Controlling the reactions of 1-bromogalactose acetate in methanol using ionic liquids as co-solvents

Article abstract of DOI:10.1039/d0ob01198c

The reactions of an acetobromogalactose in mixtures of methanol and one of seven different ionic liquids with varying constituent ions were studied. In general, small amounts of ionic liquid in the reaction mixture led to increases in the rate constant compared to methanol, whilst large amounts of ionic liquid led to decreases in the rate constant; this outcome differs significantly from previous reactions proceeding through this mechansim. Temperature dependent kinetic studies indicated that the dominant interaction driving these changes was between the ionic liquid and the transition state of the process. Through considering solvent parameters of ionic liquids, a relationship was found between the changes in the rate constant and both the hydrogen bond accepting ability and polarisability of the solvent, indicating that the interactions affecting reaction outcome are both specific and non-specific in nature; once more, these interactions were different to those observed in previous similar reactions. By changing the amount of ionic liquid in the reaction mixture, additional products not seen in the molecular solvent case were observed, the ratios of which are dependent on the anion of the ionic liquid and the proportion of ionic liquid in the reaction mixture. This demonstrates the importance of considering solvent effects on both the rate and product determining steps and the potential application of such changes is discussed.

Full text of DOI:10.1039/d0ob01198c

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DOI: 10.1039/D0OB01198C
ARTICLE
Controlling the reactions of 1-bromogalactose acetate in
methanol using ionic liquids as co-solvents†
a
a
,a
Alyssa Gilbert, Ronald S. Haines and Jason B. Harper*
Received 00th January 20xx,
Accepted 00th January 20xx
The reactions of an acetobromogalactose in mixtures of methanol and one of seven different ionic liquids with varying
constituent ions were studied. In general, small amounts of ionic liquid in the reaction mixture led to increases in the rate
constant compared to methanol, whilst large amounts of ionic liquid led to decreases in the rate constant; this outcome
differs significantly from previous reactions proceeding through this mechansim. Temperature dependent kinetic studies
indicated that the dominant interaction driving these changes was between the ionic liquid and the transition state of the
process. Through considering solvent parameters of ionic liquids, a relationship was found between the changes in the rate
constant and both the hydrogen bond accepting ability and polarisability of the solvent, indicating that the interactions
affecting reaction outcome are both specific and non-specific in nature; once more, these interactions were different to
those observed in previous similar reactions. By changing the amount of ionic liquid in the reaction mixture, additional
products not seen in the molecular solvent case were observed, the ratios of which are dependent on the anion of the ionic
liquid and the proportion of ionic liquid in the reaction mixture. This demonstrates the importance of considering solvent
effects on both the rate and product determining steps and the potential application of such changes is discussed.
DOI: 10.1039/x0xx00000x
significant amount of research has focussed on the use of ionic
liquids as solvents for organic reactions that proceed through
Introduction
The search for alternatives to traditional organic solvents has
led to significant interest in ionic liquids. Ionic liquids are
arbitrarily defined as salts with a melting point below 100 °C,
and are composed of bulky, often asymmetric, cations and
anions of low coordinating strength. The structures of the ions
frustrate crystallisation, leading to their low melting points,
while the electrostatic interactions between the ions result in
3
, 10-13
well-known mechanisms.
A particular group of reactions
that have received relatively limited attention are those that
1
proceed through a unimolecular nucleophilic substitution (S
mechanism.
N
1)
2
Reactions that proceed through both localised and
delocalised carbocation intermediates have previously been
3
1
4-19
studied in mixtures of ionic liquids and traditional solvents;
it was shown that changing the amount of ionic liquid in the
reaction mixture can lead to different effects on the rate
constant for the process. The unimolecular rate constant, k , for
1
the process increased when a small amount of ionic liquid was
present in the reaction mixture compared to the molecular
solvent. It is important to note that the effects of large
proportions of ionic liquid in the reaction mixture were found
to be dependent on the nature of the carbocation intermediate;
4
useful properties, such as negligible vapour pressure and low
5
flammability. In addition, ionic liquids have the potential to be
recyclable6 and their properties (such as viscosity and
miscibility) can be altered, and selected for, by changing the
7
constituent ions. For this reason, they have been classified as
‘
designer solvents’.8
A hinderance to the use of ionic liquids as alternative
solvents is the fact that their effects on organic reactions,
including changing both the rate of reaction and preference for
certain products, have not been readily predictable. In order to
better understand, and potentially predict, these effects a
1
k either decreased below that of the molecular solvent
1
4, 15, 17
(localised carbocation intermediate
) or remained higher
9
than that of the molecular solvent (delocalised carbocation
1
6, 18, 19
intermediate
). Therefore, it is clear that by changing the
nature of the intermediate, which in this mechanism correlates
with a significant degree of charge development in the
transition state, the ionic liquid effect can change dramatically
and understanding these changes is key if ionic liquids are to be
used in a rational fashion to control reaction outcome. These
a. School of Chemistry, University of New South Wales, Sydney, NSW, 2052,
Australia. Email: j.harper@unsw.edu.au; Fax: +612 9385 6141; Tel: +612 9385
4
692
Electronic Supplementary Information (ESI) available: Synthesis of ionic liquids and
their precursors, experimental details for kinetic analyses, nucleophile dependence
†
plot for the reaction shown in Scheme 1, Eyring plot for reaction shown in Scheme studies have also attempted to identify the interactions
1
, correlation of rate constant data with solvent parameters (including multivariate
responsible for the observed changes in the rate constant
through determining both the activation enthalpies and
regression analyses), product analyses for the reaction shown in Scheme 1 in
different ionic liquids, experimental details for isolation studies, rate data for all the
1
NMR spectra of prepared compounds. See entropies of the processes,15, 16 and correlating solvent
plots presented,
H
DOI: 10.1039/x0xx00000x
18, 19
properties to the rate constant data;
this information can in
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Journal Name
turn allow for the prediction of the effects of other ionic liquids
on these systems. Notably, the interactions responsible in each
case vary with the substrate of the reaction and understanding
the relationship between the interactions and the substrate is
necessary for rational choice of ionic liquid components.
View Article Online
DOI: 10.1039/D0OB01198C
Given the above, it was of interest to investigate an S
N
1
reaction specifically chosen because it proceeds through a
carbocation intermediate that is stabilised by the presence of a bis(trifluoromethanesulfonyl)imide ([bmim][N(SO
heteroatom; Scheme 1 shows the solvolysis of the galactose 1
Figure
1.
The
ionic
liquid
CF
1-butyl-3-methylimidazolium
], 3)‡ used in this study.
2
3
)
2
in methanol, which proceeds through an oxocarbenium
1.20E-03
intermediate.20 Not only does this reaction allow for the study
of any effects an ionic liquid may have on a reaction that
proceeds through an oxocarbenium ion, but it also allows for
the study of a substrate similar to those commonly found in
nature as ionic liquids have been extensively studied in the
1.00E-03
8.00E-04
6.00E-04
2
1, 22
dissolution of biomass
and related carbohydrate
chemistry,23 with some examples of studies using ionic liquids
4.00E-04
2
4, 25
as catalysts for carbohydrate-related conversions.
2.00E-04
Therefore, the aim of this study was to analyse the effects
of ionic liquids on the reaction shown in Scheme 1 and to
correlate any changes observed with solvent properties,
particularly comparing to other related systems to highlight the
0.00E+00
0
0.2
0.4
0.6
0.8
1
Mole fraction of [bmim][N(SO2CF3)2] 3
differences. Such
a
correlation would facilitate an
Figure 2. The dependence of the unimolecular rate constant (k
1
) of the reaction of the
understanding of how ionic liquids affect this reaction and acetobromogalactose 1 on the mole fraction of [bmim][N(SO CF ) ] 3 () in methanol at
2
3 2
potentially enable prediction of the effects that further ionic 315 K. Uncertainties reported are the standard deviation of triplicate measurements;
some uncertainties fall within the size of the markers used.
liquids would have on reactions of this type. Overall, this study
will allow for further understanding of, and perhaps a more
widespread use of, ionic liquids as solvents for S 1 processes.
N
This plot is generally the same shape as has been observed
for some,14, 16, 18 though not all, related S
19
N
1 reactions; the rate
constant increases at low mole fractions of the salt 3 compared
to the molecular solvent and then decreases at higher mole
fractions of the salt 3. However, it is the differences between
this and previous cases that are significant. In this case, the
maximum rate constant increase occurs at 
approximately 1.5 times the rate constant in the methanol case,
3
= 0.02 and is
Scheme 1. The methanolysis of the sugar derivative 1 to give the -isomer 2.
1
4
which is similar to an alkyl chloride example but notably
different to a case with a delocalised benzhydrylium
Results and discussion
1
6,18
intermediae.
3 1
Additionally, at  > 0.1, k is lower than in the
Kinetic analysis
methanol case to the point where k is only 2% that of the
1
3
methanol case at  = 0.93; such a significant decrease in rate
As outlined in the Introduction, the solvolysis of the
bromogalactose 1 in methanol (Scheme 1) typically proceeds
through a unimolecular nucleophilic substitution mechanism.
This mechanism was confirmed using nucleophile dependence
studies in which changing the amount of methanol in the
reaction mixture did not affect the rate constant for the process
constant for this reaction type has not been reported before.
Importantly, this demonstrates the effects of the proportion of
salt 3 in the reaction mixture for reactions with this type of
reagent, allows contrast with previous cases, and hence
selection of the proportion of ionic liquid to get a desired
reaction outcome.
(see Figure S1 in ESI). In addition, only the -isomer 2 was
Temperature dependence studies were used to determine
the activation parameters for this process in order to identify
formed in these mixtures; no other products were observed.
In order to study the effects of using an ionic liquid as the
solvent for this reaction, the rate constant for the process was
initially measured in mixtures containing different proportions
the underlying interactions responsible for these changes in k
when using an ionic liquid solvent. These studies were carried
out in methanol and mixtures containing either  = 0.02 or 
1
3
3
of [bmim][N(SO
2 3 2
CF ) ] 3 (Figure 1) in methanol. This ionic liquid
2
6
= 0.50. The low mole fraction of the salt 3 was selected as this
corresponds to the reaction mixture where the maximum
increase in k occurs; the higher mole fraction was selected so
1
that the origin of the rate constant decrease could be evaluated,
particularly comparing these origins to those for the previously
3
was selected as it is readily prepared and purified, and has
1
1, 27
been used widely in mechanistic studies,
particularly for
reactions that proceed through the same mechanism as the
1
4, 16, 28
reaction shown in Scheme 1.
The results of these
experiments are summarised as a plot showing the mole
fraction dependence of the rate constant (Figure 2).
N
considered S 1 system that proceeds through a localised
2
| J. Name., 2012, 00, 1-3
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carbocation.14, 15 The activation parameters determined are
shown in Table 1.
View Article Online
DOI: 10.1039/D0OB01198C
In both cases in which the ionic liquid 3 is present, there is a
measurable decrease in the entropy of activation compared to
the methanol case as well as a decrease in the enthalpy of
3
activation at the  = 0.02 case. Significantly, this is the first
example of a measurable change in both activation parameters
between the molecular solvent case and the case with a low
mole fraction of ionic liquid present for this type of reaction
mechanism.
Table 1. The activation parameters determined for the reaction of acetobromogalactose
1
2 3 2
in either methanol or mixtures of [bmim][N(SO CF ) ] 3 in methanol at the proportion
of ionic liquid 3 shown.
‡
-1 a
‡
-1
-1 a
Solvent
Methanol

0
0.02
0.49
3
H / kJ mol
72.1 ± 0.9
65.9 ± 1.3
69.7 ± 2.0
S / J K mol
-76 ± 3
Figure 3. The ionic liquids used to study the effect of varying the constituents:
[
[
bmim][N(SO
bmim][N(SO
2
CF
CF
3
)
)
2
] 3
] 3
-92 ± 4
-101 ± 6
1
(
-butyl-2,3-dimethylimidazolium
[bm im][N(SO CF ],
bis(trifluoromethanesulfonyl)imide ([bmpyr][N(SO
bis(trifluoromethanesulfonyl)imide
N-butyl-N-methylpyrrolidinium
2
3
2
)
4),
2
2
3
2
aUncertainties reported were obtained from the fit of the linear regression for the
respective Eyring plots.
2
CF
3
)
2
], 5), methyltrioctylammonium
CF ], 6), 1-butyl-3-
6
], 7), 1-butyl-3-methylimidazolium
bis(trifluoromethanesulfonyl)imide
([mtoa][N(SO
2
3 2
)
methylimidazolium hexafluorophosphate ([bmim][PF
4
tetrafluoroborate ([bmim][BF ], 8) and 1-butyl-3-methylimidazolium tricyanomethanide
In the reaction mixture containing a small amount of the salt
, these changes indicate that the ionic liquid is stabilising the
(
[bmim][C(CN)
3
], 9).
3
transition state of the process as shown by the lowered
enthalpy of activation; in doing so, the ionic liquid orders about
the transition state, hence lowering the entropy of activation
1
.80E-03
1.60E-03
.40E-03
.20E-03
.00E-03
8.00E-04
.00E-04
.00E-04
.00E-04
.00E+00
(that is, making it more negative). The change in the enthalpy
1
of activation dominates the change in the entropy of activation
with the result being an increase in the observed rate constant
1
1
at 
While the larger uncertainties associated with the activation
parameters for the  ca. 0.50 case mean that no change in the
3
= 0.02.
3
6
enthalpy of activation from the methanol case can be seen, the
significant decrease in the entropy of activation suggests that
the dominant interaction involves ordering of the ionic liquid
about the transition state of the reaction. Such organisation is
not unexpected given the high degree of charge development
in the transition state for this reaction and is consistent with
4
2
0
0
0.2
0.4
0.6
0.8
1
Mole fraction of ionic liquid
Figure 4. The dependence of the unimolecular rate constant (k
acetobromogalactose 1 on the mole fraction of on the mole fraction of either
bmim][N(SO CF ] 3 (), [bm im][N(SO CF ] 4 (), [bmpyr][N(SO CF ] 5 (),
CF ] 6 (), [bmim][PF ] 7 (), [bmim][BF ] 8 () or [bmim][C(CN) ] 9 ()
in methanol at 315 K. Uncertainties reported are the standard deviation of triplicate
measurements; some uncertainties fall within the size of the markers used.
1
) of the reaction of the
1
5, 16
what has been observed previously.
parameters also show that the decrease in k
These activation
observed at higher
1
[
2
3
)
2
2
2
3
)
2
2
3 2
)
mole fractions of the ionic liquid is due to significant ordering of [mtoa][N(SO
2
3
)
2
6
4
3
the solvent around the transition state; that is, the change in k
1
from a small to large amount of ionic liquid 3 in the reaction
mixture is a delicate balance between an enthalpic benefit
an ionic liquid on k
cf. salt 3) could indicate how the ionic liquid is interacting with
the transition state.
The dependence of the rate constant for the reaction shown
in Scheme 1 on the proportion of each of the ionic liquids 4-9
was determined to evaluate how varying the constituents of the
1
when using these ionic liquids as solvents
(stabilising the transition state – occurs at low mole fractions of
(
the salt 3) and an entropic cost (ordering around the transition
state – occurs at higher mole fractions of the salt 3).
In order to better understand how the ionic liquid 3 is
interacting with the transition state for this process, a series of
ionic liquids were selected that differ from salt 3 in either the
1
ionic liquid affects k (Figure 4; see Figures S2-S7 in ESI for mole
cation or the anion (Figure 3). Ionic liquids 4-6, which differ in
-
fraction dependence plots of each ionic liquid 4-9 individually).
Immediately obvious is that the general shape of all of the plots
are the same, irrespective of the ionic liquid used, however the
maximum increase in k differs, as does the proportion of salt in
1
the reaction mixture at which this maximum occurs.
Importantly, these results indicate that changing each of the
the cation while having the same [N(SO
2
CF
3 2
)
] anion, were
selected due to differences in both localisation of the charge
and accessibility of the charged centre(s) compared to the
+
[
bmim] cation. Ionic liquids 7-9, which differ in the anion while
+
keeping the [bmim] cation constant, have anions that vary in
both coordinating ability and size. Any changes in the effects of
1
constituents of the ionic liquid affects k . Such changes have
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J. Name., 2013, 00, 1-3 | 3
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been seen previously,18,19 though the effect is more marked in Table 2. The activation parameters determined for the reaction of aceVtoiebwroAmrtoicglealOacntloinsee
1 in either methanol or mixtures of the ionic liquids 3-9 in methanol. After each
activation parameter, the symbol in brackets indicates the change relative to methanol
case: (-): no change, (): increase, (): decrease.
DOI: 10.1039/D0OB01198C
the case seen here.
Focusing first on the effects of changing the cation of the
ionic liquid, both of the ionic liquids [bm
bmpyr][N(SO CF ] 5 display a maximum increase in k
.02 with
bmim][N(SO
fraction is generally similar for both of these ionic liquids and
again, comparable to the equivalent [bmim][N(SO CF ] 3 case.
In contrast, the largest k observed in mixtures containing
mtoa][N(SO CF ] 6 occurs at  = 0.01 and is the same
2
im][N(SO
2
CF
3
)
2
] 4 and
at  ca.
[
2
)
3 2
1
Solvent
Methanol
salt
0
H
‡
/ kJ mol-1 a
S
‡
/ J K-1 mol-1 a
0
[
a
CF
similar magnitude to that seen for
] 3. In addition, the rate constant at any mole
72.1 ± 0.9
-76 ± 3
2
)
3 2
[bmim][N(SO
[bm im][N(SO
bmpyr][N(SO
mtoa][N(SO
2
CF
3
)
2
] 3
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.49
0.48
0.48
0.45
0.51
0.48
0.50
65.9 ± 1.3 ()
68.7 ± 2.8 (-)
66.7 ± 1.0 ()
75.0 ± 0.8 ()
64.3 ± 1.4 ()
70.6 ± 1.9 (-)
75.3 ± 1.6 ()
69.7 ± 2.0 (-)
58.6 ± 3.1 ()
70.0 ± 1.0 ()
30.4 ± 1.4 ()
56.5 ± 3.3 ()
66.5 ± 2.7 ()
77.2 ± 2.2 ()
-92 ± 4 ()
-84 ± 9 (-)
-90 ± 3 ()
-68 ± 3 ()
-96 ± 5 ()
-77 ± 6 (-)
-63 ± 5 ()
-101 ± 6 (-)
-137 ± 10 ()
-99 ± 3 ()
-237 ± 4 ()
-135 ± 10 ()
-101 ± 9 ()
-71 ± 7 (-)
2
2
CF
CF
3
)
2
] 4
] 5
[
[
2
3 2
)
2
3 2
)
2
CF
3
)
2
] 6
1
[
[
bmim][PF
bmim][BF
6
] 7
] 8
[
2
)
3 2
6
4
magnitude as in methanol; there is no measurable increase. As
the mole fraction of the salt 6 in the reaction mixture increases,
k steadily decreases. These differences show that access to the
1
charged centre(s) of the cation is necessary to increase the rate
constant for this reaction, irrespective of whether the charge is
[
bmim][C(CN)
bmim][N(SO CF
bm im][N(SO
bmpyr][N(SO
mtoa][N(SO
[bmim][PF ] 7
3
] 9
[
[
[
2
3
)
2
] 3
2
2
CF
CF
3
)
2
] 4
] 5
2
3 2
)
[
2
CF
3
)
2
] 6
+
+
delocalised (as in [bmim] and [bm
2
im] ) or localised (as in
6
+
+
[
bmpyr] ). Whilst the addition of a methyl group to [bmim] to
[bmim][BF
[bmim][C(CN)
4
] 8
] 9
+
give the [bm
2
im] cation does introduce a slight steric effect,
3
clearly this effect is not great enough to negatively affect k
1
in
aUncertainties reported were obtained from the fit of the linear regression for the
this case unlike the much more significantly sterically hindered respective Eyring plots.
+
[
mtoa] cation.
cases. For ease of comparison, after each activation parameter,
an indication of the change relative to the methanol case is
shown.
Moving to the effects of changing the anion of the ionic
liquid, the mole fraction dependence plot (Figure 4) shows that
increases at 0.02 in the following order:
bmim][N(SO CF ] 3 < [bmim][C(CN) ] 9 < [bmim][BF ] 8 <
bmim][PF ] 7. As the mole fraction of salt increases, the k
] 8 and [bmim][C(CN) ] 9 is always
greater than the other ionic liquids studied (k is approximately
k
[
[
1

=
The activation parameters determined for ionic liquids
2
)
3 2
3
4
[
7
bm
show that on moving from the methanol case to  ca. 0.02
there is a decrease in both the enthalpy and entropy of
activation, as described above for [bmim][N(SO CF ] 3.
2 2 3 2 2 3 2 6
im][N(SO CF ) ] 4, [bmpyr][N(SO CF ) ] 5 and [bmim][PF ]
6
1
observed for both [bmim][BF
4
3
1
3 2
)
five times greater at  = 0.95 for the tetrafluoroborate salt 8
relative to the parent salt 3). Interestingly, mixtures containing
bmim][PF ] 7 up to  = 0.2 show the greatest increase in k of
6 7 1
all of the ionic liquids studied; beyond this proportion of salt 7,
the rate constant gradually decreases such that the rate
2
Therefore, it is clear that for these cases, the origin of the rate
constant enhancement is stabilisation of the transition state of
this reaction. This is not the situation, however, for all cases;
[
[
bmim][BF
4
] 8 shows no change within uncertainty for either
parameter compared to methanol (this outcome is consistent
4
constant is below that seen for [bmim][BF ] 8 mixtures and at
1
5
with a previous case ) and both [mtoa][N(SO
2 3 2
CF ) ] 6 and
the highest mole fraction of salt 7 the rate constant is three
times greater than that seen for the parent ionic liquid 3.
Irrespective, this analysis shows that the ionic liquid solvent
[
bmim][C(CN) ] 9 show an increase in both the enthalpy and
3
entropy of activation relative to the molecular solvent.
Importantly, these changes with the nature of the constituent
1
effects on k are also dependent on the anion.
1
8,19
ions in the ionic liquid differ from previous examples,
It is of interest to consider the microscopic origin of this
-
showing the importance of the nature of the reagent (and
hence the transition state) in determining ionic liquid solvent
anion dependence. The coordinating abilities of [N(SO
2
CF
] are similar, and the coordinating abilities of [BF
and [C(CN)
explain the order of the solvent effect. As such, the size and
3
)
2
]
]
-
29
-
and [PF
6
4
]- are similar,30 so clearly this property does not
effects.
3
Previous examples3
1, 32
have demonstrated that an increase
-
-
in both activation parameters is likely due to stabilisation of the
starting material through ordering of the solvent about it (as
opposed to less interaction with and ordering about the
transition state); this ordering is disrupted as the reaction
proceeds, causing an increase in the disorder of the system. For
this reaction, given that the changes in activation parameters
seen in each ionic liquid case at  = 0.02 compared to the
methanol case are quite small, there is the possibility that both
significant starting material–ionic liquid and transition state–
ionic liquid interactions are introduced in each case; by
changing the constituents of the ionic liquid, the dominant
interaction driving the rate constant change can vary. It is
evident here that either a more coordinating anion (as are
4 6
shape of each anion can be considered; both [BF ] and [PF ]
anions are highly symmetric. The result might be that the ions
pack more efficiently about the transition state, resulting in
-
6
greater interactions. Additionally, the larger size of the [PF ]
-
anion compared to [BF
4
] might explain why this ionic liquid
at higher mole fractions
does not give the highest increase in k
1
as any entropic cost may become significant with more ionic
liquid in the reaction mixture.
1
In order to further understand the changes in k for the
reaction shown in Scheme 1 observed for the series of ionic
liquids 4-9, temperature dependence studies were performed
at  = 0.02 and ca. 0.50. These parameters are shown in Table
2
, along with those for both the methanol case and the salt 3
4
| J. Name., 2012, 00, 1-3
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ARTICLE
present in salts 8 and 9) or a less accessible charge on the cation where a, b and c are coefficients of each parameterViaewndArtiinclde iOcnalitnee
(
[
allowing the anion to be more free to interact, in the case of the relative contribution of each paramDeOteI:r10t.o103a9n/yD0oObBs0e1r1v9e8Cd
mtoa][N(SO CF ] 6) leads to starting material interactions correlation. A p-value of < 0.05 indicates a good correlation.
These analyses were performed across each mole fraction for
2
3 2
)
becoming more dominant.*
At a higher mole fraction of salt in the reaction ( ca. 0.50), the series of ionic liquids. Including all parameters in the
both the enthalpy and entropy of activation decrease compared analysis, as well as a combination of either  and  or  and *
to the methanol case for each of the ionic liquids 4-8. These data showed no correlations with significant p-values, indicating that
indicate that by increasing the amount of each of these ionic a correlation was poor for these combinations. However,
liquids in the system, transition state interactions dominate. As analyses that contained a combination of  and * across each
mentioned previously, this results in a large decrease in k in all mole fraction showed good to very good correlations (Table 3
1
cases compared to both the methanol case and cases where and Figure 5 for a representative example, which shows this
small amounts of ionic liquid are present, as the ionic liquid relationship at the proportion of ionic liquid 3 that showed the
orders significantly about the transition state.
1
maximum increase in k ; see ESI for all analyses). Notably the
3
The exception to the above trend is the [bmim][C(CN) ] 9 importance of both  and * parameters contrasts markedly
which, as mentioned above, shows an increase in the enthalpy with the previous correlations of these solvent parameters with
of activation and no change within uncertainty for the entropy unimolecular processes on different substrates,18,19 again
of activation compared to the methanol case at 
parameters determined are the same as those at 
indicating that the dominant interactions driving the rate
constant change for this particular ionic liquid do not change as
significantly as in the case of ionic liquids 3-8, even though k
9
= 0.50. The showing the importance of the structure of the reagent.
= 0.02,
9
1
Table 3. The correlation between ln(k ) and the Kamlet–Taft parameters  and * across
each mole fraction of ionic liquids 3-9.
Mole fraction (ca.)
ln(k
1
)a
R2 b
1
decreases in a similar fashion to that seen for the other ionic
liquids. This may be a result of the same features that result in
the low viscosity of ionic liquid 9 compared to the other ionic
liquids studied,33 which may cause a change in these
0.01
-8.49 – 3.38 + 3.65*
-9.54 – 5.72 + 6.22*
0.84
0.88
0.88
0.84
0.86
0.77
0.79
0.74
0.72
0
0
.02
.05
-10.53 – 7.72 + 8.36*
-12.77 – 11.36 + 12.55*
-16.53 – 15.74 + 18.68*
-20.56 – 16.89 + 23.07*
-22.25 – 14.44 + 22.85*
-23.77 – 8.19 + 20.19*
-24.34 – 13.61 + 23.23*
0.10
0
0
0
0
.20
.35
.50
.73
interactions.
Kamlet–Taft parameter analysis
In order to further understand these key interactions that are
driving the rate constant change, and to potentially allow for
0.95
a
In all cases, p < 0.05 for all variables, indicating a significant contribution with the
b
2
the prediction of effects additional ionic liquids would have on exception of the  parameter for the  ca. 0.73 case. Adjusted R , which takes into
account the number of variables contributing to the fit.
this reaction, Kamlet–Taft solvent parameters were considered.
These parameters, while not specific to ionic liquids, have been
used previously to correlate reaction outcome with solvent
descriptors and can be used to establish which constituents of
the ionic liquid are involved in the key interactions responsible
-6.3
-6.6
1
8, 19, 34-38
for rate constant changes.
The parameters include 
(
the hydrogen bond donating ability; often associated with the
3
9
cation of the ionic liquid),  (the hydrogen bond accepting
ability of the solvent; often associated with the anion of the
ionic liquid),40 and * (the polarizability of the solvent; relating
-6.9
R² = 0.92
4
1
to both the cation and anion of the ionic liquid).
-7.2
Initial attempts to correlate the natural log of the rate
constant to each individual parameter showed poor
correlations§ (see Figures S9-S35 in ESI). Therefore, it was of
interest to determine whether a combination of these
parameters would result in a good correlation. Multiple
regression analysis is useful for this as it allows for identification
-
7.5
-
7.5
-7.2
-6.9
-9.54 – 5.72
-6.6
-6.3

+ 6.22 *

Figure 5. The relationship between the natural logarithm of the rate constant and a
combination of the  and * Kamlet–Taft parameters for the reaction of the galactose 1
of any existing correlation between multiple parameters and for each of the ionic liquids 3-9 at  ca. 0.02. Uncertainties are calculated from the
changes in reaction outcome. This method has been used standard deviation of triplicate measurements and transformed on calculating the
natural logarithm.
previously with ionic liquid systems to identify these
correlations,3
4, 42
by using the following equation:
Immediately clear from these relationships is that both the

and * parameters are important but that the coefficients for
1
ln(k ) = intercept + a + b + c*
these parameters vary as the mole fraction varies. This trend is
of note as it has not been observed previously to such a
significant degree. Generally, the effect of the mole fraction of
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ARTICLE
Journal Name
ionic liquid has not been studied extensively when looking at parameters indicates that starting material interactions, where
View Article Online
these relationships;3
4, 42, 43
where it has been, either there was hydrogen bond acceptance by the ionicDOliIq: u10id.10i3s9/lDik0eOlyB0t1o19b8Ce
no significant relationship as the mole fraction of ionic liquid occurring, are more pronounced in the cases of ionic liquids 6,
was increased,44 or where there was a significant relationship, 8 and 9 (with higher  values). The interaction responsible for
1
9
the co-solvent was acetonitrile (which has similar solvent this feature is not immediately clear, given that hydrogen bond
parameters to the ionic liquids studied in those cases). acceptance might be expected to favour the formation of the
Therefore, it is clear that the changes in the coefficients across transition state. As such, interaction with the starting material
mole fractions are likely due to interactions involving the 1 is implied. Importantly, these interactions are different to
methanol also having a significant effect. This is not unexpected those that have been implicated in the solvent effects of ionic
as methanol is a polar, hydrogen bonding solvent and therefore liquids on other similar reactions.
the Kamlet–Taft parameters are generally higher than those
4
5
seen for acetonitrile, particular the  and  parameters.
Product analysis
Ideally Kamlet-Taft parameters for the solvent mixtures
considered would be used, but these are unavailable. Attempts
to find relationships involving contributions from methanol to
the solvent parameters at each solvent composition (based on
As shown above in Scheme 1, product 2 is the only observable
species when the reaction is performed in methanol. However,
multiple products were observed throughout the mole fraction
dependence experiments described above when using ionic
liquids 3-9. These products are shown in Scheme 2.** As shown,
product 2 is present alongside a mixture of isomers 10 and 11§§
4
6, 47
48
observed correlations for both aprotic
and protic systems,
see ESI for full analyses) showed no improvement. For this
reason, the relationships shown in Table 3 will be discussed
from this point.
As mentioned, these correlations show that both the
hydrogen bond accepting ability and the polarizability of the
ionic liquid are important in affecting the rate constant.‡‡ In
this case, the two parameters have opposite effects; the
coefficient for * is always positive, indicating that an increase
(resulting from interaction of a neighbouring acetate group with
the C2, as shown in the intermediate in Scheme 2, which is then
attacked by the nucleophile), as well as product 12 which is
produced through loss of a proton from the intermediate (a
base, triethylamine, is present in the reaction mixture).
Interestingly, the presence of these products and the ratios
between them differ when changing both the ionic liquid and
the proportion of salt in the reaction mixture; importantly, the
effect of the ionic liquid is thus demonstrated on both the rate
and product determining steps. Table 4 gives a summary of
product ratios at representative key solvent compositions (for
ratios for all solvent compositions see Tables S2-S6).
1
in k is favoured when the solvent has a higher polarizability;
whereas the coefficient for  is always negative, meaning that a
solvent that is more able to accept hydrogen bonds will
decrease the rate constant for this reaction. Additionally, as the
mole fraction of the ionic liquid in the reaction mixture
increases, both of these effects become larger but the
favourable * effect becomes more pronounced. These
features are apparent in the plots of rate constant against the
mole fraction of ionic liquid (Figure 4, Figures S2-S7): i) at lower
proportions of salt in the reaction mixture, the [bmim][PF
6
] 7,
[
bmim][BF ] 8 and [bmim][C(CN) ] 9 cases gave the highest rate
4
3
constants out of the series as each of these ionic liquids have
high polarizability values; ii) at higher mole fractions of salt in
the reaction mixture, k
decrease compared to both [bmim][BF
cases even though both [bmim][BF ] 8 and [bmim[C(CN)
have high  values compared to [bmim][PF ] 7 – at these solvent
compositions, the higher * values for both ionic liquids 8 and
outweigh any detrimental hydrogen bond accepting effects,
leading to high k values across each mole fraction.
1
values in the [bmim][PF
6
] 7 cases
] 9
] 9
4
] 8 and [bmim[C(CN)
3
4
3
6
9
1
These correlations can be used to clarify the microscopic
interactions in solution that result in the changes in reaction
outcome in ionic liquids; the positive coefficient for * for each
solvent composition indicates that the dominant interactions
1
responsible for the changes in k for each ionic liquid are
favourable non-specific interactions, likely charge-charge
interactions. This further supports the proposition that the ionic
liquid components are stabilising the developing charges in the
transition state as indicated by the trends observed in the
enthalpies of activation. The negative  coefficient indicates Scheme 2. The reaction of the galactose 1 with methanol through the proposed
intermediate to give the products 2, 10-12. The ratio of these products differs when
changing the solvent composition.
that hydrogen bond acceptance from the ionic liquid is
detrimental to k ; again, looking at the trends in activation
1
6
| J. Name., 2012, 00, 1-3
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ARTICLE
Table 4. The ratio of products observed for the reaction of the galactose 1 in different increased to 0.37 and 0.73 for salt 3, demonstra
ting that the
View Article Online
solvent compositions.
formation of these two isomers is favour
D
edOI: 1 .10
as
0
m
or
3
9
e
/Dio
0
ni
O
B
c
0
l
1
iq19
uid
8
C
is present in the reaction mixture. Entries 7, 8, 10 and 11 show
that changing the cation of the ionic liquid does not influence
these product ratios; the same ratios of each product across all
mole fractions are observed for ionic liquids 4-6 within
uncertainty, suggesting that the cation is not involved in the
interactions that affect the product determining step. That
product formation is dependent on the anion of the ionic liquid
Entry
Ionic
liquid
-

salt
t /
ha
2
1
1
1
5
2
37
37
17
65
45
20
%2b,c
%10b,c
%11b,c
%12b,c
d
d
d
1
2
3
4
5
6
7
8
9
0
100
100
100
100
93 ± 2
100
63 ± 4
55 ± 6
100
-
-
-
d
d
d
3
7
8
3
7
3
5
7
3
5
7
0.02
0.02
0.02
0.37
0.33
0.73
0.72
0.74
0.93
0.93
0.95
-
-
-
d
d
d
d
d
d
-
-
-
-
-
-
-
-
d
d
5 ± 1
-d
20 ± 1
25 ± 6
-d
46 ± 5
56 ± 1
51 ± 5
2 ± 1
-d
9 ± 3
13 ± 2
-d
18 ± 9
25 ± 3
31 ± 7
is indicated in entries 6, 9 and 12 as the use of [bmim][PF ] 7
6
9 ± 4
7 ± 1
-d
36 ± 14
20 ± 3
18 ± 4
only produces product 2 up until a solvent composition of  =
0
.95 where the additional products 10-12 are observed.‡‡‡
This effect of the anion of the ionic liquid on product
d
1
1
1
0
1
2
-
formation in this reaction is not unexpected given the indication
from the Kamlet–Taft analysis, which showed that the anion is
involved in the interactions affecting the rate constant of the
reaction, and the activation parameter data, which suggested
that these interactions are with the transition state towards the
intermediate at high proportions of ionic liquid. It should be
noted, of course, that the product forming step of this reaction
d
-
d
-
a
b
Each reaction was followed to completion. Percentages were obtained from the
ratio of the integrals of representative signals of each product against an internal
standard. Uncertainties reported were obtained from the standard deviation of
triplicate measurements. Not detected using H NMR spectroscopy.
c
d
1
Several general comments can be made about the ratio of does not affect k , however the importance of the anion in both
1
products observed in different solvent compositions: as the steps is logical and suggests that the organisation of the solvent
amount of ionic liquid is increased in the reaction mixture the
about the intermediate is key to the changes in outcome seen
amount of product 2 decreases. This change suggests that the in both steps on moving to mixtures containing an ionic liquid.
relative ease of nucleophilic attack at C2 decreases with the Importantly, there is the potential for rational solvent choice to
proportion of ionic liquid present, and implies significant not only control the rate determining step of the reaction, but
interactions of the ionic liquid constituents with the also the product determining step, yielding products not readily
intermediate. In cases where the isomers 10 and 11 are available in molecular solvents.
observed, the amount of isomer 10 is always greater than 11;
this preference is likely, at least in part, due to a steric effect of Isolation studies
the sugar portion of the molecule. However, differences
Due to the different products that were observed to form using
between the ratios of these two products in cases where
different solvent mixtures, it was of interest to attempt to
different ionic liquids are used again suggest interactions of the
isolate these products from the reaction mixtures. Several
constituents of the ionic liquid with the intermediate; in this
solvent compositions were selected:
case, these interactions may hinder attack from one face of the


IL = 0, that is where methanol is the solvent alone. It
was expected that this case would be easy to isolate
the product 2.
intermediate. Product 12, likely resulting from elimination
involving the triethylamine present in solution acting as a base,
is only seen at higher mole fractions of ionic liquid in the
reaction mixture. This outcome is consistent with a decrease in
the rate of formation of those products 2, 10 and 11 that require
nucleophilic attack of methanol on the intermediate as the
amount of methanol in the reaction mixture decreases.
Importantly though, elimination is not the major reaction
pathway at any solvent composition.
4
IL = 0.02 using [bmim][BF ] 8 to compare the isolated
yields between this and the methanol case. This ionic
liquid was selected as it is water soluble and was
thought that the product 2 would be relatively easily
isolated.

2 3 2
IL = 0.02 using [bmim][N(SO CF ) ] 3 to compare the
isolated yields between two different ionic liquids that
Focussing on more specific cases, entries 2-4 show that
using a small amount of ionic liquid ( ca. 0.02) gives the same
product 2 as seen in the methanol case but at a faster rate; this
is representative of all ionic liquid cases studied. These
examples suggest that this proportion of ionic liquid is
insufficient to result in interactions with the intermediate that
change the product ratio. This outcome is significant because it
reinforces that the amounts of ionic liquid required to affect the
rate determining and product determining steps are different.
As the amount of ionic liquid is increased in the reaction
mixture, additional products are observed. Entries 5 and 7 show
that the two dioxal isomers 10 and 11 are formed to a small and
then moderate extent as the mole fraction of ionic liquid is
give the same product 2 at this low mole fraction.



2

IL = 0.32 using [bmim][N(SO
, 10 and 11 were observed in the kinetic studies.
IL = 0.75 using [bmim][N(SO CF ] 3 where all
2 3 2
CF ) ] 3 where products
2
3 2
)
products 2 and 10-12 were observed in the kinetic
studies.
Initial attempts at scales ca. 2.5 times those for the kinetics
experiments (ca. 10 mg of substrate 1) gave good, reproducible
yields for the methanol and IL = 0.02 cases However, at higher
mole fractions, isolating the products on such a small scale
proved difficult, likely due to the large amount of ionic liquid
present and difficulty separating small amounts.
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DOI: 10.1039/D0OB01198C
ARTICLE
Table 5. A summary of the isolation studies completed for the solvolysis of the galactose 1 at 42 °C in different solvent compositions showing both the extent of conversion and
yields of products 2 and 10-12.
Extent of conversiona
Yield
10c
Solvent

IL
t / h
2
10
11
12
0
2b
11c
12c
Methanol
0
2
1
>95
0
0
0
0
91 ± 3
92 ± 4
86 ± 10
22 ± 4
4 ± 2
0
0
0
0
0
0
8
3
3
3
0.02
0.02
0.32
0.76
>95
0
1
>95
0
0
0
0
0
0
5
35 ± 3
6 ± 3
46 ± 1
71 ± 2
19 ± 3
19 ± 2
0
25 ± 6
29 ± 8
11 ± 3
10 ± 3
0
45
4 ± 1
3 ± 1
a
c
1
b
Extent of conversion determined by H NMR spectroscopy after the time listed for each case. Isolated yield determined from the mass recovered after isolation.
Determined from the mass recovered after isolation as a mixture of products. Uncertainties are determined from the standard deviation of triplicate experiments.
of product. For this reason, both the IL = 0.32 and IL = 0.75
Kinetic analyses were carried out in solutions containing the
-1
-1
cases were scaled up in terms of substrate 1 (ca. 100 mg) but electrophile 1 (ca. 0.005 mol L ), triethylamine (ca. 0.02 mol L )
the total volume of the system was reduced to avoid issues and the desired solvent mixture of methanol and one of the
noted at smaller scales, resulting in a smaller proportion of ionic liquids 3-9. Nucleophile dependence studies were carried
methanol in the reaction mixture in order to ensure the mole out with the same proportions of both the electrophile 1 and
fraction of the ionic liquid remained consistent. Due to this triethylamine as above with varying concentrations of methanol
-1
change, product ratios differed from those seen originally. (ca. 0.1, 0.2, 0.3 and 0.4 mol L ) in acetonitrile. An aliquot (0.5
However, the products observed were still found to be the mL) of each stock solution was placed in an NMR tube and the
1
same. These ratios, as well as the yields of each are outlined in reactions followed using H NMR spectroscopy at the
Table 5. Product 2 was readily isolated from the mixture of appropriate temperature (mole fraction dependence studies,
products while products 10-12 were isolated as a mixture. 315 K; temperature dependence studies, over the range 306-
Initial separation of this mixture was attempted but proved 331 K). Rate constants were determined by following the
difficult so the data reported are for the unseparated mixture.
integration of the signal due to the H1 on the electrophile 1 over
time. Each rate constant was measured in triplicate. Activation
enthalpies and entropies were determined by fitting the
Experimental
53
obtained rate constants to the Eyring equation. Further details
of kinetic experiments, including rate constants and stock
solution compositions, can be found in the ESI.
Microsoft Excel (version 16.34) was used for multivariate
regression analyses of Kamlet–Taft parameters and the natural
logarithm of the obtained rate constants. All analyses can be
found in the ESI.
Isolation studies were carried out in triplicate for each case.
Full experimental details and characterisation of products are
outlined in the ESI.
The galactose 1 was commercially available and was
recrystallised from 1:1 hexane/diethyl ether and stored at 253
K until use. Analytical grade deuterated methanol was dried
over 3 Å molecular sieves before use. Triethylamine was
distilled and stored over 3 Å molecular sieves at 253 K until use.
The ionic liquids 3-5 and 7-9 were prepared according to
2
6, 49-52
modified literature procedures,
by alkylating the
appropriate heterocycle and performing a salt metathesis with
the appropriate anion. Ionic liquid 6 was prepared from the
corresponding bromide salt through a salt metathesis with
Li[N(SO
2 3 2
CF ) ]. All ionic liquids were dried under reduced
Conclusions
pressure (<0.3 mbar) for at least 7 hours and found to have <200
ppm water using the Karl Fischer titration method. Ion The work described has studied the effect of using ionic liquids
chromatography was used to determine residual halide content as solvents for the reaction of the galactose 1, including through
as <20 ppm in each ionic liquid. All synthetic procedures are solvolysis. It was found, using mole fraction dependence
completely described in the ESI.
studies, that a low proportion of ionic liquid in the reaction
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mixture leads to an increase in the rate constant compared to
the molecular solvent methanol. This effect decreases
significantly at higher mole fractions and is dependent on both
constituents of the ionic liquid. Significantly, the dependence on
the proportion of salt in the reaction mixture differed from
previous cases that proceed through the same mechanism,
demonstrating the importance of the structure of the reagent
in determining ionic liquid solvent effects. An ionic liquid with
Acknowledgements
View Article Online
DOI: 10.1039/D0OB01198C
AG acknowledges the support of the Australian Government
through the receipt of a Research Training Program Scholarship.
JBH acknowledges financial support from the Australian
Research Council Discovery Project Funding Scheme (Project
DP180103682). The authors also acknowledge the NMR facility
and the Bioanalytical Mass Spectrometry facility, both within
the Mark Wainwright Analytical Centre at the University of New
South Wales; the former for NMR support and the latter for
carrying out mass spectrometric analysis.
a more coordinating anion gave a greater increase in k
Temperature dependence studies indicated that the
dominant interaction driving these changes in k was between
1
overall.
1
the ionic liquid and the transition state of the process but that
starting material interactions are important in some cases,
showing that there is a balance between the two types of
interactions. Whilst different from what has been seen with
Notes and references
‡
It should be noted that this anion might also be named as a
5
7
secondary (sulfonyl)amide. However, imide nomenclature is
1
6,18,19
other reactions that proceed through this mechanism,
this outcome has been seen for reactions that proceed through
58
also reasonable and serves to emphasise the two substituents,
along with being consistent with previous work and what is used
5
4, 55
a different mechanism.
Importantly, it also shows the by the community in, for example, chemical catalogues.
*
It can also be argued that ionic liquids containing a more
complexity in the balance of interactions and the resultant
effects on reaction outcome that can occur in mixtures
containing ionic liquids.
Multiple regression analyses were used to better
understand these interactions; a relationship between the 0.61, however better correlations were subsequently sought.
natural logarithm of the rate constant and both the hydrogen
bond accepting ability and the polarizability of the solvent
across each mole fraction was found. This relationship showed
that non-specific, likely charge-charge interactions, are
coordinating cation (such as those with a less coordinating anion
that would make the cation more available) would result in
transition state interactions becoming more dominant.
2
§
1
Correlations between ln(k ) and  were fair with R values up to
‡
‡ It is important to note that in the  ca. 0.7 case the coefficient
for the  parameter gave a p-value of 0.14, indicating this is not a
significant fit. An additional analysis showed a significant
1
relationship of ln(k ) = -20.86 +12.46*. This observation further
supports the indication that favourable non-specific interactions
favourable for this reaction, whereas specific hydrogen bonding dominate at higher mole fractions.
** It should be noted that the product determining step occurs
interactions are disfavoured. In all cases, an ionic liquid with
greater polarizability but less able to accept a hydrogen bond
would lead to an increase in the rate constant. This relationship
after the rate determining step, so the argument presented in the
earlier sections is valid, irrespective of the product ratio.
§
§ These isomers have been synthesised previously but under
1
sheds light on the dominant interactions affecting k and can
different conditions; an additional molecular solvent is needed,
allow for the rational selection of an ionic liquid for this process. likely to avoid formation of product 2. These syntheses also
require the use of a salt such as tetrabutylammonium bromide.56
Of note is that the correlation of the parameters found was
‡
4 3
‡‡ Product ratios of both [bmim][BF ] 8 and [bmim][C(CN) ] 9
different to the correlations found for previous related systems,
once again indicating the importance of the nature of the
reagent in solvent effects for these systems.
are not discussed as in both cases an additional product was
observed at mole fraction > 0.35; it was found that adventitious
water was reacting in an irreproducible manner. See ESI for more
Finally, it was found that the product determining step of detail.
1
2
3
4
.
.
.
.
M. J. Earle and K. R. Seddon, Pure Appl. Chem, 2000, 72, 1391.
T. Welton, Chem. Rev., 1999, 99, 2071-2084.
J. P. Hallett and T. Welton, Chem. Rev., 2011, 111, 3508-3576.
S. Mallakpour and M. Dinari, in Green Solvents II: Properties and
Applications of Ionic Liquids, eds. A. Mohammad and D.
Inamuddin, Springer Netherlands, Dordrecht, 2012, DOI:
the reaction was also affected by the use of ionic liquids. At
proportions of salt in the reaction mixture, additional products
were observed that are not seen under these conditions
without the presence of an ionic liquid. This difference is likely
due to a change in the solvation of the intermediate
carbocation, resulting in different energies for the subsequent
pathways. At the highest mole fractions of ionic liquids in the
reaction, elimination was also observed, potentially due to
1
0.1007/978-94-007-2891-2_1, pp. 1-32.
5
.
H.-J. Liaw, C.-C. Chen, Y.-C. Chen, J.-R. Chen, S.-K. Huang and S.-
N. Liu, Green Chem., 2012, 14, 2001-2008.
there being less methanol in the reaction mixture available to 6. K. Ghandi, Green. Sus. Chem., 2014, 4, 44-53.
react. The ratios of these products were found to be dependent 7. J. G. Huddleston, H. D. Willauer, R. P. Swatloski, A. E. Visser and
on the anion of the ionic liquid. These results are significant as
they not only show new reactivity but also allow for control of
reaction outcome when using ionic liquids.
R. D. Rogers, Chem. Commun., 1998, 1765-1766.
M. Freemantle, Chem. Eng. News, 1998, 76, 32-37.
M. J. Earle, S. P. Katdare and K. R. Seddon, Org. Lett., 2004, 6,
8
9
.
.
7
07-710.
0. C. Chiappe and D. Pieraccini, J Phys. Org. Chem., 2005, 18, 275-
97.
1
1
2
Conflicts of interest
There are no conflicts to declare.
1. A. Gilbert, R. S. Haines and J. B. Harper, in Reference Module in
Chemistry, Molecular Sciences and Chemical Engineering,
Elsevier, 2018, DOI: 10.1016/B978-0-12-409547-2.14212-X.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 10 of 11
ARTICLE
Journal Name
1
2. R. R. Hawker and J. B. Harper, in Advances in Physical Organic 43. P. Pavez, D. Millan, C. Cocq, J. G. Santos and F. VNieowmAert,iclNe eOwnlinJe.
Chemistry, eds. I. H. Williams and N. H. Williams, Academic Press, Chem., 2015, 39, 1953-1959.
018, vol. 52, pp. 49-85.
DOI: 10.1039/D0OB01198C
2
44. R. R. Hawker, R. S. Haines and J. B. Harper, Org. Biomol. Chem.,
2018, 16, 3453-3463.
1
1
1
1
3. S. T. Keaveney, R. S. Haines and J. B. Harper, in Encyclopedia of
Physical Organic Chemistry, Wiley, New Jersey, 2017, vol. 2.
4. B. Y. W. Man, J. M. Hook and J. B. Harper, Tetrahedron Lett.,
45. P. G. Jessop, D. A. Jessop, D. Fu and L. Phan, Green Chem., 2012,
14, 1245-1259.
2
005, 46, 7641-7645.
46. R. Rinaldi, Chem. Commun., 2011, 47, 511-513.
5. H. M. Yau, S. A. Barnes, J. M. Hook, T. G. A. Youngs, A. K. Croft 47. Y. Dong, T. Takeshita, H. Miyafuji, T. Nokami and T. Itoh, Bull.
and J. B. Harper, Chem. Commun., 2008, 3576-3578. Chem. Soc. Jpn., 2018, 91, 398-404.
6. S. T. Keaveney, B. P. White, R. S. Haines and J. B. Harper, Org. 48. D. Yalcin, A. J. Christofferson, C. J. Drummond and T. L. Greaves,
Biomol. Chem., 2016, 14, 2572-2580.
7. E. Kochly, N. Lemon and A. Deh-Lee, Molecules, 2016, 21, 60.
8. A. Gilbert, R. S. Haines and J. B. Harper, Org. Biomol. Chem., 2019,
Phys. Chem. Chem. Phys., 2020, DOI: 10.1039/D0CP00201A.
49. L. Cammarata, S. G. Kazarian, P. A. Salter and T. Welton, Phys.
Chem. Chem. Phys., 2001, 3, 5192-5200.
1
1
1
7, 675-682.
50. S. N. Baker, E. B. Brauns, T. M. McCleskey, A. K. Burrell and G. A.
Baker, Chem. Commun., 2006, 2851-2853.
51. E. E. L. Tanner, R. R. Hawker, H. M. Yau, A. K. Croft and J. B.
Harper, Org. Biomol. Chem., 2013, 11, 7516-7521.
52. I. S. Molchan, G. E. Thompson, R. Lindsay, P. Skeldon, V.
Likodimos, G. E. Romanos, P. Falaras, G. Adamova, B. Iliev and T.
J. S. Schubert, RSC Adv., 2014, 4, 5300-5311.
1
2
2
9. A. Gilbert, G. Bucher, R. S. Haines and J. B. Harper, Org. Biomol.
Chem., 2019, 17, 9336-9342.
0. M. Miljkovic, Carbohydrates: Synthesis, Mechanisms, and
Stereoelectronic Effects, Springer-Verlag, New York, 2009.
1. A. Brandt, J. Gräsvik, J. P. Hallett and T. Welton, Green Chem.,
2
013, 15, 550-583.
2
2
2. A. S. Amarasekara, Isr. J. Chem. , 2019, 59, 789-802.
3. O. A. El Seoud, A. Koschella, L. C. Fidale, S. Dorn and T. Heinze, 54. R. R. Hawker, R. S. Haines and J. B. Harper, Chem. Commun.,
53. H. Eyring, J. Chem. Phys., 1935, 3, 107-115.
Biomacromolecules, 2007, 8, 2629-2647.
2018, 54, 2296-2299.
2
2
4. S. Marullo, C. Rizzo and F. D'Anna, Front. Chem., 2019, 7.
5. J. Song, B. Zhang, J. Shi, H. Fan, J. Ma, Y. Yang and B. Han, RSC
Adv., 2013, 3, 20085-20090.
55. K. S. Schaffarczyk McHale, R. R. Hawker and J. B. Harper, New J.
Chem., 2016, 40, 7437-7444.
56. C.-W. Li, K.-W. Hon, B. Ghosh, P.-H. Li, H.-Y. Lin, P.-H. Chan, C.-H.
Lin, Y.-C. Chen and K.-K. T. Mong, Chem. Asian J., 2014, 9, 1786-
1796.
2
2
6. H. Srour, H. Rouault, C. C. Santini and Y. Chauvin, Green Chem.,
2
013, 15, 1341-1347.
7. H. M. Yau, S. T. Keaveney, B. J. Butler, E. E. L. Tanner, M. S. Guerry, 57. IUPAC. Compendium of Chemical Terminology, 2nd ed. (the
S. R. D. George, M. H. Dunn, A. K. Croft and J. B. Harper, Pure
Appl. Chem., 2013, 85, 1979.
8. X. Creary, E. D. Willis and M. Gagnon, J. Am. Chem. Soc., 2005,
"Gold Book"). Compiled by A. D. McNaught and A. Wilkinson.
Blackwell Scientific Publications, Oxford (1997). Online version
(2019-) created by S. J. Chalk. ISBN 0-9678550-9-8.
https://doi.org/10.1351/goldbook.
2
2
3
3
3
3
3
1
27, 18114-18120.
9. B. B. Hurisso, K. R. J. Lovelock and P. Licence, Phys. Chem. Chem. 58. IUPAC. Compendium of Chemical Terminology, 2nd ed. (the
Phys., 2011, 13, 17737-17748.
0. S. Spange, R. Lungwitz and A. Schade, J. Mol. Liq., 2014, 192, 137-
"Gold Book"). Compiled by A. D. McNaught and A. Wilkinson.
Blackwell Scientific Publications, Oxford (1997). Online version
(2019-) created by S. J. Chalk. ISBN 0-9678550-9-8.
https://doi.org/10.1351/goldbook.
1
43.
1. H. M. Yau, A. K. Croft and J. B. Harper, Faraday Discuss., 2012,
54, 365-371.
1
2. H. M. Yau, A. G. Howe, J. M. Hook, A. K. Croft and J. B. Harper,
Org. Biomol. Chem., 2009, 7, 3572-3575.
3. I. Y. López-Cortés, G. A. Iglesias-Silva, M. Ramos-Estrada and J. L.
Rivera-Rojas, Fluid Phase Equilib, 2020, 514, 112543.
4. R. Bini, C. Chiappe, V. L. Mestre, C. S. Pomelli and T. Welton, Org.
Biomol. Chem., 2008, 6, 2522-2529.
3
3
5. B. J. Butler and J. B. Harper, J. Phys. Org. Chem., 2018, 31, e3819.
6. J. Alarcón-Espósito, R. Contreras, R. A. Tapia and P. R.
Campodónico, Chem. Eur. J., 2016, 22, 13347-13351.
7. P. Pavez, D. Millán, J. I. Morales, E. A. Castro, C. López A and J. G.
Santos, J. Org. Chem., 2013, 78, 9670-9676.
3
3
3
8. S. T. Keaveney, R. S. Haines and J. B. Harper, ChemPlusChem,
2
017, 82, 449-457.
9. R. W. Taft and M. J. Kamlet, J. Am. Chem. Soc., 1976, 98, 2886-
894.
2
4
4
0. M. J. Kamlet and R. W. Taft, J. Am. Chem. Soc., 1976, 98, 377-383.
1. M. J. Kamlet, J. L. Abboud and R. W. Taft, J. Am. Chem. Soc., 1977,
9
9, 6027-6038.
4
2. M. A. Ab Rani, A. Brant, L. Crowhurst, A. Dolan, M. Lui, N. H.
Hassan, J. P. Hallett, P. A. Hunt, H. Niedermeyer, J. M. Perez-
Arlandis, M. Schrems, T. Welton and R. Wilding, Phys. Chem.
Chem. Phys., 2011, 13, 16831-16840.
1
0 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01198C
Using an ionic liquid in the solvent mixture for the reaction of a galactose substrate leads to changes
in both the rate constant and the products as the solvent composition changes.