substituent parameters
ing work of Hammett,40,41 substituent effects are generally well remain valid in ionic liquids. However, it has been proposed
understood; it is relatively ‘easy’ to predict the substituent that the ionic liquid cation is capable of enhancing the elec-
effects if there is a good understanding of the reaction mecha- tron withdrawing ability of substituents that have significant
nism, allowing specific substituents to be chosen to alter reac- resonance character,
a phenomenon known as Cation-
tion outcome in a desired manner.42,43 It is also well known Solvation-Assisted-Resonance.48 This highlights that it may be
that changing the solvent can alter the substituent effects,42,43 necessary to modify the extent to which the resonance and
hence it would be interesting to examine if this might be inductive character of a substituent contributes to the overall
exploited in ionic liquids as a different solvent may allow substituent parameters when using ionic liquids.
access to different substituent effects than those seen in
typical molecular solvents.
Previous work36,39 on the condensation of benzaldehyde 2a
and hexan-1-amine 3 (Scheme 1) found that there was an
There have been few previous studies that have examined increased rate constant for the rate-determining addition step
substituent effects in ionic liquids, with the two principal when using an ionic liquid instead of acetonitrile. It was
investigations focusing on the Menschutkin reaction.31,44 Both found that the critical interaction was between the ionic liquid
studies found that in molecular solvents the Hammett plot cation and the nitrogen lone pair on the nucleophile 3, as on
was non-linear due to a shift from a ‘tight’ or ‘closed’ tran- moving to the transition state there was an increase in disorder
sition state (i.e. the extent of bond formation and bond break- in the system, resulting in an entropically driven rate increase.
ing are comparable) for electron withdrawing groups to more
This manuscript describes efforts to extend this under-
of a ‘loose’ or ‘open’ transition state (i.e. the extent of bond standing and examines the effect of varying the para substitu-
breaking is greater than the extent of bond formation) for elec- ent on the electrophilic reagent (benzaldehydes 2a–f). This
tron donating groups. When using the ionic liquid 1-butyl-3- was carried out in order to examine the substituents effects of
methylimidazolium
bis(trifluoromethanesulfonyl)imide this two-step process to determine whether the fundamental
([Bmim][N(CF3SO2)2], 1) both investigations found that the understanding of substituent effects derived in molecular sol-
ionic liquid behaved in a similar fashion to molecular sol- vents can be applied in an ionic liquid. Consideration of the
vents, although the extent of bond breaking in the transition substituent effects was anticipated to also provide valuable
state, and hence positive charge development, was found to be insight into whether there are any changes in the reaction
greater in the ionic liquid.31,44
mechanism or rate-determining step between the different
solvent types, which will contribute to the developing under-
standing of ionic liquid solvent effects.
Initially described are the outcome of the reactions in aceto-
nitrile, and then in mixtures of the commonly used ionic
Scheme 1 The condensation of benzaldehydes 2 with the amine 3, which first undergoes addition to give the intermediate aminols 4 and then
eliminates water to give the product imines 5.
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liquid [Bmim][N(CF3SO2)2] 1 in acetonitrile to determine if the
substituent effects are dependent on the proportion of ionic
liquid in the reaction mixture. It is also of particular interest to
examine the effect of the ionic liquid 1 on the elimination
step, as this was not able to be determined previously.36,39 The
ionic liquid solvent effects on elimination processes are not
yet completely understood, with only a few examples in the
literature.21,28,49–52 Hence, a thorough investigation of the
effect of the ionic liquid on the outcome of the elimination
process is an additional point of interest.
Scheme 2 Mechanism to which the kinetic data was numerically inte-
grated in cases where intermediate build-up was detected.
dividing by the initial amine 3 concentration in the reaction
mixture. Where appropriate, the activation parameters were
then determined through fitting the obtained data using the
Microsoft Excel 14.4.3 LINEST function to the bimolecular
Eyring equation31,55 (eqn (1)).
Experimental
ꢀ
ꢁ
k2;A
kBRT2
h
ΔS‡ ΔH‡
ln
¼
ꢀ
ð1Þ
R
RT
Benzaldehydes 2a–f and hexan-1-amine 3 were all commer-
cially available, and were either distilled (species 2a–c, 2e and
3) or sublimed (species 2d and 2f) under reduced pressure
then stored at 253 K prior to use. Analytical grade deuterated
acetonitrile was dried over molecular sieves for at least 48 h
before use. The ionic liquid 1 was prepared according to litera-
ture methods:53,54 1-methylimiazole was treated with butyl
bromide to afford the intermediate bromide salt ([Bmim][Br]),
followed by salt metathesis with lithium bis(trifluoromethane-
sulfonyl)imide to give [Bmim][N(CF3SO2)2] 1. The ionic liquid
1 was dried to constant weight at 70 °C under reduced pressure
immediately before use, and was found to have <0.1% water
using Karl Fischer titration methodology and contained
<0.1 mol% residual halide by ion chromatography.
For aldehydes 2d–f, where intermediate build-up was
detected, integrations of the aldehyde signal in the starting
material 2 at δ ca. 10, the corresponding proton in the inter-
mediate 4 at δ ca. 5 and the imine proton in the product 5 at
δ ca. 8.5 were obtained from the processed 1H NMR spectra.
This data was then numerically integrated (fourth-order
Runge-Kutta) to fit the mechanism outlined in Scheme 2 using
the SOLVE function in Microsoft Excel 14.4.3 to optimize the
rate constants. This allowed determination of the unimolecu-
lar rate constants for the elimination step (k1,E) and the reverse
of the addition process (k−1,A), and the pseudo-first order rate
constant for the (forward) addition step (k1,A) which was then
converted to the bimolecular rate constant (k2,A) by dividing by
the initial amine 3 concentration in the reaction mixture. For
the elimination step the activation parameters were deter-
mined using the unimolecular Eyring equation (eqn (2)).55
Reaction progress was monitored using 1H NMR spectro-
scopy on either a Bruker Avance III 400, Bruker Avance III 500
or Bruker Avance III 600 spectrometer with either a BBFO or
TBI probe using ca. 0.5 mL of reaction mixture (details below)
in a 5 mm NMR tube. Results were shown to be reproducible
between the different spectrometers.
ꢀ
ꢁ
k1;E
kBT
h
ΔS‡ ΔH‡
ln
¼
ꢀ
ð2Þ
R
RT
Kinetic analyses were carried out in solutions containing
the benzaldehyde 2 of interest (ca. 0.02 mol L−1) and the
amine 3 (ca. 0.25 mol L−1) at a given temperature and specific
mole fraction of the ionic liquid, with the remaining solvent
being made up by deuterated acetonitrile. NMR samples con-
taining both the benzaldehyde 2 and amine 3 and the solvent
mixture were prepared, and these samples were stored in
liquid nitrogen to halt the reaction prior to analysis.
Tables containing the exact mole fractions of ionic liquid 1
used in the reaction mixture, amine 3 concentrations, temp-
erature and rate constants for all the systems described below
can be found in the ESI.†
Results and discussion
In each case the reaction was monitored in situ until more
than 95% of the benzaldehyde 2 was consumed, with the Before discussing the effects of substituents on the electro-
spectrometer set to the desired temperature for the duration of phile on the reaction shown in Scheme 1, it is necessary to
the reaction, and all kinetic analyses were performed in tripli- discuss how the mechanism of the reaction influences analysis
cate. NMR spectra were processed using either the Bruker of the kinetic data. The condensation of each of the benzal-
TOPSPIN 1.3 software or the MestReNova 7.1.1 software. For dehydes 2a–f with the amine 3 proceeds through an addition-
the 4-methylbenzaldehyde 2b cases, where no intermediate elimination mechanism (Scheme 1); there is initial nucleo-
build up was detected, the pseudo-first order rate constants for philic attack of the amine 3 onto the carbonyl of the benz-
the reactions were calculated using integrations of the alde- aldehyde 2 and proton transfer to give the intermediate
hyde signal in the starting material 2 at δ ca. 10.0, obtained aminol 4; this has been found to proceed either via a con-
1
from the processed H NMR spectra, by fitting the natural log- certed mechanism in the gas phase,56 or through a stepwise
arithm of the integrations to a linear function using the Micro- process in aqueous solutions.57 When performed in organic
soft Excel 14.4.3 LINEST function. Bimolecular rate constants solvents, experimental work suggests that there is significant
(k2,A) were obtained from the pseudo-first order constants by charge development in the transition state, which is consistent
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with either the concerted or stepwise mechanism.58 This and the nucleophilic nitrogen centre on the amine 3. It is
addition step is then followed by the subsequent elimination important to note that the cation–nucleophile interaction also
of water from the aminol 4 to give the product 5. The apparent resulted in an enthalpic cost relative to the reaction in aceto-
bimolecular rate constant (k2,app) for this two step process nitrile, yet the entropic benefit was more significant. In that
(that is, the rate constant of product formation) will depend on work it was only possible to examine the addition process, as
the rate constant of both the addition (k2,A) and elimination the elimination step was significantly faster than addition.
(k1,E) processes, as well the rate constant for the reverse of the Hence it was of interest to investigate the aldehydes 2b and
addition process (k−1,A), as shown in eqn (3).
2d–f, firstly to examine the substituent effects on the process
in acetonitrile and the ionic liquid 1, as well as a number of mix-
tures of acetonitrile and [Bmim][N(CF3SO2)2] 1 and, secondly, to
attempt to monitor the second step of the reaction to allow the
effects of the ionic liquid 1 on the elimination process to be
examined. It was anticipated that increasing the electron with-
drawing ability of the para substituent (σp) would further remove
electron density from the electrophilic carbon, activating it and
hence increasing k2,A. It was hoped that this increase in the rate
constant of the addition step would result in k2,A no longer being
significantly smaller than k1,E, leading to intermediate build-up
and hence allowing k1,E to be determined.
Initially the reaction between the benzaldehydes 2 and
hexan-1-amine 3 was monitored in acetonitrile; unsurprisingly
for the methyl substituted aldehyde 2b, which has a substitu-
ent with a σp value intermediate to that of the substituents on
substrates 2a and 2c, no intermediate build up was observed.
Interestingly, for aldehydes 2d–f, containing an electron with-
drawing group, significant build up of the intermediate
aminol 4 was observed, allowing k2,A, k−1,A and k1,E to be deter-
mined (Table 1); importantly, for these cases k−1,A was found
to be non-negligible when compared to k1,E. Firstly the substi-
tuent effects of the addition step will be discussed, and then
the importance of k−1,A for the different substituents will be
considered further.
k2;A ꢁ k1;E
k2;app
¼
ð3Þ
k
ꢀ1;A þ k1;E
Previous work on the unsubstituted36 and methoxy substi-
tuted36,39 benzaldehydes 2c and 2a, respectively, found that for
all the cases considered (different temperatures and different
proportions of acetonitrile in a number ionic liquids) no build
up of the intermediate 4 was ever detected. This indicated that
the elimination step was significantly faster than the addition
step, and hence that the addition step was rate-determining.
This was unsurprising for these aldehydes as they bear an elec-
tron-donating group, which will deactivate them towards
nucleophilic attack.
This previous work made an assumption that the bulk of
any aminol 4 formed was converted to product 5 rather than
reverting to starting material 2; that is k−1,A ≪ k1,E. This
assumption was supported by the fact that for all systems con-
sidered (more than 25 solvent mixtures of 10 different ionic
liquids) the apparent rate constant (k2,app) data produced
linear Eyring plots. This could be due to the value k−1,A/k1,E
being constant over the range of temperatures considered, and
hence both the reverse addition and elimination processes have
the same activation parameters in all solvent systems though it
is considered that this is unlikely. Alternatively, a linear Eyring
plot suggests that k−1,A is negligible compared to k1,E and that
therefore k2,app = k2,A for aldehydes 2a and 2c (see eqn (3)). The
validity of this assumption will be further reinforced in the sub-
sequent discussions on the Hammett relationships.
As the data in Table 1 shows, as the σp value of the substitu-
ent on the aldehyde substrate 2 was increased, there was an
increase in the rate constant of the addition step (k2,A). The
Hammett plot of k2,A (Fig. 1) is linear (R2 = 0.985), with gradi-
ent (or reaction constant, ρ) = 2.92 0.09 indicating that this
addition step is very susceptible to the electronic nature of the
substituent. Such a large and positive ρ value suggests that
there is a flow of electrons towards the aromatic ring when
One of the main conclusions from the previous investi-
gations on benzaldehydes 2a36,39 and 2c36 was that the use of
an ionic liquid accelerated the reaction due to an entropically
favourable interaction between the cation of the ionic liquid
Table 1 The rate constants for the reaction between the substituted benzaldehydes 2 and hexan-1-amine 3 in acetonitrile at 281 K for the addition
step (k2,A) and, where possible, for the reverse addition process (k−1,A), the addition equilibrium position (KA), elimination rate constant (k1,E) and the
overall rate constant of reaction (k2,app = (k2,A × k1,E)/(k−1,A + k1,E)). Uncertainties quoted represent the standard deviation of three replicates
Substituent
k2,A/10−3 L mol−1 s−1
k−1,A/10−3 s−1
KA/L mol−1
k1,E/10−3 s−1
k2,app/10−3 L mol−1 s−1
a
a
b
a
a
b
a
a
2a R = MeO36,39
2b R = Mea
2c R = H36
2d R = Cl
2e R = CF3
2f R = NO2
0.13 0.02
0.27 0.03
0.75 0.06b
6.74 0.03
33.0 0.9
98.6 5.4
0.13 0.02
0.27 0.03
0.75 0.06
1.26 0.12
2.26 0.21
3.23 0.35
7.51 0.07b
1.73 0.10
0.60 0.05
0.24 0.03
7.51 0.11
8.21 0.23
7.03 0.67
0.9 0.1
4.0 0.2
11.7 1.2
a As the addition step was rate determining, no formation of the intermediate was detected using NMR spectroscopy so only k2,A could be
b
determined. k1,E could be determined using a greatly increased nucleophile concentration ([3] = 2.5 mol L−1), yet under these conditions k2,A
was too fast to be accurately measured and hence k−1,A and KA were unable to be determined. k2,A was determined from a different set of
experiments using a lower nucleophile concentration.
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Table 2 The activation parameters for the addition step in the reaction
of each of the aldehydes 2a, 2c and 2d in acetonitrile
Substrate
σp
ΔH‡ a/kJ mol−1
ΔS‡ a/J K−1 mol−1
2a R = MeO36
2c R = H36
2d R = Cl
−0.27
0
0.24
14.2 1.0
27.2 2.5
46.4 3.7
−333.1 3.3
−272.1 8.6
−185.2 13.3
a Uncertainties quoted are from the fit of the linear regression.
hyde 2 there was an increase in both the enthalpy and entropy
of activation, with the increased entropy being more signifi-
cant, leading to an overall reduction in the activation energy.
This resulted in an increase in k2,A as the electron withdrawing
nature of the substituent was increased (see Table 1 and
Fig. 1).
Fig. 1 Hammett plot of the second order rate constant for the addition
step (k2,A) of the reaction between benzaldehydes 2a–f and the amine 3
in acetonitrile at 281 K. Uncertainties are reported as the standard devi-
ation of three replicates.
The increased enthalpy of activation with larger σp suggests
that as the electron-withdrawing ability of the substituent on
the aldehyde 2 increases, the extent to which bonds are broken
in the transition state increases. All of this is consistent with
the transition state lying later along the reaction coordinate as
σp increases. This is accompanied by an increase in the
degrees of freedom in the transition state, as indicated by the
less negative entropy of activation moving down Table 2.
The substituent effects on the addition step have been
thoroughly discussed, so it is now of interest to examine the
substituent effects on the elimination step; note that k1,E was
only able to be determined for aldehydes 2c–f. As the electron
withdrawing ability of the substituent on the substrate 2 was
increased the elimination rate constant (k1,E) decreased, with
the Hammett plot of k1,E (Fig. 2) being linear (R2 = 0.984) with
ρ = −1.88 0.08. A negative ρ value suggests that on transition
state formation there is a flow of electrons away from the aro-
matic ring, the opposite to what is seen for the addition step,
and is consistent with positive change build up, with the
ρ value comparable to that found for the hydrolysis of
acetals.61 It is also important to note that the magnitude of
ρ is smaller for the elimination step than for the addition step,
indicating that the elimination process is less affected by the
substituents’ electronic character than the addition case.
To determine the origin of these changes in the elimination
rate constant, the activation parameters of the elimination
process were determined for the chloro 2d, trifluoromethyl 2e
and nitro 2f cases (Table 3). Interestingly the activation para-
meters for the trifluoromethyl 2e and nitro 2f cases were the
same within uncertainty, while the activation parameters for
the chloro 2d case were markedly different; although generally
as the σp of the substituent increased, both the enthalpy and
entropy of activation decreased. This data shows that for this
unimolecular process, the rate decrease in the elimination
step on going from substrate 2d to 2e to 2f is due to a decrease
in the entropy of activation. This trend is consistent with the
transition state lying earlier along the reaction coordinate as σp
increases, resulting in a decreased extent of bond breaking
with larger σp.
moving to the transition state. This trend is exactly as would
be expected for this reaction type, and is consistent with
related nucleophilic additions to carbonyl groups.59,60 It
should be noted that it is feasible to separately fit the rate con-
stants for σp ≤ 0 and σp > 0, and this results in large, positive
ρ values for both fits (ρ = 3.19 0.12 and ρ = 2.17 0.06,
respectively, Fig. S9†). A decreased reaction constant at higher
σp could suggest that there is a shift from an open transition
state for σp ≤ 0 to a more closed transition state for σp > 0.
The linearity of the fit in Fig. 1 is particularly important in
the context of the earlier discussion suggesting that for alde-
hydes bearing an electron donating group k−1,A ≪ k1,E. The
data in Table 1 and Fig. 1 assumes that k−1,A is negligible for
aldehydes 2a–c where σp ≤ 0, but not for aldehydes 2d–f with
σp > 0 where intermediate build up was readily observed; the
values of k−1,A for these cases were determined from fitting as
described in the Experimental section. This linear correlation
yielding a ρ value as would be expected further reinforces the
validity of the assumptions made, and indicates that for sub-
strates bearing a para substituent with σp ≤ 0, k−1,A is not kine-
tically significant, and that for electron withdrawing
substituents the value of k−1,A becomes kinetically significant.
It is also important to highlight that during the fitting it was
noted that k1,E was not sensitive to the values of k−1,A, hence
the assumptions discussed above are only relevant for k2,A
.
It is also of interest to examine the activation parameters of
the addition step in acetonitrile, as these values will be com-
pared to those determined in the ionic liquid 1 subsequently
to determine the origin of any ionic liquid solvent effect. The
activation parameters for the chloro substrate 2d were deter-
mined as an exemplar electron-withdrawing case to compare
with the parent 2c and methoxy 2a aldehydes (Table 2).‡ It was
found that with increasing σp of the substituent on the alde-
‡Attempts were made to determine the activation parameters for the substrates
2e and 2f, but due to the magnitude of k2,A for these cases the subtle changes in
the rate constant with changing temperature were not sufficiently large to allow
activation parameters to be accurately determined.
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Fig. 3 Hammett plot of the apparent second order rate constant
(k2,app) for the reaction between the benzaldehydes 2a–f and the amine
3 in acetonitrile at 281 K. Uncertainties are reported as the standard
deviation of three replicates.
Fig. 2 Hammett plot of the first order rate constant for the elimination
step (k1,E) of the reaction between benzaldehydes 2c–f and the amine 3
in acetonitrile at 281 K. Uncertainties are reported as the standard devi-
ation of three replicates.
In summary, in acetonitrile the substituent effects on reac-
tion outcome are relatively straightforward: increasing the elec-
tron withdrawing ability of the substituent increases the rate
constant for the addition step with a concomitant decrease in
the rate constant for the elimination process. This increase in
k2,A, and the decrease in k1,E, results in a change in the rate
determining step from addition to elimination as the electron
withdrawing nature of the substituents increases.
Table 3 The activation parameters for the elimination step in the reac-
tion of each of the aldehydes 2d–f in acetonitrile
Substrate
σp
ΔH‡ a/kJ mol−1
ΔS‡ a/J K−1 mol−1
2d R = Cl
2e R = CF3
2f R = NO2
0.24
0.53
0.78
90.3 6.7
54.7 3.5
51.5 2.8
21.2 24.1
−111.8 12.2
−130.1 9.6
a Uncertainties quoted are from the fit of the linear regression.
Given the above, it is of interest to investigate how the ionic
liquid 1 would affect the substituent effects observed in aceto-
nitrile. For all the benzaldehydes 2a–f the reaction was con-
ducted in a range of mole fractions of [Bmim][N(CF3SO2)2] 1 in
acetonitrile.
Firstly the effect of the ionic liquid 1 on the addition step
will be considered; as mentioned earlier previous work on the
electron-donating aldehydes 2a and 2c found that as the pro-
It is also interesting to note that as the electron
withdrawing ability of the substituent increased (on going
from chloro to trifluoromethyl to nitro) there was a shift in
the equilibrium position of the addition process (KA, Table 1).
As a result, despite the decreased elimination rate constant,
the overall rate constant of the process (k2,app) still increases as
the electron-withdrawing ability of the substituent was
increased.
portion of an ionic liquid in the solvent mixture was increased
36,39
there was a steady increase in k2,A
.
In those cases, the rate
enhancement in the ionic liquid 1 was shown to be the result
of an entropic benefit overcoming an enthalpic cost; this
enthalpic cost corresponds to coordination and stabilisation of
the nucleophile 3 by the cation of the ionic liquid (this can
also be thought of as a decrease in the apparent nucleophili-
city of hexan-1-amine 3 in [Bmim][N(CF3SO2)2] 1 relative to
acetonitrile). On moving to the transition state, where the
nucleophilic centre on 3 is no longer available to coordinate
with the ionic liquid cation, there was an increase in disorder
in the system resulting in a substantial entropic benefit relative
to acetonitrile. For all substrates 2b and 2d–f as the amount of
[Bmim][N(CF3SO2)2] 1 in the reaction mixture was increased
there was a gradual increase in k2,A, as expected (Table 4,
Fig. S2 and S5† for substrates 2d and 2e, respectively, and
Fig. 4 and S1† for substrates 2f and 2b, respectively, where k2,A
was determined at a number of different values of χIL). It is
important to note the characteristic ‘dip’ in the mole fraction
plot at χIL ca. 0.4, this has appeared many times in our pre-
vious work,28,36,39 and the source of this decrease in the rate
constant at a particular proportion of ionic liquid is still under
This last point is best demonstrated by the Hammett plot
of the apparent second order rate constant (k2,app) for the
overall process (Fig. 3); that is, k2,A for aldehydes 2a–c and k2,A
× k1,E/(k−1,A + k1,E) for species 2d–f (eqn (3)). Clearly, with
increased σp there is an increase in k2,app, indicating that as
the electron-withdrawing nature of the substituent increases
there is increased formation of the imine 5. Immediately
apparent is that the Hammett plot is not linear but instead
has decreasing slope with increasing σp; this is clearly demon-
strated by the large change in ρ from ca. 3 at low values of σp
to ca. 0.5 at the higher values of σp. This downwards curvature
of a Hammett plot is consistent with a change in the rate-
determining step of the process,42,59 which can also be clearly
seen by the rate constants presented in Table 1 where the rate-
determining step is addition for low σp and elimination for
high σp. Further, it indicates a much greater dependence on
the electronic nature of the substituent for the process that is
rate determining at low values of σp than for the rate-determin-
ing step at high values of σp, as discussed earlier.
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Table 4 The rate constant for the addition step (k2,A) for the reaction
between the substituted benzaldehydes 2 and hexan-1-amine 3, in
acetonitrile and at representative mole fractions of [Bmim][N(CF3SO2)2] 1
in acetonitrile at 281 K
k2,A a/10−3 L mol−1 s−1
Substituent
Acetonitrile
χIL 0.2
χIL 0.9
2a R = MeO39
2b R = Me
2c R = H36
2d R = Cl
2e R = CF3
2f R = NO2
0.13 0.02
0.27 0.03
0.75 0.06
6.74 0.03
33.0 0.9
98.6 5.4
0.49 0.02
1.46 0.06
2.74 0.03
32.9 1.5
93.1 1.6
130 16
0.81 0.04
2.83 0.01
4.86 0.04
37.4 1.9
136
3
250 10
Fig. 5 Hammett plot (using one linear fit) of the second order rate con-
stant for the addition step (k2,A) of the reaction between benzaldehydes
2a–f and the amine 3 in [Bmim][N(CF3SO2)2] 1/acetonitrile (χIL ca. 0.2) at
281 K. Uncertainties are reported as the standard deviation of three
replicates.
a Uncertainties quoted represent the standard deviation of three
replicates.
Fig. 4 The bimolecular rate constant for the addition step (k2,A
)
between 4-nitrobenzaldehyde 2f and the amine 3 in different mole frac-
tions of [Bmim][N(CF3SO2)2] 1 in acetonitrile at 281 K. Uncertainties are
reported as the standard deviation of three replicates.
Fig. 6 Hammett plot (using two linear fits) of the second order rate
constant for the addition step (k2,A) of the reaction between benzal-
dehydes 2a–f and the amine 3 in [Bmim][N(CF3SO2)2] 1/acetonitrile
(χIL ca. 0.2) at 281 K. Uncertainties are reported as the standard deviation
of three replicates.
investigation. Importantly, for all substrates considered use of
the ionic liquid 1 increases the rate constant of the addition
step relative to acetonitrile, highlighting the utility of ionic
liquids in promoting nucleophilic attack of a nitrogen centre
onto a carbonyl group.
electron withdrawing substituents; this is consistent with pre-
vious studies.19,31
As the data in Table 4 shows, as the σp value of the substitu-
ent on the aldehyde substrate was increased there was an
increase in the rate constant of the addition step (k2,A). The
Hammett plot of k2,A at χIL ca. 0.2 (Fig. 5) is linear (R2 = 0.937),
with ρ = 2.43 0.16, as is the Hammett plot at χIL ca. 0.9
(Fig. S10†) with R2 = 0.967 and ρ = 2.41 0.12. For these cases
the linear correlation is not as strong as that seen in aceto-
nitrile, and hence it is reasonable to consider two separate
linear correlations for σp ≤ 0 and σp > 0; at χIL ca. 0.2 ρ = 2.77
0.19 for σp ≤ 0, and ρ = 1.11 0.11 for σp > 0 (Fig. 6), with a
similar trend seen at χIL ca. 0.9 (Fig. S11†). For both mole frac-
tions of [Bmim][N(CF3SO2)2] 1 in acetonitrile the magnitude of
ρ is greater for σp ≤ 0 than σp > 0, suggesting that the reaction
is more susceptible to electronic effects for electron donating
substituents. Such a trend is indicative of a shift from an open
transition state for σp ≤ 0 to a more closed transition state for
Regardless of whether one or two linear fits are used, large,
positive ρ values result, indicating that once again there is elec-
tron flow towards the aromatic system on moving to the tran-
sition state, and that while the addition step is very susceptible
to the electronic nature of the substituent when in the ionic
liquid 1, it is slightly less effected by the substituent than
when in acetonitrile (where ρ = 2.92 0.09). In order to investi-
gate this further the activation parameters for the different
substituents in acetonitrile and in the ionic liquid 1 (χIL
ca. 0.2) need to be compared (Table 5).
As Table 5 shows, as σp increases the magnitude of the
enthalpic cost when moving from acetonitrile to χIL 0.2
decreases; that is, the difference between the enthalpy of acti-
vation in acetonitrile and χIL 0.2 is largest for the methoxy sub-
strate 2a, and is smallest for the chloro case 2d. The same
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Table 5 The activation parameters for the addition step in the reaction
of the aldehydes 2a, 2c and 2d, and the amine 3 in acetonitrile and in
[Bmim][N(CF3SO2)2] 1/acetonitrile (χIL ca. 0.2)
Table 7 The rate constant for the elimination step (k1,E) for the reaction
between the substituted benzaldehydes 2 and hexan-1-amine 3, in
acetonitrile and
a selected number of mole fractions of [Bmim]-
[N(CF3SO2)2] 1 in acetonitrile at 281 K
Substrate
χIL
ΔH‡ a/kJ mol−1
ΔS‡ a/J K−1 mol−1
k1,E a/10−3 s−1
2a R = MeO36,39
2c R = H36
2d R = Cl
0
0.22
0
0.22
0
0.22
14.2 1.0
37.0 0.9
27.2 2.5
34.5 1.5
46.4 3.7
47.5 3.0
−333.1 3.3
−242.1 3.1
−272.1 8.6
−233.2 1.7
−185.2 13.3
−168.1 11.1
k1,E (χIL 0.9)/k1,E
Substituent Acetonitrile χIL 0.2
χIL 0.9
(acetonitrile)b
2d R = Cl
2e R = CF3
2f R = NO2
1.73 0.10
0.60 0.05
0.24 0.03
1.99 0.03 1.73 0.18 1.00 0.12
1.38 0.05 2.62 0.14 4.34 0.10
0.71 0.08 1.27 0.06 5.31 0.15
a Uncertainties quoted are from the fit of the linear regression.
a Uncertainties quoted represent the standard deviation of three
replicates. b Uncertainties quoted are compounded from those
previous in the table.
Table 6 The difference in the activation parameters for the addition
step in the reaction of the aldehydes 2a, 2c and 2d and the amine 3
moving from acetonitrile to χIL ca. 0.2 of [Bmim][N(CF3SO2)2] 1
of ionic liquid in the reaction mixture was increased (Table 7,
Fig. S3 and S6† for substrates 2d and 2e, respectively, and
Fig. 7 for substrate 2f where k1,E was determined at a number
of different values of χIL). Interestingly, this data shows that
the magnitude of the rate enhancement seen when using the
ionic liquid 1, relative to acetonitrile, increases as the electron-
withdrawing ability of the substituent is increased.
χIL 0 → 0.2
Substrate
Δ(ΔH‡)a/kJ mol−1
Δ (ΔS‡)a/J K−1 mol−1
2a R = MeO36,39
2c R = H36
2d R = Cl
22.8 1.4
7.3 2.6
1.2 4.8
91.0 4.5
38.9 8.8
17.1 17.4
In order to understand the microscopic origin of the
changes in k1,E seen when using [Bmim][N(CF3SO2)2] 1 in the
reaction mixture, the activation parameters of the elimination
process were determined in a number of mixtures of [Bmim]-
[N(CF3SO2)2] 1 and acetonitrile for aldehydes 2d–f (Table 8).
For each case the activation parameters were determined in
acetonitrile (as discussed earlier) and at χIL ca. 0.2 to allow
comparison between the different substrates, with additional
activation parameters determined for the trifluoromethyl 2e
and nitro 2f cases to determine whether the activation para-
meters varied as the mole fraction of ionic liquid in the
solvent mixture was changed.
a Uncertainties quoted are compounded from those reported in
Table 5.
trend is also seen for the entropy of activation; this is shown
clearly in Table 6.
It is unlikely that on changing the substituent on the benz-
aldehyde 2 that the extent of interaction between the cation of
the ionic liquid and the amine 3 would change, hence it is
likely that these changes in activation parameters are the
result of differences in the solvation of the transition state.
This can be best explained by recalling what was discussed
earlier for the addition step in acetonitrile: as σp increased
both the enthalpy and entropy of activation increased and a
later transition state was suggested. Such a change would also
result in a greater build-up of charge (both on the oxygen and
nitrogen centres) and hence a greater extent of interaction
between the ionic liquid 1 and the transition state. The ener-
getic result of such an interaction would be to decrease the
enthalpy (benefit) and entropy of activation (cost) relative to
acetonitrile; the opposite of the energetic result of cation–
nucleophile 3 interaction. Therefore, increasing ionic liquid–
transition state interaction would result in a greater ‘offsetting’
of the enthalpic cost and entropic benefit from the cation–
nucleophile interaction, bringing the activation parameters for
the ionic liquid 1 and acetonitrile closer together. This is
clearly demonstrated in Table 6.
Immediately apparent is that the use of the ionic liquid 1
resulted in an increase in both the enthalpy and entropy of
activation for the elimination step in the reaction of benzal-
dehydes 2e and 2f with the amine 3, relative to acetonitrile.
Another important consideration is the effect of use of an
ionic liquid on the rate constant for the elimination step; for
the chloro substrate 2d the rate constant was essentially
unaffected by use of [Bmim][N(CF3SO2)2] 1 while for substrates
2e and 2f there is a gradual increase in k1,E as the proportion
Fig. 7 The unimolecular rate constant for the elimination step (k1,E
)
between 4-nitrobenzaldehyde 2f and the amine 3 in different mole frac-
tions of [Bmim][N(CF3SO2)2] 1 in acetonitrile at 281 K. Uncertainties are
reported as the standard deviation of three replicates.
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Table 8 The activation parameters for the elimination step (k1,E) in the
reaction between the substituted benzaldehydes 2 and hexan-1-amine 3
in acetonitrile, and mixtures of [Bmim][N(CF3SO2)2] 1 in acetonitrile
Table 9 The rate constant for the reverse addition step (k−1,A) for the
reaction between the substituted benzaldehydes 2 and hexan-1-amine
3, in acetonitrile and a selected number of mole fractions of [Bmim]-
[N(CF3SO2)2] 1 in acetonitrile at 281 K
Substituent
2d R = Cl
χIL
ΔH‡ a/kJ mol−1
ΔS‡ a/J K−1 mol−1
k−1,A a/10−3 s−1
0
0.22
0
90.3 6.7
71.8 2.1
54.7 3.5
70.5 4.1
67. 2 2.1
55.2 4.3
72.6 3.0
84.8 2.6
87.6 4.4
21.2 24.1
−40.5 7.6
−111.8 12.2
−48.6 14.9
−55.5 7.7
−117.2 14.9
-51.8 11.0
−6.1 9.0
Substituent
Acetonitrile
χIL 0.2
χIL 0.9
2e R = CF3
0.21
0.95
0
2d R = Cl
2e R = CF3
2f R = NO2
7.51 0.11
8.21 0.23
7.03 0.67
39.2 0.6
24.7 0.4
10.2 2.2
38.5 0.2
33.0 0.6
28.9 1.6
2f R = NO2
0.06
0.22
0.88b
a Uncertainties quoted represent the standard deviation of three
replicates.
11.4 16.2
a Uncertainties quoted are from the fit of the linear regression. b The
substrate 2f was not completely soluble in 1, so a small amount of
acetonitrile was used to aid solubility resulting in a slightly decreased χIL.
ment in the transition state will dictate which interaction is
dominant. The importance of considering the subtle balance
of the different interactions between the ionic liquid and
species along the reaction coordinate has been highlighted in
a number of different studies,12 and further demonstrates the
complexity of ionic liquid solvent effects, along with rein-
forcing the importance of gaining a thorough understanding
of this reaction media so that their effect on reaction outcome
can be readily predicted.
Finally, for the elimination process it is also important to
compare the Hammett plots in acetonitrile and the ionic
liquid 1; in the ionic liquid 1 the log plot§ was linear at χIL 0.2,
with gradient = −0.83 0.08 (R2 = 0.955, Fig. S12†). This shows
that: (1) build-up of positive charge in the transition state is
key as was seen in acetonitrile, and (2) the magnitude of the
slope is significantly smaller in the ionic liquid 1 than in
acetonitrile. This suggests that the charge development in the
transition state is decreased in the ionic liquid and hence k1,E
is less susceptible to the electronic nature of the substituent
when using the ionic liquid 5. At a higher mole fraction (χIL
0.9, Fig. S13†), the equivalent log plot was no longer linear;
this is likely due to the very different ionic liquid–transition
state interactions for the different substrates 2d–f, as discussed
above.
For the electron-withdrawing cases the rate constants for
the reverse of the addition step (k−1,A) were able to be deter-
mined (Table 9, and Fig. S4 and S7† for substrates 2d and 2e,
respectively, and Fig. S8† for substrate 2f where k−1,A was deter-
mined at a number of different values of χIL), showing that use
of the ionic liquid 1 also increased the rate constant of this
process relative to acetonitrile. Importantly, while k−1,A
remained relatively unchanged for substrates 2d–f in aceto-
nitrile, when in the ionic liquid 1 there was a gradual decrease
in k−1,A as σp increases.
Such a trend is indicative of the ionic liquid 1 ordering about
and stabilising the species 4 to a greater extent than the tran-
sition state leading to the product 5. Based on previous studies
that suggest that interaction between an ionic liquid cation
and a nitrogen lone pair is important,28,31,33,35,36,38,39 it is
reasonable to assume that the main interaction here is once
again between the cation and the nitrogen lone pair on the
aminol 4. Such an interaction would inhibit bond formation,
resulting in an increased enthalpy of activation relative to
acetonitrile. Once again the entropic benefit incurred when
using the ionic liquid 1 is more significant than the enthalpic
cost, resulting in an entropically driven rate enhancement; this
further reinforces the importance of entropic effects when
using ionic liquids. This conclusion is supported by kinetic
studies on the base-induced, bimolecular elimination of a
benzisoxazole,
a nitrogen-containing substrate, where a
similar trend in the activation parameters was found when
using an ionic liquid.52
Interestingly, for the chloro substrate 2d there was the
opposite trend in the activation parameters for the elimination
step seen when using the ionic liquid 1; that is, a decrease in
both the enthalpy and entropy of activation relative to aceto-
nitrile. This can be readily rationalised by considering the
earlier conclusion that the transition state of the chloro ana-
logue 4d involves significantly more bond breaking and charge
development than the trifluoromethyl and nitro cases. With
greater charge separation there will be increased ionic liquid–
transition state interaction, which would stabilise the tran-
sition state and be enthalpically favourable, yet the increased
ordering would introduce an entropic cost. Hence, for the
chloro case 4d, which involves significant build-up of charge
in the transition state, it can be concluded that the extent of
ionic liquid–transition state interaction is greater than the
cation–nucleophile interaction, leading to the energetic result
of the transition state interaction being dominant.
While data for the substrate 2c is not available, a plot of the
log of the rate data§ is linear, with gradient = −1.08 0.12
§As the rate constant for the unsubstituted case was not available, a ‘true’
Hammett plot could not be obtained. However, a plot of the log of the rate con-
stants for the other species has a slope corresponding to the reaction constant
so can be used for comparison.
It is important to note that for all substrates 2d–f it is likely
that there will be both cation–aminol 4 and ionic liquid–tran-
sition state interaction, and that the extent of charge develop-
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(R2 = 0.951, Fig. S14†) at χIL 0.2, and gradient = −0.53 0.05
(R2 = 0.947, Fig. S15†) at χIL 0.9. A negative value for the gradi-
ent suggests that on transition state formation there is a flow
of electrons away from the aromatic ring. Interestingly, the
magnitude of the slope decreases when moving from χIL 0.2 to
0.9, suggesting that with increasing amounts of the ionic
liquid 1 in the reaction mixture k−1,A is less affected by the
electron-withdrawing ability of the substituent. The impli-
cations of this change in k−1,A will be discussed in the context
of k2,app below.
To conclude this work, it is now essential to see how the
overall rate constant for the process (k2,app) changed when
moving between acetonitrile and [Bmim][N(CF3SO2)2] 1, and to
compare the Hammett plot of k2,app in acetonitrile and mix-
tures of acetonitrile and [Bmim][N(CF3SO2)2] 1. As the amount
of the ionic liquid 1 in the reaction mixture was increased,
there was a gradual increase in k2,app for all substrates 2a–f
(Table 10). In other words, for all of the benzaldehydes 2a–f
the use of the ionic liquid 1 resulted in an increase in the rate
of imine formation relative to acetonitrile. This is significant
as it further demonstrates the ability of ionic liquids to accele-
rate organic reactions, and highlights the utility of using an
ionic liquid solvent to promote imine formation.
Interestingly, in mixtures containing the ionic liquid 1
there was not a gradual increase in k2,app with increasing σp as
seen for acetonitrile; this is best seen by considering the
Hammett plot for k2,app in [Bmim][N(CF3SO2)2] 1 (Fig. 8 for χIL
0.2 and Fig. S16† for χIL 0.9). Clearly, the Hammett plot no
longer shows a clear concave-down profile as seen for aceto-
nitrile, with a similar trend seen across the range of pro-
portions of ionic liquid used. It is important to note that the
k2,app values for the electron withdrawing cases 2d–f lie lower
than expected based on the acetonitrile Hammett plot (Fig. 3),
with the chloro case 2d in particular standing out, as it slower
than the parent benzaldehyde 2c.
Fig. 8 Hammett plot of the apparent bimolecular rate constant (k2,app
)
for the overall addition-elimination reaction between benzaldehydes
2a–f and the amine 3 in [Bmim][N(CF3SO2)2] 1 in acetonitrile (χIL 0.2) at
281 K. Uncertainties are reported as the standard deviation of three
replicates.
above, for the process in the ionic liquid 1, and how each
would affect k2,app (see eqn (3), reproduced below). The key
points are: (1) k2,A increases with larger σp, and hence changes
in the rate constant of the addition step could not explain the
decreased k2,app values for σp > 0; (2) k1,E decreases as the elec-
tron-withdrawing ability of the substituent increases, with the
chloro substrate 2d having a particularly low k1,E value, hence
this could contribute to the lower k2,app and (3) k−1,A also
decreases as σp increases, with k−1,A being significantly larger
for the chloro case 2d than for nitro 2f. By considering eqn (3)
it is clear that this difference in k−1,A would have the largest
impact on k2,app for all electron withdrawing substrates, and
would account for the decreases in the apparent rate constant.
k2;A ꢁ k1;E
k2;app
¼
ð3Þ
k
ꢀ1;A þ k1;E
The different shape of these Hammett plots highlight that
In other words, for the chloro substrate 1d the large rate
the ionic liquid 1 is affecting the overall condensation process constant for the reverse of the addition process shifts the equi-
differently to acetonitrile. This difference can be rationalised librium position of the addition step to the left, resulting in a
by considering the three separate rate constants, discussed significant decrease in the overall rate constant of formation of
the imine 5. This decrease in k2,app is compounded by the
lower k1,E values for substrate 1d, further decreasing k2,app
.
The magnitude of k−1,A decreases when moving from chloro 1d
to trifluromethyl 1e to nitro 1f, resulting in the extent to which
k2,app is decreased by k−1,A becoming less significant as σp
increases. Importantly, this trend in k2,app further reinforces
the assumptions described earlier that k−1,A is significant for
σp > 0 and is not significant for σp ≤ 0: the k2,app values for
aldehydes 2a–c follow the expected trend, with deviations seen
only for the electron withdrawing substituents highlighting
that the rate constant for the reverse of the addition process is
only significant for σp > 0. It is also important to highlight
than in acetonitrile k−1,A remains relatively unchanged
between the electron withdrawing cases, resulting in a smooth
Table 10 The apparent bimolecular rate constant (k2,app) for the overall
addition-elimination reaction between the substituted benzaldehydes 2
and hexan-1-amine 3, in acetonitrile and a selected number of mole
fractions of [Bmim][N(CF3SO2)2] 1 in acetonitrile at 281 K
k2,app a/10−3 L mol−1 s−1
Substituent
Acetonitrile
χIL 0.2
χIL 0.9
2a R = MeO39
2b R = Me
2c R = H36
2d R = Cl
2e R = CF3
2f R = NO2
0.13 0.02
0.27 0.03
0.75 0.06
1.26 0.12
2.26 0.21
3.23 0.35
0.49 0.02
1.46 0.06
2.74 0.03
1.58 0.06
4.95 0.34
8.41 0.17
0.81 0.04
2.83 0.01
4.86 0.04
1.60 0.15
9.99 0.69
10.5 0.69
concave-down profile of the Hammett plot of k2,app
.
a Uncertainties quoted represent the standard deviation of three
replicates.
Lastly, the work presented throughout this manuscript
suggests that the typically used substituent parameters
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describing electronic effects in molecular solvents are still
valid in ionic liquid media for the reaction of substituted benz-
aldehydes 2a–f. The Hammett plots for each of the separate
steps produced good linear correlations, with reaction con-
stants in line with what would be expected for these reaction
types.47 This allows us to suggest that it is not necessary to
modify the substituent parameters when utilising ionic liquid
solvents.
3 A. de la Hoz, A. Diaz-Ortiz and A. Moreno, Chem. Soc. Rev.,
2005, 34, 164–178.
4 H. M. Yau, S. T. Keaveney, B. J. Butler, E. E. L. Tanner,
M. S. Guerry, S. R. D. George, M. H. Dunn, A. K. Croft and
J. B. Harper, Pure Appl. Chem., 2013, 85, 1979.
5 P. Wasserscheid and W. Keim, Angew. Chem., Int. Ed., 2000,
39, 3772–3789.
6 S. Z. El Abedin and F. Endres, Acc. Chem. Res., 2007, 40,
1106–1113.
7 K. R. Seddon, Kinet. Catal. Engl. Transl., 1996, 37, 693–697.
8 C. L. Hussey, Pure Appl. Chem., 1988, 60, 1763–1772.
9 M. J. Earle, J. M. S. S. Esperanca, M. A. Gilea,
J. N. Canongia Lopes, L. P. N. Rebelo, J. W. Magee,
K. R. Seddon and J. A. Widegren, Nature, 2006, 439, 831–
834.
10 J. P. Hallett and T. Welton, Chem. Rev., 2011, 111, 3508–
3576.
11 M. T. Clough, C. R. Crick, J. Grasvik, P. A. Hunt,
H. Niedermeyer, T. Welton and O. P. Whitaker, Chem. Sci.,
2015, 6, 1101–1114.
12 S. T. Keaveney, R. S. Haines and J. B. Harper, in Encyclo-
pedia of Physical Organic Chemistry, ed. U. Wille, Wiley, in
press.
13 J. P. Hallett, C. L. Liotta, G. Ranieri and T. Welton, J. Org.
Chem., 2009, 74, 1864–1868.
14 G. Ranieri, J. P. Hallett and T. Welton, Ind. Eng. Chem. Res.,
2008, 47, 638–644.
15 N. L. Lancaster, T. Welton and G. B. Young, J. Chem. Soc.,
Perkin Trans. 2, 2001, 2267–2270.
Conclusions
In summary, use of the ionic liquid 1 resulted in increased
imine formation relative to acetonitrile, highlighting the poss-
ible synthetic utility of using an ionic liquid solvent for con-
densation reactions. Extensive kinetic analysis showed that the
ionic liquid 1 increased the rate constant for each of the three
individual steps that make up the reaction relative to aceto-
nitrile, with the rate increases generally driven by the ionic
liquid solvating the reagents to a greater extent than the tran-
sition state. The effect of changing the para substituent on the
substrate 2 on the rate constant of each of the three processes
was found to vary between acetonitrile and the ionic liquid 1,
with the Hammett plot for the overall addition-elimination
process being markedly different in [Bmim][N(CF3SO2)2] 1
than in acetonitrile. These differing substituent effects were
found to arise due to the greater susceptibility of the ionic
liquid 1 to respond to subtle changes in the extent of charge
development in the transition state as the electronic nature of
the substituent was varied; this is important as it is the first
time that the sensitivity of an ionic liquid to differing degrees
of charge development has been demonstrated through acti-
vation parameters. Overall, the importance of considering the
delicate balance of microscopic interactions between the ionic
liquid and species along the reaction coordinate has been
further reinforced.
16 H. Yanai, H. Ogura and T. Taguchi, Org. Biomol. Chem.,
2009, 7, 3657–3659.
17 C. Chiappe, D. Capraro, V. Conte and D. Pieraccini, Org.
Lett., 2001, 3, 1061–1063.
18 R. Bini, C. Chiappe, E. Marmugi and D. Pieraccini, Chem.
Commun., 2006, 897–899.
19 R. Bini, C. Chiappe, C. S. Pomelli and B. Parisi, J. Org.
Chem., 2009, 74, 8522–8530.
20 F. D’Anna, V. Frenna, R. Noto, V. Pace and D. Spinelli,
J. Org. Chem., 2006, 71, 5144–5150.
Acknowledgements
21 F. D’Anna, V. Frenna, V. Pace and R. Noto, Tetrahedron,
2006, 62, 1690–1698.
STK 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 like to acknowledge the
NMR Facility within the Mark Wainwright Analytical Centre at
the University of New South Wales for NMR support.
22 M. J. Earle, S. P. Katdare and K. R. Seddon, Org. Lett., 2004,
6, 707–710.
23 S. T. Keaveney, J. B. Harper and A. K. Croft, RSC Adv., 2015,
5, 35709–35729.
24 B. Kirchner, O. Hollóczki, J. N. Canongia Lopes and
A. A. H. Pádua, Wiley Interdiscip. Rev.: Comput. Mol. Sci.,
2015, 5, 202–214.
25 C. Chiappe and C. S. Pomelli, Phys. Chem. Chem. Phys.,
2013, 15, 412–423.
26 S. Zahn, M. Brehm, M. Brüssel, O. Hollóczki,
M. Kohagen, S. Lehmann, F. Malberg, A. S. Pensado,
M. Schöppke, H. Weber and B. Kirchner, J. Mol. Liq.,
2014, 192, 71–76.
Notes and references
1 A. F. Trindade, P. M. P. Gois and C. A. M. Afonso, Chem.
Rev., 2009, 109, 418–514.
2 C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215– 27 C. D. Hubbard, P. Illner and R. van Eldik, Chem. Soc. Rev.,
1292.
2011, 40, 272–290.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 8925–8936 | 8935

View Article Online
Paper
Organic & Biomolecular Chemistry
28 S. T. Keaveney and J. B. Harper, RSC Adv., 2013, 3, 15698– 45 K. E. Johnson, R. M. Pagni and J. Bartmess, Monatsh.
15704. Chem., 2007, 138, 1077–1101.
29 B. Y. W. Man, J. M. Hook and J. B. Harper, Tetrahedron 46 Y. Chu, H. Deng and J.-P. Cheng, J. Org. Chem., 2007, 72,
Lett., 2005, 46, 7641–7645. 7790–7793.
30 H. M. Yau, S. A. Barnes, J. M. Hook, T. G. A. Youngs, 47 Z. Wang, H. Deng, X. Li, P. Ji and J.-P. Cheng, J. Org. Chem.,
A. K. Croft and J. B. Harper, Chem. Commun., 2008, 3576–3578. 2013, 78, 12487–12493.
31 H. M. Yau, A. G. Howe, J. M. Hook, A. K. Croft and 48 H. Deng, X. Li, Y. Chu, J. He and J.-P. Cheng, J. Org. Chem.,
J. B. Harper, Org. Biomol. Chem., 2009, 7, 3572–3575. 2012, 77, 7291–7298.
32 S. G. Jones, H. M. Yau, E. Davies, J. M. Hook, 49 H. M. Yau, S. J. Chan, S. George, J. Hook, A. Croft and
T. G. A. Youngs, J. B. Harper and A. K. Croft, Phys. Chem.
Chem. Phys., 2010, 12, 1873–1878.
33 H. M. Yau, A. K. Croft and J. B. Harper, Faraday Discuss.,
2012, 154, 365–371.
34 E. E. L. Tanner, R. R. Hawker, H. M. Yau, A. K. Croft and
J. B. Harper, Org. Biomol. Chem., 2013, 11, 7516–7521.
35 E. E. L. Tanner, H. M. Yau, R. R. Hawker, A. K. Croft and
J. B. Harper, Org. Biomol. Chem., 2013, 11, 6170–6175.
36 S. T. Keaveney, K. S. Schaffarczyk McHale, R. S. Haines and
J. B. Harper, Org. Biomol. Chem., 2014, 12, 7092.
J. Harper, Molecules, 2009, 14, 2521–2534.
50 B. C. Ranu and R. Jana, J. Org. Chem., 2005, 70, 8621–
8624.
51 F. D’Anna, S. L. Marca and R. Noto, J. Org. Chem., 2008, 73,
3397–3403.
52 F. D’Anna, S. La Marca, P. Lo Meo and R. Noto, Chem. –
Eur. J., 2009, 15, 7896–7902.
53 H. Srour, H. Rouault, C. C. Santini and Y. Chauvin, Green
Chem., 2013, 15, 1341–1347.
54 S. Steines, P. Wasserscheid and B. Drießen-Hölscher,
J. Prakt. Chem., 2000, 342, 348–354.
37 B. J. Butler and J. B. Harper, New J. Chem., 2015, 39, 213–219.
38 S. T. Keaveney, D. V. Francis, W. Cao, R. S. Haines and 55 H. Eyring, J. Chem. Phys., 1935, 3, 107–115.
J. B. Harper, Aust. J. Chem., 2015, 68, 31–35.
39 S. T. Keaveney, R. S. Haines and J. B. Harper, Org. Biomol.
Chem., 2015, 13, 3771–3780.
40 L. P. Hammett, J. Chem. Phys., 1936, 4, 613–617.
41 L. P. Hammett, J. Am. Chem. Soc., 1937, 59, 96–103.
42 N. S. Isaacs, Physical Organic Chemistry, Addison Wesley
Longman Limited, Harlow, 1998.
56 N. E. Hall and B. J. Smith, J. Phys. Chem. A, 1998, 102,
4930–4938.
57 M. Ciaccia and S. Di Stefano, Org. Biomol. Chem., 2005, 13,
646–654.
58 M. Ciaccia, R. Cacciapaglia, P. Mencarelli, L. Mandolini
and S. Di Stefano, Chem. Sci., 2013, 4, 2253–2261.
59 H. H. Jaffé, Chem. Rev., 1953, 53, 191–261.
43 C. D. Ritchie and E. S. Lewis, J. Am. Chem. Soc., 1962, 84, 60 H. M. Yau, R. S. Haines and J. B. Harper, J. Chem. Educ.,
591–594. 2015, 92, 538–542.
44 R. Bini, C. Chiappe, C. S. Pomellic and B. Parisi, J. Org. 61 B. Capon and K. Nimmo, J. Chem. Soc., Perkin Trans. 2,
Chem., 2009, 74, 8522–8530.
1975, 1113–1118.
8936 | Org. Biomol. Chem., 2015, 13, 8925–8936
This journal is © The Royal Society of Chemistry 2015